COMP Programming

229th ACS National Meeting
San Diego, CA
March 13 - 17, 2005
W. D. Cornell, Program Chair

COMP 1 [809475]:  John Pople: The early years

A. David Buckingham, Department of Chemistry, Cambridge University, Lensfield Road, Cambridge CB2 1EW, United Kingdom, Fax: +44 1223 336362,

I shall comment on John Pople's life in the west of England as a boy, his time as a student at Cambridge University and as a member of the Cambridge Theoretical Chemistry Group, his summer visits to the National Research Council of Canada, and his time as a senior scientist at the National Physical Laboratory in Teddington. I shall also mention my experience as John's first graduate student and as a long-time friend.

COMP 2 [806758]:  A half-century of a PP friendship

Robert G. Parr, Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599-3290,


COMP 3 [818384]:  John Pople, the early years: From Carnegie Tech to Carnegie-Mellon

Mark S. Gordon, Chemistry Department and Ames Laboratory USDOE, Iowa State University, 201 Spedding Hall, Ames, IA 50011, Fax: 515-294-5204,

Professor Pople's early years, from the beginning at Carnegie Institute of Technology, the development of the CNDO/INDO methods, the original framework of the program that ultimately became Gaussian, and the trnasformation to Carnegie-Mellon University will be discussed.

COMP 4 [827540]:  The birth of Gaussian

Warren J. Hehre, Wavefunction, Inc, 18401 Von Karman Avenue, Suite 370, Irvine, CA 92612, Fax: 949-955-2118,

As was usually the case, John Pople was way ahead of his time. He was worrying about "mflops" years before the phrase came into common use. John's approach to the "two-electron integral problem" in the late 1960's led directly to the birth of Gaussian 70, the first of the "Gaussian" programs, and more importantly to the realization that ab initio (Hartree-Fock) calculations could serve as practical tools for chemists. The underlying idea is simple. Atomic orbitals come in sets ("shells"), for example, a "2p shell" comprising 2px, 2py and 2pz orbitals or a "2sp shell", comprising a 2s orbital in addition to the three 2p orbitals. The individual two-electron integrals resulting from combinations of atomic orbitals on four different shells (256 integrals in the case of four sp shells)share significant information in common, and it is much more efficient to evaluate the full set of integrals all together rather than one integral at a time. John's imaginative algorithm did just this and is what made Gaussian possible.

COMP 5 [803646]:  The later years: CMU, Stockholm and beyond

Peter M.W. Gill, Research School of Chemistry, Australian National University, Canberra ACT 0200, Australia, Fax: 61-2-6125-0750,

I met John in 1984, joined his group in 1988 and remained with him for five years. It was an intensely exciting time for me, as I found myself thrust to the cutting edge of quantum chemical developments, and the scientific momentum that I gained in Pittsburgh has continued to fuel my research activities to the present day. Despite moving from the US, first to New Zealand and later to England, I had the good fortune to retain John and Joy's friendship to the end. It was a privilege to know both the public scientist and the private man.

My lecture will sketch the progress of the last two decades of John's life, outlining the computational highlights and reflecting on the lessons that can be learned from one of the most influential chemists of our time.

COMP 6 [807999]:  John in Evanston: Some reminiscences and thoughts

Mark A. Ratner, Department of Chemistry, Northwestern University, 2145 Sheridan Rd., Evanston, IL 60208-3113, Fax: 491 7713,

John Pople's scientific career was completed in his years at Northwestern, where he served as Trustee's Professor of Chemistry. During that time, his remarkable scope and insight were made even clearer, as he began work on relativistic quantum chemistry, on image potentials, on metal cluster calculations, on new aspects of DFT calculations and on the entropy of a fried egg, the project that he was pursuing at the time of his death. This was also the period during which his tremendous contributions to the chemical sciences were recognized by the Nobel Foundation in an appropriate (if belated) fashion.The clarity of John's vision, the economy and directness of his science and the warmth and supportiveness of his scientific personality did a great deal to shape the nature of the contemporary chemical sciences. On a smaller scale, they also helped to shape the Northwestern Chemistry Department. This short talk will include both some reminiscences and a comment or two on the science involved!

COMP 7 [845865]:  A friendship late in life

Walter Kohn, Department of Physics, University of California, Santa Barbara, Santa Barbara, CA 93106,

COMP 8 [831962]:  Computers as tools of discovery

Uzi Landman, School of Physics, Georgia Institute of Technology, Atlanta, GA 30332-0430

Dictionary definitions of "to simulate" vary - from "pretend to be" and "imitate or counterfeit", to "produce a computer model of a process". In this talk we will discuss and demonstrate methodological and scientific issues pertaining to the use of computer simulations as faithful representations of complex natural phenomena of predictive power,rather then "imitation and counterfeit". Examples will include: nano-scale fluid dynamics - nanojets; nanocatalysis by supported gold clusters; transport and reactions of ionization holes in DNA; formation and properties of highly correlated electron molecules in two-dimensional quantum dots, and bosonic crystallites in traps.

COMP 9 [805490]:  Application of non-Hamiltonian molecular dynamics to chemical systems

Glenn Martyna, Physical Science Division, IBM Research, TJ Watson Research Center, PO Box 218, Yorktown Heights, NY 10598, Fax: 914-945-4506,

The theory of non-Hamiltonian dynamical systems and their application to the study of the equilibrium properties of complex chemical processes has been an important topic research in the impressive career of Professor M.L. Klein. Here, the basic non-Hamiltonian molecular dynamics formalism is given followed by the basic equations for stable, ergodic, constant temperature and constant pressure methods. The techniques are then applied within the Car-Parrinello formalism to describe the properties of neat liquid water at two temperatures and the solvation of a peptide fragment, N-methyl acetamide, in water.

COMP 10 [832735]:  Stochastic linear scaling for metals and non metals

Michele Parrinello and Florian R Krajewski, Physical Chemistry ETH (Zurich), c/o USI-Campus Via Buffi 13, Lugano 6900, Switzerland, Fax: +41-91-9138-817,

Total energy electronic structure calculations, based on density functional theory or on the more empirical tight binding approach, are generally believed to scale as the cube of the number of electrons. By using the localisaton property of the high temperature density matrix we present exact deterministic algorithms that scale linearly in one dimension and quadratically in all others. We also introduce a stochastic algorithm that scales linearly with system size. These results hold for metallic and non metallic systems and are substantiated by numerical calculations on model systems.

COMP 11 [825773]:  Probing long time-scale events with advanced simulation techniques

Bin Chen, Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803-1804, Fax: 225-578-3458,

Despite the recent advent of multi-teraflop computing platforms, long time-scale events such as phase transition and protein folding remain out of reach for conventional simulation methods. The sampling difficulties for these long-time scale events are caused by large free energy barriers and the inherent micro-heterogeneity of the phase space. Although the former problem can now be surmounted by a host of free-energy based methods (including umbrella sampling), a separate approach is still required to deal with the latter problem. For example, for vapor-liquid nucleation the micro-heterogeneity arises from the presence of a spectrum of microphase regions (e.g., monomers and clusters). These microphase regions differ to a great extent on both energetic and entropic factors. In contrast, the random displacements used in the conventional Metropolis Monte Carlo scheme and the force-driven diffusion employed by molecular dynamics lack the balance of these two factors. This leads to slow transfer of particles between the micro-phase regions. A novel technique, called aggregation-volume-bias Monte Carlo (AVBMC), can overcome this problem by explicitly dividing the space surrounding a molecule into the associating and non-associating regions. This allows for direct transfer between microphase regions, thereby bypassing the time and spatial constraints imposed on molecular dynamics and Metropolis Monte Carlo techniques. AVBMC can be combined with configurational-bias Monte Carlo, umbrella sampling, histogram-reweighting, and density of states methods to study nucleation phenomena for complex systems. Applications to nucleation of neat water using polarizable force fields and mixtures containing water, alcohols, and alkanes as well as protein crystallization will be presented.

COMP 12 [833259]:  BioSimGrid: A distributed database for the storage and analysis of biomolecular computer simulations

Jonathan W Essex1, Stuart E Murdock1, Robert J Gledhill1, Kaihsu Tai2, Muan Hong Ng3, Steve Johnston3, Bing Wu4, Hans Fangohr3, Paul Jeffreys4, Simon Cox3, and Mark Sansom2. (1) School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, United Kingdom, Fax: +44 (0)23 8059 3781,, (2) Department of Biochemistry, University of Oxford, (3) e-Science Centre, University of Southampton, (4) e-Science Centre, University of Oxford

BioSimGrid aims to deliver a biomolecular simulation data repository to enable more efficient storage, access, exchange and analysis of biomolecular simulation data. The project seeks to exploit the concepts of the Grid, where large computational and data resources are made available to users in a highly accessible manner. The ability to submit, search, query, retrieve, and post-process biomolecular simulation data in a uniform way is important for allowing more efficient data sharing. In this presentation, the design and operation of the current version of the software will be described, and future extensions outlined. The application of BioSimGrid to the comparative analysis of a number of protein simulations (acetylcholinesterase with bacterial outer-membrane phospholipase, and a number of mutants of the prion protein with each other) will also be presented.

COMP 13 [832715]:  Binding energy calculation for FKBP receptor and ligands by generalized BAR method

Hideaki Fujitani1, Yoshiaki Tanida1, Masakatsu Ito1, Michael R. Shirts2, Christopher D. Snow3, Guha Jayachandran2, and Vijay S. Pande2. (1) Fujitsu Laboratories Ltd, 10-1 Morinosato Wakamiya, Atsugi, Japan, Fax: 81-46-250-8844,, (2) Department of Chemistry, Stanford University, (3) Biophysics Program, Stanford University

Generalized Bennett acceptance ratio method (BAR; M. Shirts et al. 2003) enable us to calculate the binding energy of realistic complex systems interacting with the explicit waters by the massively parallel computational method. In order to suit the generalized BAR method, we have developed special computer, BioServer, which has 1920 FR-V processors (high performance and low power processor with 8 way VLIW architecture made by FUJITSU) in one rack. Molecular dynamics (MD) calculations can be efficiently performed on BioServer using Gromacs MD package. In order to get accurate binding energy, we used the Amber 1999 force field for the FKBP receptor and new general Amber force field (GAFF; J. Wang et al. 2004) for ligands. We compare our calculated binding energies for nine ligands with experimental inhibition constants, and we show BioServer is suitable to do the computational drug design.

COMP 14 [814623]:  Coupled reference interaction site model (RISM)/simulation approach for free energy of solvation

Holly Freedman and Thanh N. Truong, Henry Eyring Center for Theoretical Chemistry/Department of Chemistry, University of Utah, 315 S. 1400 E. Rm 2020, Salt Lake City, UT 84112,

A novel methodology will be discussed for the determination of solvation free energies from molecular simulation. A single molecular dynamics or Monte Carlo simulation is first carried out on an explicitly solvated system of interest. The resulting radial distribution functions of solvent atoms about all solute atoms are used as input to the solvation free energy expression derived from RISM integral equation theory. Thus simulation may be applied to solvation free energy determination in an alternative approach to the accurate but extremely laborious free energy perturbation and thermodynamic integration techniques. Applications to problems including the molecular conformation of the alanine dipeptide, the tautomeric equilibrium of cytosine, and the potential of mean force profile of an SN2 reaction in aqueous solution will be presented.

COMP 15 [831256]:  Computational strategy for binding of phenylalanine analogs in phenylalanyl-tRNA synthetase

Peter Michael Kekenes-Huskey1, Ismet Caglar Tanrikulu1, Victor Wai Tak Kam1, Nagarajan Vaidehi2, and William A. Goddard III2. (1) Department of Chemistry, Caltech, MC 139-74, Caltech Division of Chemistry, Pasadena, CA 91125,, (2) Materials and Process Simulation Center, California Institute of Technology

A computational strategy has been developed that captures the binding characteristics of phenylalanine analogs to the phenylalanyl-tRNA synthetase (pheRS). Binding to this synthetase is a requisite for incorporation into a translated protein, therefore this approach can provide an indirect measure of incorporation for a candidate analog. The protocol couples a ligand torsion sampling algorithm, moleculeGL, with a side chain replacement program, SCREAM, to generate conformations that maximize binding. This protocol has been applied to binding of the twenty natural amino acids and several phenylalanine analogs in select hosts and compared to measured kcat/km data. The reported binding energies correlate well with measured kcat/km data for AMP activation, thus establishing the efficacy of the approach. Furthermore, this strategy has been applied to several amino acid analogs of interest, yielding binding data for wild-type proteins, as well as proposed mutations to improve binding.

COMP 16 [807221]:  Computational study of IAG-nucleoside hydrolase: Determination of the preferred ground state conformation and the role of active site residues

Devleena Mazumder Shivakumar, Department of Chemistry & Biochemistry, University of California Santa Barbara, Santa Barbara, CA 93106,, and Thomas C. Bruice, Department of Chemistry and Biochemistry, University of California at Santa Barbara

The mechanism of action of inosine–adenosine–guanosine nucleoside hydrolase (IAG-NH) has been investigated by long-term molecular dynamics (MD) simulation in TIP3P water using stochastic boundary conditions and CHARMM forcefield. Special attention has been given to the role of leaving group pocket residues, conformation of the bound substrate at the active site of IAG-NH and the protonation state of the residue Asp40. This is the first time the structure of flexible loop (missing from all the five X-ray structures) in IAG-NH is reported and its role in catalysis highlighted. Five MD studies have been performed with: enzyme substrate complexes: Enzyme•anti-Adenosine with Asp40-COOH [E(40H)•Ade(a)], Enzyme•anti-Adenosine with Asp40-COO- [E(40)•Ade(a)], Enzyme•syn-Adenosine with Asp40-COOH [E(40H)•Ade(s)], Enzyme•syn-Adenosine with Asp40-COO- [E(40)•Ade(s)] and Enzyme•anti-Inosine with Asp40-COO- [E(40)•Ino(a)]. The protonation state of Asp40 obtained from MD simulation is also confirmed by Poisson Boltzmann equation module for continuum electrostatics. Results from all the five MD simulations as well as Normal mode analysis will be discussed in details.

COMP 17 [828482]:  Intermolecular potentials of mean force of amino acid side chain interactions in aqueous medium

Sergio A. Hassan, Center for Molecular Modeling, National Institutes of Health, DHHS, Bethesda, MD 20892,

Continuum approximations of solvent effects in mesoscopic systems such as proteins and other biopolymers require an accurate description of hydrogen-bonding (HB) interactions in solution. Here, a systematic study of the potentials of mean force (PMF) of all H-bonded amino acid in water is reported. HB partners are classified according to the hybridization states of the donor and acceptor atoms, and the net charge of the interacting pairs. Constrained molecular dynamics simulations are carried out to calculate the intermolecular mean force (MF) in TIP3P water. Long-range forces are calculated using PME summation in a cubic lattice with PBC. Intermolecular PMF are obtained by integrating the MF along a specified reaction path and statistical errors estimated. Results from long (30-100 ns) dynamics simulations of small (50-100 aa) proteins with the SCP-based continuum model of solvent effects are reported. The implications of these results for quantifying protein-protein/ligand interactions and association/dissociation rates are discussed.

COMP 18 [819693]:  Prediction of protein geometry and stability changes for arbitrary single point mutations

Andrew Bordner and Ruben Abagyan, Department of Molecular Biology, The Scripps Research Institute, 10550 N Torrey Pines Road, TPC-28, La Jolla, CA 92037

We have developed a method to predict the changes in both the side chain conformations and the stability of proteins due to single point mutations. A procedure using Monte Carlo based molecular mechanics calculations to predict the geometry of the mutated protein was validated on a large set of X-ray structures for pairs of proteins differing by a single point mutation. An empirical energy function, that included contributions from both the folded and denatured protein conformations, was then fit to experimental stability data using the predicted geometry. This set contained a substantial amount of small to large residue mutations not considered by previous studies. The prediction method gave a standard error of 1.1 kcal/mol for 97% of an independent test set. A fit to the stability data using exclusively conformation independent residue parameters suggests mutations for improving protein stability in the absence of structural information.

COMP 19 [833180]:  Side-chain conformational changes on ligand binding: An analysis of the PDB

Francesca Toschi1, Andrew R. Leach2, Paul Bamborough2, and Jonathan W Essex1. (1) School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, United Kingdom, Fax: +44 (0)23 8059 3781,, (2) Computational Chemistry and Informatics, GlaxoSmithKline Research and Development

Ligand binding may involve a wide range of structural changes in the receptor protein, from hinge movements of entire domains to small side-chain rearrangements in the binding pocket residues. In this presentation, the analysis of side-chain dihedral angles for a range of apo-apo, apo-holo, and holo-holo protein pairs is reported. A range of different thresholds to determine the extent of conformational change were applied, with the results providing insight into the intrinsic flexibilities of amino acid side chains, and the extent of side-chain conformational change on ligand binding. Particular emphasis will be placed on complexes of HIV-1 Protease, Endothiapepsin, and Streptavidin. The implications of these results for the prediction of side-chain conformation in the context of rational drug design will be discussed.

COMP 20 [829940]:  Small-system effects in molecular dynamics simulations

Randall B. Shirts, Scott R. Burt, and Aaron M. Johnson, Department of Chemistry and Biochemistry, Brigham Young University, C100 Benson Building, Provo, UT 84602, Fax: 801-422-0153,

Molecular dynamics simulations are now ubiquitous for predicting bulk behavior of chemical systems. Applications range from drug discovery to materials engineering. I present some fundamental results for finite-size systems that indicate the nature and size of corrections that must be considered in extrapolating finite-system results to bulk properties. These corrections include (1) the difference in effective temperature between particles of different mass induced by the center of mass constraint, (2) corrections to the velocity and kinetic energy distributions and associated statistics, (3) corrections to equations of state like the virial expansion, and (4) corrections to relations depending on the average and average relative velocity (e.g. mean free path and collision rate). In most cases, it is more efficient to apply corrections to results from a small simulation than take large enough systems to make the corrections negligible.

COMP 21 [830710]:  Sub-microsecond conformer transitions of protein inhibitor, fasciculin to acetylcholinesterase

Jennifer Bui, Department of Chemistry/ Biochemistry, University of California San Diego, 9500 Gilman Drive MC 0365, la jolla, CA 92093, Fax: 858-534-7042,, and J Andrew McCammon, Howard Hughes Med. Inst., NSF Ctr. Theor. Biol. Physics, Dept. Chem. and Biochem., and Dept. Pharmacol, University of California, San Diego

Protein-protein interactions are ubiquitous in biological system. Recognition of binding is a key to high affinity interactions of protein complexes. The fasciculins (FAS), 61-amino-acid peptides, are potent inhibitors of synaptic acetylcholinesterase. Four fasciculins have been characterized to date: FAS1 and FAS2 from the venom of Dendroaspis angusticeps, toxin C from the venom of D.polylepis and FAS3 from the venom of D.viridis . The sequences of FAS1 and FAS2 are nearly identical and differ only by one residue at the position 47. The dynamic nature of the encounter between FAS molecules and acetylcholinesterase can shed light on conformational variations before and after bindings. This work presents the dynamical study, in terms of the accessible conformational space, at sub-microsecond time scale. Employing principle component analysis and clustering analysis methods in analyzing the sub-microsecond molecular dynamics (MD) trajectories of FAS1 and FAS2, and compared with a 15-nanosecond MD simulation of FAS bound to acetylcholinesterase, the important modes of conformational variations and transitions of FAS upon complexation have been identified and will be discussed.

COMP 22 [833736]:  A gating mechanism proposed from a 15 nanosecond simulation of a complete human alpha-7 nicotinic acetylcholine receptor model

Richard James Law, Chemistry & Biochemistry, UCSD/HHMI, mc0365, 9500 Gilman Drive, La Jolla, CA 92093, Fax: 858-534-4974,, J. Andrew McCammon, Howard Hughes Medical Institute, Department of Chemistry and Biochemistry, University of California, San Diego, and Richard Henchman, Department of Chemistry and Biochemistry, University of California, San Diego

The nicotinic acetylcholine receptor (nAChR) is a well characterized ligand gated ion channel yet a proper description of the mechanisms involved in gating, opening, closing, ligand binding, and desensitization does not exist. Until recently, atomic resolution structural information on the protein was limited, but with the production of the X-ray crystal structure of the L.stagnalis acetylcholine binding protein (AChBP) and the electron microscopy (EM) image of the transmembrane domain of the torpedo electric ray nicotinic channel, we were provided with a window to examine the mechanism by which this channel operates. A 15 nanosecond (ns) all-atom simulation of a homology model of the homomeric human α7 form of the receptor was conducted, in a solvated POPC bilayer, and examined in detail. The receptor was unliganded. The structure undergoes a twist-to-close motion that correlates movements of the C-loop in the ligand binding domain, via the β10-strand that connects the two, with the 10ş rotation and inward movement of two non-adjacent subunits. The Cys-loop appears to act as a stator around which the α-helical transmembrane domain can pivot and rotate relative to the rigid β-sheet binding domain. The M2-M3 loop may have a role in controlling the extent or kinetics of these relative movements. All of this motion, along with essential dynamics analysis, is suggestive of the direction of larger motions involved in gating of the channel.

COMP 23 [820326]:  A comparison of MacroModel methodologies for ligand conformation generation

John C. Shelley, Schrodinger Inc, 1500 SW First Avenue, Suite 1180, Portland, OR 97201, Fax: 503-299-4532,

Generation and consideration of collections of ligand conformations is often an important part of computational drug design efforts. The type of generation employed is often influenced by the time available, number of ligands to search, desired thoroughness of the search, and sensitivity to the quality of the generated conformations. We present the results for a number of searching approaches using MacroModel including random torsional searches (MCMM), low mode searches, mixed mode searches and systematic searches applied to a large collection of molecules. The systematic searches are carried out with a new MacroModel module, ConfGen, which is designed to generate quality ensembles of ligand conformations rapidly. Quality of the results will be judged by identification of the global minimum structure, having a conformer with a small RMS relative to the same ligand from crystal structures of protein-ligand complexes and completeness of the conformational collections generated.

COMP 24 [821067]:  Low-coordination silicon compounds. Interplay and synergism between experiment and theory

Yitzhak Apeloig, Department of Chemistry and The Lise Meitner – Minerva Center for Computational Quantum Chemistry, Technion – Israel Institute of Technology, Haifa 32000, Israel, Fax: 972-4-8292000,

Silicon is the closest congener of carbon. Yet the fundamental properties of many silicon and carbon compounds are very different. This is especially evident for low – coordination compounds, such as multiple bonds to silicon or silylenes whose chemistry has begun to be unraveled only in the last two decades, following the synthesis of the first stable compounds of these types. These exciting developments were occurring at the time when computational methods reached maturity, and consequently quantum mechanical calculations made numerous crucial contributions to silicon chemistry, and in many cases theoretical predictions preceded and directed experimental work.

Some of the intriguing differences between silicon and carbon compounds will be discussed, demonstrating how the synergism between theory and experiment can be used to discover new chemistry. Three examples are:

(a)Carbenes dimerize to give double bonds while silylenes (R2Si:) in addition to disilene 1, can also produce novel low – coordination cyclic dimers of type 2, unprecedented in organic chemistry. The factors which control the dimerization mechanism of silylenes will be discussed.

(b) The surprising structures of multiply-bonded silicon compounds in general, and trisilaallene in particular will be discussed.

(c) The first compound with a Si≡Si triple bond was recently isolated. The unique nature of triple bonds to silicon and the interplay of theory and experiment in the quest of their synthesis will be discussed.

COMP 25 [818848]:  The schizophrenic effect of geminal fluorination on the kinetic stability of molecules containing strained rings

Weston Thatcher Borden1, David A. Hrovat1, Christine Isborn2, Scott B. Lewis3, and Stephen Getty4. (1) Department of Chemistry, University of North Texas, P.O. Box 305070, Denton, TX 76203-5070,, (2) Department of Chemistry, University of Washington, (3) Department of Chemistry, James Madison University, (4) Du Pont Chemical Company

Experiments by Dolbier and coworkers have found that geminal fluorination has a large effect on lowering the barrier to cis-trans isomerization of 1,2-dimethylcyclopropane and an even larger effect on lowering the barrier to racemization of optically active 1-ethyl-2-methylcyclopropane. In contrast, Dolbier has found that that geminal fluorination has almost no effect on the barrier to rearrangement of methylenecyclopropane. Finally, Lemal and coworkers have shown that geminal fluorination dramatically stabilizes [2.2.2]propellane toward ring opening to 1,4-dimethylenecyclohexane. In order to understand these very different effects of geminal fluorination, ab initio calculations have been performed; and the results of these calculations will be discussed.

COMP 26 [804177]:  Stable carbon(0) compounds: Theoretical analysis of molecules with unusual bonding situations

Gernot Frenking, Fachbereich Chemie, Philipps Universität Marburg, Hans-Meerwein-Strasse, D-35039 Marburg, Germany,

We report about a combined theoretical/experimental study of the structures and bonding situation of carbodiphosphoranes C(PR3)2. The results suggest that carbodiphosphoranes should be considered as Lewis acid-base complexes between a naked carbon atom with the electron configuration (2s)2;(2pz)2;(2px)0;(2py)0 which serves as the acceptor moiety and two phosphane donors PR3. Carbodiphosphoranes have two electron lone-pairs at the carbon atom which make C(PR3)2 a very strong Lewis base. This becomes evident by the fact that carbodiphosphoranes may even bind CO2 in a donor-acceptor complex which is stable enough to become the subject of an x-ray structure analysis.

COMP 27 [818555]:  What IS the acidity of imidazole? An assessment of theoretical protocols for calculation of pKa values

Brian F. Yates and Alison M. Magill, School of Chemistry, University of Tasmania, Private Bag 75, Hobart TAS 7001, Australia, Fax: +61 3 6226-2858,

Recently we have exploited the method of Liptak and Shields in calculating highly accurate pKa values for a number of heterocyclic systems. However in attempting to carry out a series of systematic benchmark calculations on imidazole, we discovered that there is a significant discrepancy between high-level theoretical calculations and the accepted experimental value for the acidity of imidazole. We have studied this discrepancy further and carefully evaluated the various steps in the pKa calculation in an effort to determine the source of the disagreement with experiment.

COMP 28 [811535]:  Intramolecular hydrogen bonds versus other weak interactions

Otilia Mó, Departamento de Química, C-9, Universidad Autónoma de Madrid, Cantoblanco, 28049-Madrid, Spain, Fax: +34-91-497-5238,

The equilibrium geometries of β-chalcogenovinylaldehydes, HC(=X)-CH=CH-CYH (X = O, S; Y = Se, Te) correspond to chelated structures which are stabilized through the formation of X-H•••Y, X••••H-Y intramolecular hydrogen bonds or through X•••Y chalcogen-chalcogen interactions. The nature and strength of these interactions have been investigated through the use of high-level ab initio calculations, which show that for tellurium containing compounds the X••••TeH chalcogen-chalcogen interactions are much stronger that the X-H•••Te, X••••H-Te intramolecular hydrogen bonds, while the reverse stability order is observed for O and S containing compounds. The possible role of resonance assisted phenomena on the stability of these chelated structures was also investigated through a detailed analysis of the NMR properties of oxygen-containing systems. The conclusion was that neither the coupling constants nor the proton chemical shifts provide any evidence for the existence of resonance assisted phenomena.

COMP 29 [826389]:  On the roles of π-stacking, hydrogen bonding and donor-acceptor interaction in acrolein complexes of chiral oxazaborolidinone catalysts

Ming Wah Wong, Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore, Fax: +65-67791691,

Chiral N-sulphonylated 1,3,2-oxazaborolidin-5-ones have been shown to be efficient catalysts for asymmetric reactions. For instance, Corey et al have shown that N-tosyltryptophan-derived oxazaborolidinone catalyst is able to achieve an unprecedented enantioselectivity of greater than 200:1 for the Diels-Alder reactions between cyclopentadiene and 2-bromoacrolein. A better understanding of the origin of enantioselection is crucial to the rational development of new synthetic methodology and to the successful application and extension of enantioselective reactions. In this study, we have examined several acrolein complexes of Lewis acidic chiral N-sulphonylated oxazaborolidinones by means of ab initio and density functional calculations. The structures of these acrolein complexes indicate that π-stacking, hydrogen bonding and donor-acceptor interaction play essential roles in understanding the enantioselectivity of these chiral catalysts. We propose an alternative explanation to the high enantioselectivity of the oxazaborolidinone catalysts in terms of the most stable tridentate complex involves the s-trans acrolein. Furthermore, we find that the formyl hydrogen of acrolein prefers a hydrogen bond with the oxygen atom of the N-sulphonylated group in the acrolein-catalyst complexes and in the transition states. This is in sharp contrast to Corey's transition state model which favours the formation of formyl C-H•••O hydrogen bond with the ring oxygen.

COMP 30 [814789]:  Dynamics on the way to forming glass

David Chandler, Department of Chemisty, 210 Gilman Hall, University of California, Berkeley, Berkeley, CA 94720, Fax: 510-643-1566,, and Juan P. Garrahan, University of Nottingham

We have developed a new view of glass forming materials based upon a statistical mechanics of trajectory space. This space-time view has provided a geometric explanation of dynamic heterogeneity, and a series of distinguishing predictions, including dynamic scaling and universality. A few of our most recent predictions will be discussed.

COMP 31 [831533]:  Structure and interactions in nematic-colloid dispersions

Tatiana G. Sokolovska, Ruslan O. Sokolovskii, and Gren N. Patey, Department of Chemistry, University of British Columbia, Vancouver, BC V6T1Z1, Canada, Fax: 604-822-2847,,

Microscopic theory and computer simulations are used to obtain molecular density and orientational distributions about colloidal particles immersed in a model nematic fluid. In the presence of a weak external field that serves to fix the bulk director, it is shown that these distributions are highly directional, and lead to strong, directional interactions amongst the colloidal particles. The nature and physical origin of the colloid-nematic structure, together with its dependence on the colloid-molecule interactions and on the applied field strength will be discussed.

COMP 32 [825909]:  Simulation studies of structure and retention in chromatographic systems

J. Ilja Siepmann1, Ling Zhang2, Li Sun2, Collin D. Wick2, and Mark R. Schure3. (1) Departments of Chemistry, Chemical Engineering and Materials Science, University of Minnesota, 207 Pleasant St. SE, Minneapolis, MN 55455, Fax: 612-626-7541,, (2) Department of Chemistry, University of Minnesota, (3) Theoretical Separation Science Laboratory, Rohm and Haas Company

Various driving forces have been suggested to explain retention in reversed-phase liquid chromatography (RPLC). To provide molecular-level information on structure and retention mechanism in RPLC, configurational-bias Monte Carlo simulations in the Gibbs and isobaric-isothermal ensembles were carried out for the following model systems/processes: (i) partitioning of solutes between a bulk n-hexadecane and water/methanol mixtures representing the retentive and mobile phase, respectively; (ii) an isolated n-octadecane chain solvated in water/methanol or water/acetonitrile mixtures; (iii) structure and retention of a model stationary phase consisting of dimethyl octadecyl silane chemisorbed on the (111) face of beta-cristobalite.

COMP 33 [848106]:  Nucleation phenomena in polymer crystallization

Richard H. Gee, Chemistry and Material Science Directorate, Lawrence Livermore National Laboratory, Mail Code L-268, 7000 East Avenue, Livermore, CA 94550, Fax: 925-422-6810,

COMP 34 [833463]:  Crossover from free Rouse to entangled chain dynamics in polyethylene melts

Jean-Paul Ryckaert, Polymer Physics, Université Libre de Bruxelles, CP223, boulevard de Triomphe, 1050 Bruxelles, Belgium, Fax: 02-650-56-75,

Well equilibrated strongly entangled C1000 polyethylene melts in the 400K-500K temperature range are studied by molecular dynamics on the basis of an atomistic potential over a time window going from a few fs up to 20ns. This wide time range allows to extract from MD trajectories experimentally relevant time correlation functions, e.g. the incoherent intermediate scattering function Fs(Q,t) probed by neutron spectroscopy and the C-H bond orientational relaxation function G(t), probed by 13C NMR T1 relaxation measurements. These functions show successively an initial microscopic regime, a free Rouse regime and an entangled Rouse regime. Temperature effects in the dynamical relaxation will also be discussed as the dynamical interpretation of NMR data requires a chain relaxation model including the temperature dependence of the relevant relaxation times.

COMP 35 [816276]:  Simulating polymersomes: A fruitful collaboration in rational coarse graining

Dennis E. Discher, Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA 19104,, and Michael L. Klein, Department of Chemistry, Center for Molecular Modeling, University of Pennsylvania

Block-copolymer amphiphiles have been observed to assemble into vesicles and other morphologies long known for lipids but with remarkably different properties. In a fruitful collaboration making use of phenomolgical measures from the Discher group, coarse-grain molecular dynamics (CG-MD) developed by the Klein group have been extended to elaborate structures and properties of diblock copolymer assemblies in water. By varying the hydrophilic/hydrophobic ratio of the copolymer in line with experiment, bilayer, cylindrical and spherical micelle morphologies spontaneously assemble. Varying the molecular weight (MW) with hydrophilic/hydrophobic ratio appropriate to a bilayer yields a hydrophobic core thickness that scales for large MW as a random coil polymer, in agreement with experiment. The extent of hydrophobicsegment overlap in the core increases nonlinearly with MW, indicative of chain entanglements and consistent with the dramatic decrease reported for lateral mobility in polymer vesicles. Calculated trends with MW as well as hydrophilic/hydrophobic ratio thus agree with experiment, demonstrating that CG-MD simulations provide a rational design tool for novel Materials Science with block copolymers and their assemblies.

COMP 36 [819363]:  Protein-ligand interactions and computer-aided drug design

William L. Jorgensen, Juliana Ruiz-Caro, and Julian Tirado-Rives, Department of Chemistry, Yale University, New Haven, CT 06520-8107, Fax: 203-432-6299,

Drug development is being pursued through computer-aided design, synthesis, and assaying. The design begins with use of the BOMB program, which rapidly constructs combinatorial libraries given the structure of the target protein and a selected core and substituents. BOMB grows the analogs inside the protein's binding site, performs a thorough conformational search, and estimates the analog's binding affinity or activity using scoring functions. The QikProp program is applied to filter all designed molecules to insure that they have drug-like properties including solubility and cell permeability. MC/FEP simulations are then performed to refine the predictions for the best scoring leads using hundreds of explicit water molecules and extensive sampling for the protein and ligand. Recent methodological advances and representative applications will be presented with emphasis on inhibitor development for HIV reverse transcriptase.

Some references: Prediction of Drug Solubility from Structure. W. L. Jorgensen and E. M. Duffy, Adv. Drug Delivery Reviews, 54, 355-366 (2002). Validation of a Model for the Complex of HIV-1 Reverse Transcriptase with the Novel Non-nucleoside Inhibitor TMC125. Blagović, M. U.; Tirado-Rives, J.; Jorgensen, W. L., J. Am. Chem. Soc., 125, 6016-6017 (2003). General Model for Estimation of the Inhibition of Protein Kinases Using Monte Carlo Simulations. Tominaga, Y. & Jorgensen, W. L., J. Med. Chem. 47, 2534-2549 (2004). The Many Roles of Computation in Drug Discovery. Jorgensen, W. L., Science 303, 1813-1818 (2004).

COMP 37 [807610]:  Free energy calculations in structure-based drug design

J Andrew McCammon, Howard Hughes Med. Inst., NSF Ctr. Theor. Biol. Physics, Dept. Chem. and Biochem., and Dept. Pharmacol, University of California, San Diego, 9500 Gilman Drive, MC0365, La Jolla, CA 92093-0365, Fax: 858-534-4974,

Quantitative knowledge of binding affinities and selectivities based on standard free energies can be helpful in the engineering of new drugs. This talk will describe recent progress in the methods for computing such free energies of binding.

Images and animations related to this work can be found at the website

COMP 38 [824444]:  Calculation of binding affinities

Michael K. Gilson, Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, MD 20850, Fax: 301-738-6255

Abstract text not available.

COMP 39 [834529]:  Challenges in pKa calculations for internal residues in proteins

Bertrand Garcia-Moreno, Daniel G. Isom, and Carolyn A. Fitch, Department of Biophysics, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, Fax: 410-516-4118,

Internal ionizable residues in proteins play significant biological roles in all aspects of energy transduction and catalysis. They titrate with shifted pKa values because the protein is not as polarizable as water. They are extremely difficult to reproduce with structure-based calculations because the dielectric response of proteins is difficult to treat quantitatively. A large set of apparent pKa values of internal Lys and Glu residues in staphylococcal nuclease measured recently in our lab suggest that the protein interior is considerably more polarizable than is generally acknowledged. The molecular origins of this high apparent polarizability are not yet known. We will present data to show that quantitative treatment of the reorganization of the protein concomitant with ionization of internal groups is the most serious challenge faced by computational methods for calculation of electrostatic energies in environments sequestered from bulk solvent (i.e. protein interior, active sites, and interfaces between macromolecules).

COMP 40 [817575]:  Are fragment-protein binding energies sufficient to predict compound affinity? p38 as a case study in structure based design using fragments

Frank P. Hollinger1, Zenon Konteatis1, Enrique L. Michelotti2, Ted T. Fujimoto1, Jennifer L. Ludington1, Michael Karpusas3, Marina Bukhtiyarova3, Mike Saporito3, Xiaomei Chai3, Katrina Northrop3, and Eric Springman3. (1) Technology & Informatics, Computational Chemistry, Locus Pharmaceuticals, Inc, Four Valley Square, 512 Township Line Road, Blue Bell, PA 19422, Fax: 215-358-2020,, (2) Department of Chemistry, Locus Pharmaceuticals, Inc, (3) Department of Biology, Locus Pharmaceuticals, Inc

The development of a novel grand canonical Monte Carlo (GCMC) simulation paradigm permits the generation of binding free energies for fragments to a protein. The output of such a simulation provides all the information necessary to accurately identify high affinity interaction sites, binding sites and druggable binding sites on a protein surface. Using novel analysis tools we are able to combine fragments into synthetically accessible drug-like molecules for evaluation against a desired protein target. A case study will be presented describing the design of novel, potent and selective allosteric inhibitors for p38-alpha. Biological and structural experimental data will be presented which validates our process of using fragment based ligand design approaches.

COMP 41 [821623]:  Computational studies of protein-solvent and protein-ligand interactions

Kaushik Raha and Kenneth M. Merz Jr, Department of Chemistry, The Pennsylvania State University, 105 Chemistry Building, University Park, PA 16802,

We have studied electrostatic properties of proteins and their interactions with solvent and ligands at various levels of theory using computational methods such as molecular dynamics simulations, molecular mechanics, and linear-scaling quantum mechanics based methods. We elucidate dielectric permittivity of proteins and find that it is a unique property that depends on the charge, composition and conformational flexibility of the protein. We have also designed a quantum mechanics based scoring function to calculate free energy of binding in protein-ligand interaction that can capture trends in diverse sets of protein-ligand complexes. We also show the importance of electrostatic interactions in discriminating native binding mode from decoy “poses”. In related studies we use pairwise decomposition of residue interaction energy to dissect the interaction between different parts of the protein and the bound ligand. Finally, we demonstrate that these methods can be used in structure based drug discovery to understand structure-activity relationships.

COMP 42 [843431]:  Can topological indices transmit information on properties but not on structures?

Alexandru T. Balaban, Marine Sciences Department, Texas A&M University at Galveston, 5007 Avenue U, Galveston, TX 77551, Fax: 409-740-4787,

Information on atom connectivity of hydrogen-depleted formulas for organic compounds can be provided by various topological indices, which use different graph invariants for this purpose. If one wishes to include information on stereochemistry, more sophisticated approaches are needed. Topological indices are based on local (vertex) graph invariants, LOVIs, which can be integers or real numbers. For a given structure, these LOVIs are assembled into one numerical value (the topological index, TI) which again can be an integer or a real number. So far, no TI was designed which would be able to be in a one-to-one correspondence with a chemical structure; there are always several structures that correspond to a numerical value of a TI, giving rise to the degeneracy of TIs. The higher the degeneracy, the lower the discrimination ability of the TI. However, real-number LOVIs and real-number TIs have lower degeneracy than integer-number analogs. For such analogs and a few real-number TIs with low discrimination ability, there exist algorithms for finding all possible structures associated with a given TI; this is the so-called “inverse problem” that arises when one wishes to test structures fitting in a QSAR, QSTR or QSPR “window” or interval of biological activity, toxicity, or value of a physical property, respectively. A brief review will be presented for TIs of high and low degeneracy, for TIs that have algorithms for the corresponding inverse problems, and for TIs which offer promise that they could be associated with biological, physical or chemical properties without the possibility of retrieving information on the chemical constitution of the corresponding compounds.

COMP 43 [851394]:  Coding and decoding chemical structure information

Johann Gasteiger and Dimitar Hristozov, Department of Organic Chemistry, Computer-Chemie-Centrum, University of Erlangen-Nuremberg, Naegelsbachstrasse 25, 91052 Erlangen, Germany, Fax: +49-9131.8526566,

Chemical structures can be represented to various degrees of sophistication, from the constitution, through the 3D structure, to molecular surfaces. At each level, different physicochemical properties can be considered. Mathematical transformations allow one to obtain uniform structure codes for each different level of structure representation. These structure codes can be used to model a variety of physical, chemical or biological properties. Studies on the WOMBAT database will be reported. It will also be shown to what extent structure information can be regained from these structure codes.

COMP 44 [821669]:  Molecular shape and electrostatics in the encoding of relevant chemical information

Anthony Nicholls, OpenEye Scientific Software Inc, 3600 Cerrillos Rd., Suite 1107, Santa Fe, NM 87505,, and J. Andrew Grant, Lead Discovery, AstraZeneca Pharmaceuticals Ltd

Molecular shape and electostatic profile are key descriptors of molecular activity. In addition, they derive from the underlying chemical composition but not uniquely, i.e. different molecules may have similar shape and electrostatics. As such they have the property of a searchable one-way hash function: they encode much that is relevant of the underlying molecule while hiding its identity. This presentation will discuss various methods by which shape and electrostatics may be represented for rapid search and retrieval and used as a "safe" surrogate for chemical content.

COMP 45 [852042]:  Confusing descriptors: Where chemical information gets dizzy

Cristian G. Bologa, Marius Olah, and Tudor I. Oprea, Division of Biocomputing, University of New Mexico School of Medicine, MSC 084560, 1 University of New Mexico, Albuquerque, NM 87131-0001,

Structures from WOMBAT (WOrld of Molecular BioAcTivity) [1] were investigated with several descriptor systems. For 79,483 unique non-stereoisomeric compounds, we found multiple “confused“ instances: For 2D-descriptors, 314 duplicates (0.4%) across 80 descriptors (487 pairs); for MESA-implemented [2] MDL keys, 4391 duplicates (5.5%) across 320 keys; for Daylight fingerprints [3], 7166 duplicates (9.0%) for 512-keys, 5010 duplicates (6.3%) for 1024-keys, and 4092 duplicates (5.1%) at the 2048 level. The WOMBAT-derived set of 512 keys had 6202 (7.8%) duplicates. Our results indicate that, for several chemical descriptor systems, it is not always possible to provide a 1:1 map between chemical structure and chemical description. This implies that we can devise an information–rich, yet “confused” descriptor system, i.e., a chemical information exchange tool allowing for chemical structure ambiguity.

[1] WOMBAT is available from [2] The MDL 320 keys fingerprinter is available from [3] The Daylight fingerprinter is available from

COMP 46 [804198]:  Anonymous sd (.asd) files

Tim Clark, Friedrich-Alexander-Universite Erlangen-Nürnberg, Computer-Chemie-Centrum, Nagelsbachstrasse 25, D-91052 Erlangen, Germany, Fax: +49-9131-8526565,

A complete description of molecules and their intermolecular binding properties is presented that does not include information about the 2D structure. The molecule is described in terms of its shape (as an shrink-wrap isodensity surface) and the values of four local properties (the molecular electrostatic potential and the local ionization energy, electron affinity and polarizability) at the triangulation points on this surface. All five descriptors (the shape and the four local properties) are fitted to spherical-harmonic expansions, whose degree can be varied in order to adjust the resolution of the molecular description. The anonymous sd-file (.asd) contains only the coefficients of the five spherical-harmonic fits and thus provides an extremely information-rich description of the molecule without its 2D structure.

COMP 47 [852038]:  Similarity-based descriptors (SIBAR) as tool for exchange of chemical information

Gerhard F. Ecker, Barbara Zdrazil, and Dominik Kaiser, Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, Vienna A-1090, Austria, Fax: +431-4277-9551,

Recently we published the successful application of a set of new descriptors based on similarity values, denoted as SIBAR-descriptors (Similarity Based SAR). These descriptors are based on calculation of similarity (on basis of euclidian distances) for each compound of the data set to each compound of a reference set, using common descriptors. These euclidian distances (= similarity values) are then further used for QSAR-studies. Both the references set as well as the descriptors used for calculating the SIBAR-values are tailored to the specific QSAR-problem. Best results have been obtained when targeting ADMET-problems. In any case it needs the knowledge of the reference set to retrieve the corresponding descriptors. Assuming that only the descriptors for calculating the SIBAR-values, but not the structures of the reference compounds are available, it should be impossible to trace back the chemical structure of the original compounds of the training set.

COMP 48 [851558]:  Encoding and exchange of chemical information using substructural molecular fragments

Alexandre Varnek, Denis Fourches, and Vitaly P. Solov’ev, Laboratoire d’Infochimie, Louis Pasteur University, 4, rue B. Pascal, Strasbourg 67000, France, Fax: +33-3-88416104,

In this presentation, we describe how chemical information can be encoded in substructural molecular fragments, then used for “in silico” design of new compounds. The Substructural Molecular Fragments method is based on the representation of a molecule by its fragments and on the calculation of their contributions to a given property. Two different classes of fragments are considered “sequences” and “augmented atoms”. The sequences represent the shortest path between each pair of atoms; their length vary from 2 to 15 atoms An augmented atom represents a selected atom with its first coordination sphere. The both classes of fragments involve either atoms and bonds, or atoms only, or bonds only. Once a given compound is split into constitutive fragments, any its quantitative property is calculated from the fragments contributions using several linear and non-linear fitting equations. The best structure-property models are selected according to statistical criteria. Thus, the information concerning a given data set is stored in the files containing types of fragments, their contributions and corresponding fitting equations. In the framework of the ISIDA project ( we have developed a knowledgebase which stores the structure-property models based on fragment descriptors using PostgreSQL environment. Since the model is loaded to the knowledgebase, it immediately becomes available for all users of INTRANET via a client application. The stored models can be efficiently used for a virtual screening of large combinatorial libraries. Several examples of application of chemical information encoded in substructural molecular fragments for “in silico” design of new compounds possessing desirable chemical or biological activities will be given.

COMP 49 [810564]:  One- and two-bond spin-spin coupling constants across X-H-Y hydrogen bonds

Janet E. Del Bene, Department of Chemistry, Youngstown State University, One University Plaza, Youngstown, OH 44555, Fax: 330-941-1579,

One-bond X-H (1JX-H) and H-Y (1hJH-Y) and two-bond X-Y (2hJX-Y) spin-spin coupling constants across X-H-Y hydrogen bonds have been computed for X and Y the second-period elements 13C, 15N, 17O, and 19F, using the equation-of-motion coupled cluster singles and doubles method (EOM-CCSD). Relationships have been established among the signs and magnitudes of coupling constants, X-Y and X-H distances, and hydrogen bond type. For complexes with traditional hydrogen bonds, the reduced Fermi-contact terms and the reduced spin-spin coupling constants 1KX-H and 2hKX-Y are positive, except for 2hKF-F for the equilibrium structure of (HF)2, while 1hKH-Y is negative. As the degree of proton-shared character of the hydrogen bond increases, all reduced coupling constants become positive. The signs of 1KX-H, 1hKH-Y, and 2hKX-Y are interpreted in terms of the Nuclear Magnetic Resonance Triplet Wavefunction Model (NMRTWM). Determination of the signs and magnitudes of coupling constants could be useful for confirming the presence or absence of a proton-shared hydrogen bond.

COMP 50 [808708]:  Theoretical modeling of single molecule magnets

E. R. Davidson, Department of Chemistry, University of Washington, Seattle, WA 98195-1700,

Single molecule magnets usually have several transition metal centers with high spin. These spins couple to form molecules with net magnetic moments. In some cases the zero field splitting leads to molecules that act like magnets, albeit with a Curie temperature below 5 K. Traditionally such molecules are described by a Heisenberg Hamiltonian that assumes a net spin for each metal center and an empirical exchange coupling between centers. Methods for extracting the spin and exchange parameters from calculations of the wave function and energy will be discussed. Reasons for not using conventional quantum chemistry methods such as UHF will be explained.

COMP 51 [812256]:  Donor/acceptor interaction: Electronic structural analysis and associated vibronic features

Marshall D. Newton, Department of Chemistry, Brookhaven National Laboratory, Building 815, Upton, NY 11973, Fax: 631-344-5815,

Electronic interaction between localized donor and acceptor sites, especially as mediated by intervening molecular spacers (‘bridges') are fundamental to many features of chemical behavior, including long-range electron ( and hole) transfer. The analysis of such interactions and schemes for computational implementation are discussed, including the role of nuclear modes in modulating the electronic structure effects. Results for specific molecular systems are illustrated.

COMP 52 [817566]:  Correlation potential in density functional theory and recollections of Pople's entry into DFT

Mel Levy, Departments of Physics and Chemistry, North Carolina A & T State University/Greensboro, NC and Tulane University/New Orleans, Louisiana, 906 Haddington Court, Whitsett, NC 27377,

The first part of the lecture will concern interactions with Professor Pople in 1990, when he began to think about DFT. At that time, I gave a talk at Carnegie Mellon University and he much later said that our discussions then influenced him into analyzing the possibilities of the theory for computational chemistry. I will also recall a special joyous occasion in New Orleans in 1999 and earlier help that he gave me. The second part of the lecture will discuss the generation of the DFT correlation potential both from the "density condition" within perturbation theory [1,2] and as an explicit functional of the density without the use of perturbation theory. Recent progress in time-independent excited-state DFT [3] will also be discussed.

1. A. Goerling and M. Levy, Int. J. Quantum Chem., Symp. 29, 93 (1995). 2. S. Ivanov and M. Levy, J. Chem. Phys. 116, 6924 (2002). 3. M. Levy and Á. Nagy, “Variational Density-Functional Theory for an Individual Excited State”, Phys. Rev. Lett. 83, 4361 (1999).

COMP 53 [807156]:  Recent progress in the development of exchange-correlation functionals

Gustavo E. Scuseria, Department of Chemistry, Rice University, Houston, TX 77005,

This presentation will address our current efforts to develop more accurate exchange-correlation functionals for DFT. The functionals to be discussed include a new meta-GGA denoted TPSS [1], a screened exchange hybrid especially designed with solids in mind [2], local hybrids [3], and a current (j) dependent extension of PBE [4]. Extensive benchmarks and applications to actinide oxides (UO2 and PuO2) will also be presented.

[1] J. Tao, J. P. Perdew, V. N. Staroverov, and G. E. Scuseria, Phys. Rev. Lett. 91, 146401 (2003).

[2] J. Heyd, G. E. Scuseria, and M. Ernzerhof, J. Chem. Phys. 118, 8207 (2003).

[3] J. Jaramillo, M. Ernzerhof, and G. E. Scuseria, J. Chem. Phys. 118, 1068 (2003).

[4] S. N. Maximoff, M. Ernzerhof, and G. E. Scuseria, J. Chem. Phys. 120, 2105 (2004).

COMP 54 [817218]:  A new hybrid DFT functional: Accurate description of excited states, charge-transfer states, and van der Waals interactions

Kimihiko Hirao, Department of Applied Chemistry, University of Tokyo, Tokyo, Japan, Fax: 81-3-5841-7241,

Density functional theory (DFT) has advanced to one of the most popular theoretical approaches to calculate molecular properties. The first-order molecular properties (energies, geometries, frequencies, dipole moments, etc) are well predicted by local GGA functionals. However, DFT fails to describe induced or response properties. Although the valence-excited states can be well described by time-dependent DFT (TDDFT), TDDFT significantly underestimates the Rydberg and charge transfer (CT) excitation energies. The computed oscillator strengths have substantial errors. Also DFT fails to describe van der Waals interactions. This failure has been attributed to the wrong long-range behavior of the standard exchange functionals. Recently we have proposed a long-range exchange correction scheme for GGA functional. In the scheme, the two-electron operator is separated into the short-range and long-range parts by using the standard error functions. The long-range exchange interaction is described by the Hartree-Fock exchange integral and the short-range part is replaced by the GGA exchange functional. The present long-range corrected functional has been successfully applied to the various molecular properties. It remedies the underestimation of Rydberg excitation energies and reproduces the correct asymptotic behavior of the CT excitation energies. The van der Waals interactions can be described accurately by the present scheme with combining Andersson's potential.

COMP 55 [820956]:  Molecular dynamics simulations of the open and closed conformations of KirBac3.1.: Structural changes during ion channel gating

Carmen Domene, Physical and Theoretical Chemistry Laboratory, Department of Chemistry, University of Oxford, South Parks Road, Oxford OX1 3QZ, United Kingdom, Fax: 44-1865275410,

A central challenge remaining in ion channel biophysics is to understand the mechanisms of channel gating. Ion channels do not stay open all of the time. Instead, they are 'gated' by either the binding of small molecules e.g. neurotransmitters or intracellular regulators to the channel protein or by changes in voltage across the membrane. This reversible transition from the closed to the open state is believed to operate via conformational changes.

Molecular Dynamics Simulations were used to test the validity of the open state model of the inward rectifying K+ channel KirBac3.1. This channel was experimentally captured in its closed and open states providing 'snapshots' of the gating process. For the first time, we were able to compare conformational changes associated with channel opening in the same family of K+ channels.

COMP 56 [832905]:  Molecular modeling of ion channels: From ab initio calculations to structural bioinformatics

Paolo Carloni, Sector of statistical and biological physics and INFM-Democritos Center, International School for Advanced Studies, SISSA/ISAS, 34100 Trieste, Italy, Via Beirut 2-4, 34014 Trieste, Italy, Fax: 0039-040-3787-528,
Abstract text not available.

COMP 57 [821124]:  Activation of Shaker B, a voltage-gated potassium channel

Mounir Tarek and Werner Treptow, Equipe de Dynamique des Assemblages Membranaires, Université Henri Poincaré, UMR 7565 CNRS-UHP, BP 239, Vandoeuvre-Lčs-Nancy Cedex 54506, France, Fax: 33-3-83 68 43 87,

Excitability is an electrical property of the membrane of excitable tissues, e.g., neurons, cardiac and muscular fibers. Voltage-gated (Kv) ion channels are complex molecular structures that control this cellular excitability at the molecular level. These proteins enable ions to flow through the plasmatic membrane in response to variations of the local electrical-chemical potential. Structural and functional characterization of such ion channels is crucial and has direct applications in pharmaceutical and medical research. In this paper, we present results from MD simulations of Shaker B, a voltage-gated potassium channel, and related channels aimed at investigating the stability, the activation mechanism, and the conductive properties of Kv channels.

COMP 58 [814284]:  Mechanism of proteolysis of anthrax lethal factor. An ab initio and hybrid QM/MM molecular dynamics study

Alessandra Magistrato, INFM-Democritos Center and International School for Advanced Studies (SISSA/ISAS), via Beirut 2-4, Trieste 34014, Italy, Fax: +39-040-3787529,

The disease anthrax is caused by lethal factor (LF), an enzyme component of the toxin produced by the bacterium Bacillus Anthracis. Our studies are devoted to shed light on the binding and proteolytic mechanism of MAPKK kinase family promoted by anthrax lethal factor. At first, based on the X-ray structure of LF we have provided an understanding of the structural determinants and the hydrogen bond network that surrounds the LF active site, using static and dynamic density functional (DFT) calculations. Subsequently, classical molecular dynamics simulations have been performed on the entire protein structure and the solvent waters in order to clarify the binding and the specific substrate-protein interactions of MAPKK to the active site of LF. Finally, hybrid quantum/classical (QM/MM) molecular dynamics simulations have been performed on the entire protein structure and the solvent in order to understand the exact mechanism by which LF cleaves the NH2-termini of the MAPK-kinase family.

COMP 59 [816047]:  Structure and function of vanadium haloperoxidases

Simone Raugei, Statistical and Biological Physics, SISSA, Via Beirut 2-4, Trieste 34014, Italy, Fax: 0039 040 3787528

Since the discovery of vanadium-containing enzymes two decades ago, there has been a growing interest in the biological, pharmacological, and industrial applications of vanadium. Among these enzymes, haloperoxidases, which contain vanadium(V) as vanadate or related ions, are the most efficient halide oxidants known to date. Therefore, it is of interest to study these enzymes for their appealing utility in industrial-scale biocatalytic conversions. In the presence of hydrogen peroxide, this class of enzymes catalyzes the two-electron oxidation of a halide ion, X-, to the hypohalous acids, HXO. HXO can further react with a wide range of nucleophilic molecules to yield a number of halogenated substances. By employing ab initio and QM/MM approaches, we investigated the electronic structure of the active site vanadate moiety, and the bonding pattern of the peroxo group and of halides anions. Furthermore, the formation of the intermediate peroxide form was also examined by QM/MM MD.

COMP 60 [822030]:  Understanding protein-ligand interactions and binding free energy with an empirical solvation-based model

Glen E. Kellogg1, Micaela Fornabaio1, Pietro Cozzini2, Andrea Mozzarelli2, Francesca Spyrakis2, and Donald J. Abraham1. (1) Department of Medicinal Chemistry and Institute for Structural Biology & Drug Discovery, Virginia Commonwealth University, Box 980540, Richmond, VA 23298-0540, Fax: 804-827-3664,, (2) Department of Biochemistry and Molecular Biology, University of Parma

We have been developing a number of computational models and tools to explore the types and strengths of protein-ligand interactions. Our overarching goal is to build an understanding of the phenomena surrounding ligand binding in terms of simple and intuitive principles. Thus, we have presented HINT (Hydropathic INTeractions) as a uniquely empirical paradigm for free energy scoring of biomolecular interactions. The key to HINT is the experimental data from water/1-octanol partitioning of small molecules, an event not unlike ligand binding. We have shown that this model provides predictions with accuracy comparable to other free energy methods, and have recently extended the method to enhance our predictions by including: a) the effects of bridging water in the active site, and b) ionization states of protein residues and ligand functional groups in the active site (through computational titration). In this presentation we will report on a detailed examination of the XSCORE data set (230 protein-ligand complexes) using these tools to prepare corrected molecular models and evaluate the resulting protein-ligand interactions.

COMP 61 [833444]:  Exploring protein ligand interactions: Binding free energies, docking and scoring

Charles L. Brooks III, Molecular Biology, TPC6, Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037,

In this talk I will review recent progress from our group in the development of methods and protocols that explore the nature of protein-ligand binding landscapes. These include free energy calculations with atomically detailed models, where we examine the role of ligand configurational entropy loss and solvent expulsion in the binding process. I will also discuss key factors we have found that influence the accuracy of scoring functions in protein-ligand docking and describe ongoing large-scale “Internet computing” experiments using Predictor@home and the BOINC middleware environment to explore protein grid-based docking calculations.

COMP 62 [832805]:  Computational modelling of inhibition and catalysis in malaria proteases

Johan Aqvist, Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, POB 596, SE-751 24 Uppsala, Sweden, Fax: 46-18-536971,

The most virulent of the malaria parasites, P. falciparum, has several proteases involved in the degradation of host cell hemoglobin and these have emerged as highly promising drug targets. We will discuss recent theoretical and experimental work on inhibitor binding to the plasmepsin aspartic proteases, where methodological aspects of binding affinity calculations also will be addressed. Further, the so-called histo-aspartic protease (HAP) from P. falciparum presents a new type of active site and computer simulation studies of substrate binding and catalysis in this enzyme will be presented.

COMP 63 [821708]:  Modeling protein-ligand interactions via high throughput docking and induced fit methods

Richard A. Friesner, Department of Chemistry, Columbia University, 3000 Broadway, MC 3110, New York, NY 10027, Fax: 212-854-7454

We will discuss application of high throughput docking methods (Glide) and protein structural refinement methods (Prime) to the problem of predicting the structures and binding affinities of protein-ligand complexes. We have examined a wide variety of pharmaceutically relevant test cases, including one system, p38 MAP kinase, for which we have obtained experimental binding affinities for selected ligands. A key aspect of our approach to the problem is separation of cases where the ligand fits into a given rigid receptor structure (in which case a rigid docking program should be able to correctly dock, and score, the ligand), from cases where the ligand is incompatible with the receptor conformation, i.e. the correct ligand pose would exhibit steric clashes with the conformation in question. In these latter cases, it is necessary to carry out an induced fit calculation, in which protein flexibility is incorporated. We have developed an automated induced fit protocol by combining Glide and Prime; this protocol will be described and examples of its use will be presented.

COMP 64 [846581]:  Structure-based modeling of the hERG channel: A two-state linear interaction energy model for ligand binding

Brett A. Tounge, Computer Assisted Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C, P. O. Box 776, Welsh and McKean Roads, Spring House, PA 19477-0776, Fax: 215-628-4985,, Ramkumar Rajamani, Computer-Aided Drug Discovery, Johnson & Johnson Pharmaceutical R & D, and Charles H. Reynolds, Johnson & Johnson Pharmaceutical R&D
Homology models based on available K+ channel structures have been used to construct a two-state representation of the hERG cardiac K+ channel. These states are used to capture the flexibility of the channel. We show that this flexibility is essential in order to correctly model the binding affinity of a set of diverse ligands. Using this multiple state approach, a binding affinity model was constructed for set of known hERG channel binders. The predicted pIC50s are in good agreement with experiment (RMSD: 0.56 kcal/mol). In addition, these calculations provide structures for the bound ligands that are consistent with published mutation studies. These computed ligand bound complex structures can be used to guide synthesis of analogs with reduced hERG liability

COMP 65 [833356]:  Hierarchical energy functions for the design of protein binding interfaces

David F. Green, Biological Engineering Division & Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, 32 Vassar St., Room 32-211, Cambridge, MA 02139, Fax: 617-252-1816,, Michael D. Altman, Department of Chemistry & Computer Science and Artificial Intelligence Laboratory, MIT, and Bruce Tidor, Biological Engineering Division & Department of Electrical Engineering and Computer Science, MIT

Discrete conformational search methods have been demonstrated as a powerful means for designing novel proteins, and an obvious extension is to the design of protein complexes. Protein--protein binding interfaces pose a particular challenge due to the conformational flexiblity of both binding partners and the need to account for solvation. While the complexity of this search can be handled with various algorithms, simplified energetic and structural models are generally required. A hierachical approach, refining initial results with more accurate models, provides a means to search large spaces while ensuring accurate predictions. Here we outline several considerations for such a treatment. A framework for describing how ensembles of structures traverse the hierarchy is detailed. We also demonstrate how improvements at the lowest level affect the final results. While the methodology is detailed for designing protein complexes, it is easily extensible to related problems, including de novo ligand design and docking.

COMP 66 [826979]:  Electronic structure studies of materials chemistry using embedded cluster models

Krishnan Raghavachari, Department of Chemistry, Indiana University, 800 E. Kirkwood Avenue, Bloomington, IN 47405, Fax: (812) 855-8300,

Accurate quantum chemical calculations using embedded cluster models have been performed to investigate the surface chemistry of semiconductor materials and the endohedral chemistry of carbon nanotubes. In this talk, we consider new techniques for cluster termination as well as cluster embedding and discuss their applicability in such computational studies. Recent examples using our results to provide assignments and novel interpretations of experimental spectroscopic observations will be discussed.

COMP 67 [818976]:  Computation of zero-field splitting in triplet heteroarylnitrenes

Zdenek Havlas1, Mojmir Kyvala1, and Josef Michl2. (1) Institute of Organic Chemistry and Biochemistry, Academy of Sciences of Czech Republic, 166 10 Prague 6, Czech Republic, (2) Department of Chemistry, University of Colorado, Boulder, CO 80309, Fax: 303-492-0799,

We report the zero-field splitting parameters D and E of a series of heteroaromatic triplet arylnitrenes Ar-N computed at the CASSCF(14,14)/cc-pVDZ to CASSCF(14,11)/cc-pVDZ levels at B3LYP/cc-pVTZ geometries, using the full Breit-Pauli Hamiltonian (Ar = phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-pyrazinyl, 3-pyridazinyl, and 1,3,5-triazinyl). A comparison of spin-spin dipolar and spin-orbit coupling contributions shows that the latter increase the D value by about 10% and have an irregular effect on the small E value. Experimental values had been measured on nitrenes prepared by irradiation of matrix isolated aryl azides [1-3] and are 10-15% lower than those presently calculated. The triplet species produced from 3-pyridazyl azide is exceptional in that its D value does not agree with that calculated for 3-pyridazylnitrene at all, and we propose that it has another structure.

[1] Kuzaj, M; Lüerssen, C.; Wentrup, C. Angew. Chem. Int. Ed. Engl. 1986, 25, 480. [2] Wasserman, E. Prog. Phys. Org. Chem. 1971, 8, 319. [3] Wentrup, C.; Kvaskoff, D., private communication.

COMP 68 [822592]:  Calculation of the dispersion energy between large molecules: Graphene plates and the graphene-water system

Peter Pulay and Alan R. Ford, Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, Fax: 479-575-4049,

We have recently developed an efficient parallel canonical second-order Moller-Plesset (MP2) program. This program, and related newer developments: the calculation of MP2 forces, and current work on an efficient parallel coupled cluster code, will be discussed, with particular attention to parallel disk storage. We have studied the interaction between graphene plates, and between graphene plates and water. The efficiency of our code made it possible to use large models, e.g. two circumcoronene molecules, C54H18 with fairly large basis sets (about 2000 basis functions) on a modest size cluster. MP2 overestimates the dispersion attraction between aromatic systems. However, spin-component scaled MP2 (SCS-MP2) is in good agreement with high-level results, e.g. CCSD(T), for smaller model systems. The results will be discussed in the light of the hydrophobic effect and water depletion between two closely spaced hydrophobic surfaces, and models of interaction between graphitic surfaces.

COMP 69 [818389]:  A complete basis set model chemistry for excited states

George A. Petersson, Hall-Atwater Laboratories of Chemistry, Wesleyan University, Middletown, CT 06459-0180, Fax: 860-685-2211,

Extrapolation schemes for calculations employing a single reference configuration are now used routinely. We have begun the development of complete one-electron basis set (CBS) extrapolation schemes for multi-configuration methods. We select the full valence complete active space self consistent field (CASSCF) multiconfiguration reference for a CISD calculation of the dynamic correlation energy. Extrapolation requires a well defined sequence of approximations and a model for the convergence of this sequence. The convergence of full valence CASSCF energies to the complete basis set limit is very similar to the basis set convergence of UHF energies. This similarity is exploited with extrapolations employing quadruple-ζ UHF energies to extrapolate double- and triple-ζ CASSCF calculations. In an analogous fashion, well established MP2 correlation energy extrapolations are used to estimate the dynamic error in CASSCF-CISD calculations. The six lowest energy singlet and triplet states of the N2 molecule provide a well documented set of test cases for this method. Preliminary results for the calculated (and experimental) excitation energies, Te in eV, from the N2 X1Σg+ ground state to the A3Σu+, B3Πg, W3Δu, B'3Σu+, a'1Σu-, a1Πg, and w1Δu excited states are: 6.247 (6.224), 7.406 (7.392), 7.468 (7.415), 8.193 (8.217), 8.494 (8.450), 8.573 (8.590), and 9.005 (8.939) respectively.

COMP 70 [824994]:  Quantum photochemistry

Donald G. Truhlar1, Ahren W. Jasper1, Shikha Nangia1, Chaoyuan Zhu1, Piotr Piecuch2, and Michael J. McGuire2. (1) Department of Chemistry and Supercomputing Institute, University of Minnesota, 207 Pleasant St. SE, Minneapolis, MN 55455-0431, Fax: 612-626-9390,, (2) Department of Chemistry, Michigan State University

We will discuss the two steps in the calculation of the dynamics of photochemical processes: (1) obtaining the potential energy surfaces and the terms coupling them; (2) calculation of the dynamics itself. For step 1 we use the fourfold way [H. Nakamura and D. G. Truhlar, Journal of Chemical Physics 118, 6816 (2003)] for the direct calculation of diabatic surfaces and couplings. We will present results for the photodissociation of ammonia as an example of the method. For step 2 we use non-Born-Oppenheimer trajectories calculated by coherent switching with decay of mixing [C. Zhu, S. Nangia, A. W. Jasper, and D. G. Truhlar, Journal of Chemical Physics 121, 7858 (2004)]. We will present tests against accurate quantum dynamics for weakly interacting surfaces, avoided crossings, and conical intersections and discuss the effect of treating coherence and decoherence in different ways. This work was supported in part by the National Science Foundation.

COMP 71 [825418]:  Advanced computational methods applied to chemistry

Theresa L. Windus1, Yuri Alexeev1, Edoardo Apra1, Manojkumar Krishnan2, Vinod Tipparaju2, Bruce J. Palmer2, and Jarek Nieplocha2. (1) Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, 902 Battelle Boulevard, P.O. Box 999, MSIN: K8-91, Richland, WA 99352, Fax: 509-375-6631,, (2) Computational Science and Mathematics, Pacific Northwest National Laboratory

John Pople was one of the driving forces behind the development of widely used computer codes to solve important chemical problems. Our work will describe how advanced computational science techniques are continuing to be applied to solve large, challenging chemical issues. In particular, we will discuss the use of the common component architecture and multiple levels of parallelism within NWChem to enable dynamic environments for performing large computations on high performance architectures. Several applications will be discussed to show the flexibility and viability of the software.

COMP 72 [828291]:  Practical approaches to condensed phase quantum dynamics based on quantum decoherence

Peter J. Rossky, Institute for Theoretical Chemistry, Dept. of Chemistry & Biochemistry, University of Texas at Austin, 1 University Station A5300, Austin, TX 78712, Fax: 512-471-1624,

The computationally convenient description of the quantum mechanical dynamics of electronic systems and of light nuclei in condensed phases is an important goal for the accurate atomistic representation of chemical and biochemical processes. In electronic systems, the rate of decay of an excited state is influenced by the coherence among the amplitudes for the initial state and the component decay channels. For a species in a condensed phase, the dynamics of the bath can strongly dissipate this coherence and thus modify the rate of electronic evolution. For nuclear dynamics, the coherence between alternative nuclear paths has a parallel significance, and interaction with the surroundings has a similar dissipating effect. Practical approaches to simulation of these cases, which take advantage of the loss of coherence, will be described. These only require evaluation of the classical molecular dynamics of nuclei. The evolution of electronic excited states and the description of the dynamics of light nuclei, including the dissipative role of the environment, will be illustrated in practical cases, including electronic excited state relaxation in solution and in isolated large molecules, and motion in neat liquid para-H2 and He(4).

COMP 73 [832798]:  Linearized path integral approach to calculating non-adiabatic time correlation functions

David F Coker, Department of Chemistry 590 Commonwealth Ave., Boston University, 590 Commonwealth Avenue, Boston, MA 02215, Fax: 617-353-6466,, and Sara Bonella, Department of Chemistry, Boston University

In statistical mechanics, time correlation functions are central quantities which bridge the microscopic dynamics and fluctuations of a given system to macroscopic, phenomenological quantities, such as transport coefficient or relaxation times. While relatively standard numerical methods provide a viable tool for their evaluation for classical systems, full quantum mechanical calculations of time correlations functions are currently out of the realm of affordable computations. Consequently, many approximate techniques have been developed to tackle this problem. In this presentation we outline a new mixed quantum-classical approach, belonging to the family of the so-called linearization methods, which addresses the evaluation of time correlation functions of nuclear or electronic operators evolving in the presence of non-adiabatic effects. We begin by rewriting the function in a basis set defined as the tensor product of nuclear positions and diabatic electronic states. The approach involves linearizing in the difference between forward and backward nuclear paths while keeping keeping all orders in the electronic occupation paths described using the Mapping Hamiltonian formulation. Results are present for excited state reaction dynamics in various model condensed phase systems.

COMP 74 [828830]:  Electrochemistry in a very small cell: A computational approach

Michiel Sprik1, Jochen Blumberger1, and Yoshitaka Tateyama2. (1) Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, United Kingdom, Fax: +44-1223-336362,, (2) National Institute for Materials Science

Electrochemists control the thermodynamic driving force of redox reactions in an electrochemical cell by applying a voltage to the electrodes. In computations the same effect can be achieved by shifting the potential energy surfaces of different oxidations states with respect to each other (omitting any physical electrode). We have implemented this method using density functional theory based ab initio molecular dynamics simulation ("Car-Parrinello")[1]. In this talk we summarize the latest results we have obtained applying this method to a number of small redox active aqueous solutes (mainly transition metal complexes). We compare our computations to experiment (redox potentials) as well as theory (Marcus Theory of electron transfer.)

[1] J. Blumberger, L. Bernasconi, I. Tavernelli, R. Vuilleumier, M. Sprik, J. Am. Chem. Soc. 126, 3928 (2004)

COMP 75 [807803]:  A coarse grain simulation methodology for structured solutions

John C. Shelley, Schrodinger Inc, 1500 SW First AVenue, Suite 1180, Portland, OR 97006, Fax: 503-299-4532,

A methodology for developing coarse grain models for simulating specific structured solutions will be presented. In this approach coarse grain sites, corresponding to roughly 10 atoms, are selected so as to mimic the overall framework of the molecules of interest. The intramolecular and intermolecular interactions are parameterized so as to reproduce data from experiment and aspects of intra site distributions obtained from atomistic simulations. The resulting models have reproduced key phenomena and have proved useful in predictive studies. While this is encouraging the model will be examined critically to highlight its strengths and weaknesses with an eye towards prospects for future enhancements.

COMP 76 [829452]:  The performance of metadynamics in flexible docking

Francesco L. Gervasio, Physical Chemistry, ETH Zuerich, Research group Prof. Parrinello, Usi Campus, CH-6900 Lugano, Switzerland, Fax: +41 (91) 9138817,, Allesandro Laio, Research Group Prof. Parrinello, ETH Zurich, and Michele Parrinello, Physical Chemistry ETH (Zurich)

We apply our recently developed metadynamics method to the docking of ligands on flexible receptors in water solution. This method mimics the real dynamics of a ligand exiting or entering an enzyme and in so doing reconstructs the free energy surface. We apply it to four classical docking cases: beta-trypsin/benzamidine, beta-trypsin/ chloro-benzamidine, immunoglobulin McPC-603/phosphocoline and CDK2/staurosporine. In every case studied the method is able to predict the docked geometry and the free energy of docking. Its added value with respect to many other available methods is that it reconstructs the complete free energy surface including all the relevant minima and the barriers between them.

COMP 77 [819284]:  Binding MOAD (Mother of All Databases)

Heather A. Carlson1, Mark L. Benson2, Richard D. Smith3, and Liegi Hu1. (1) Department of Medicinal Chemistry, University of Michigan, Ann Arbor, 428 Church Street, Ann Arbor, MI 48109,, (2) Bioinformatics Program, University of Michigan, Ann Arbor, (3) Biophysics Research Division, University of Michigan, Ann Arbor

There is a wealth of information about protein-ligand interactions contained in the PDB. We present a comprehensive database of those structures: Binding MOAD (Mother of All Databases). The methods involved in currating the dataset will be covered. Binding MOAD contains 5359 valid protein-ligand complexes. There are 2660 unique ligands and 2090 unique protein families. Over 5000 crystallography papers were searched for binding data, and 1378 (26%) of the complexes are augmented by binding affinity information. We have mined the dataset for information about the biophysics of molecular recognition. The binding sites have been analyzed for amino acid content, geometry, atomic contacts, ligand volume, binding site volume, and degree of solvent exposure. These are then compared to the large number of Ki, Kd, or IC50 values to correlate the size and makeup of the binding site with the binding affinity.

COMP 78 [833580]:  SAR, binding mode and radioprotective effects of a novel class of Checkpoint2 kinase inhibitors

Frank U. Axe1, Kristen L. Arienti2, Anders Brunmark3, Kelly McClure4, Alice Lee5, Jon Blevitt3, Danielle Neff3, Liming Huang4, Shelby Crawford3, Chennagiri R. Pandit3, Lars Karlsson3, and J. Guy Breitenbucher6. (1) Department of Chemistry, Johnson and Johnson Pharmaceutical Research and Development, 3210 Merryfield Row, San Diego, CA 92121, (2) Department of Chemistry, Johnson and Johnson Pharmaceutical Research and Development, LLC, (3) (4) Department of Chemistry, Johnson & Johnson Pharmaceutical Research & Development, L.L.C, (5) Department of Chemistry, University of California at Berkeley, (6) Pharmaceutical Research Institute, RW Johnson

Checkpoint2 (Chk2) kinase is a potentially important target in radiation treatment of cancer patients. A novel series of 2-arylbenzimidazoles were found to inhibit this target selectively. Molecular docking was used to predict the binding mode of this novel kinase chemotype in the ATP pocket of Chk2. This binding model was used to rationalize the SAR and to develop a refinement strategy to improve potency and optimize other medicinal properties. These compounds were found to be ATP competitive and provide dose dependent protection of human CD4+ and CD8+ T-cells from apotosis due to ioninzing radiation.

COMP 79 [832944]:  Understanding protein-ligand interactions in the field of kinases

Isabelle Morize, Dorothea Kominos, and Robert Pearlstein, Molecular Modeling, Sanofi-Aventis, Route 202-206, PO Box 6800, JR1-203A, Bridgewater, NJ 08807, Fax: 908-231-3577,

Kinases are a challenge for drug design, due to multiple factors: one of which being the flexibility exhibited by these proteins. Understanding protein-ligand interactions is one of the primary steps in designing new compounds with improved affinity, along with the right properties to make them drugs. Working on multiple targets from the same family, such as kinases, and getting access to structural information, has been an advantage for modelers, since it has afforded them a knowledge-driven approach to exploit common patterns, highlight differences, and rapidly apply this knowledge via proprietary structures displaying drug-like properties with regard to affinity, selectivity, toxicity, absorption, distribution, metabolism and excretion. Navigation into the biological and chemical spaces, in order to identify the best intersection (i.e. best targets/best compounds) is one of our primary objectives, and we will present the lessons we learned during this voyage.

COMP 80 [834602]:  Characterization of protein-ligand interaction sites using computational solvent mapping

Sandor Vajda1, Michael Silberstein2, and Karl Clodfelter2. (1) Department of Biomedical Engineering, Boston University, 44 Cummington St, Boston, MA 02215, Fax: 617-353-6766,, (2) Program in Bioinformatics, Boston University

Computational solvent mapping moves molecular probes - small organic molecules containing various functional groups – around the protein surface, finds favorable positions using empirical free energy functions, clusters the conformations, and ranks the clusters on the basis of the average free energy. The mapping procedure reproduces the available experimental solvent mapping results, eliminating the problem of spurious local minima associated with previous computational methods. The most important result is that using at least six different probes, the consensus site at which most probes overlap is always a major subsite of the functional site. In addition, the amino acid residues that interact with the probes also bind the specific ligands of the protein, and thus the method provides detailed and reliable information on the functional sites. We apply the approach to cytochrome P450s and peroxisome proliferator activated receptors (PPARs), and show that it yields substantial biological insight and facilitates drug design.

COMP 81 [834204]:  End point free energy calculations: What it takes for success with FK506 Binding Protein

Jessica M. J. Swanson, Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92037-0365, Fax: 858-534-7042,, and J. Andrew McCammon, Howard Hughes Medical Institute, Department of Chemistry and Biochemistry, University of California at San Diego

End-point free energy calculations have received increasing attention over the last decade. These methods combine gas phase energies from explicit solvent simulations with continuum solvation energies to evaluate the free energy of the bound and free states of a binding reaction. This work explores the importance of using compatible implicit and explicit solvent models. We report the effects of using different continuum parameter sets including a set of radii that have been recently optimized for Poisson-Boltzmann calculations with the AMBER (parm99) partial charges. These radii were benchmarked against explicit solvent electrostatic solvation energies to provide the optimal explicit and implicit energetic agreement. Different radii were reported for abrupt and cubic spline smoothed surface definitions. We report the effect of these surface definitions on the measured free energies as well as their relative computational demand.

COMP 82 [820166]:  Dynamics of buried water in proteins

Chandra S Verma, Computational Biology, Bioinformatics Institute, 30 Biopolis Way, #07-01 Matrix, Singapore 138671, Singapore, Fax: 65-6478-9077,

Using water as a paradigm for ligand binding we find that the the vibrational spectrum of the protein, particularly the low freqeuncy modes, undergoes a red shift upon ligand binding; this leads to entropic stabilization which is in contrast to the classical notion that ligand binding induces a tightening of the protein. Further, the pathways of entry of this liagdn into and out of the protein are characterized by a rugged energy landscape that requries a departure in analysis from the standard two-state paradigm underlying the Arrhenius scenario. This methodology is then extended to resolving a long standing disagreement between NMR and crystallographic data on whether waters can exist in hydrophobic cavities in proteins, by finding in the affirmative.

COMP 83 [833478]:  A new approach to efficiently explore the free energy surface, trace the reaction pathways and converge the free energy barriers

Bernd Ensing, Center for Molecular Modeling, Department of Chemistry, University of Pennsylvania, 231 S. 34th Street, Philadelphia, PA 19104, Fax: 215-573-6233,, Alessandro Laio, Research Group Prof. Parrinello, ETH Zurich, Michele Parrinello, Computational Science, Department of Chemistry and Applied Biosciences, ETH Zurich, and Michael L. Klein, Department of Chemistry, University of Pennsylvania

The recently introduced hills method is a powerful tool to compute the multi-dimensional free energy surface of intrinsically concerted reactions. We have extended this method by focusing our attention on localizing the lowest free energy path that connects the stable reactant and product states. This path represents the most probable reaction mechanism, similar to the zero temperature IRC, but also includes finite temperature effects. The transformation of the multi-dimensional problem to a one-dimensional reaction coordinate allows for accurate convergence of the free energy profile along the lowest free energy path using standard free energy methods. The power of the method is exemplified by a number of interesting chemical and biophysical problems, among which the concerted enzyme catalyzed phosphate transfer reaction, the anti-microbial peptide nanotube insertion into a lipid bilayer and the exploration of the free energy landscape of the reactions between F- and CH3CH2F showing the E2 and SN2 reaction channels simultaneously.

COMP 84 [833231]:  Application of digital filters to enhance conformational change in protein systems

Adrian P. Wiley and Jonathan W Essex, School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, United Kingdom, Fax: +44 (0)23 8059 3781,
Motions in biological molecules can occur on timescales beyond those accessible to molecular dynamics simulations, and algorithms that enhance conformational sampling are therefore of considerable interest. Reversible Digitally Filtered Molecular Dynamics (RDFMD) is able to enhance sampling by amplifying the low frequency motions as a simulation evolves. In this presentation, methods to optimise the performance of RDFMD are described, and applications of this approach to enhancing the conformational motion in E. coli dihydrofolate reductase, T4 lysozyme, and HIV-1 protease, are described.

COMP 85 [827552]:  Atomically detailed simulations of conformational transitions in DNA Polymerases: Implications for DNA synthesis fidelity mechanisms

Karunesh Arora, Department of Chemistry, New York University, 31 Washington Place, Silver Center for Arts and Science, New York, NY 10003, Fax: 212-995-4152,, and Tamar Schlick, Department of Chemistry, Courant Institute of Mathematical Sciences, and the Howard Hughes Medical Institute, New York University

DNA polymerases play a key role in maintaining genome integrity by repairing damaged DNA bases. If the damaged DNA is replicated unrepaired it may lead to cancer and premature aging. The fidelity of polymerases depends on their ability to incorporate correct rather than incorrect nucleotides complementary to the template DNA; such fidelities lie in the range from 1 to nearly 106 errors per million nucleotides incorporated. Based on kinetic and structural data, it is likely that high fidelity enzymes (like pol beta) undergo conformational changes prior to nucleotide incorporation such as to tailor-fit correct base-pairs rather than incorrect units, while low fidelity enzymes (like Dpo4) discriminate correct from incorrect base-pairs very poorly due to a much more open active site. To this end, we have developed and applied a combination of molecular dynamics and novel long-time dynamics simulation methodologies to determine conformational transition pathways of Pol beta and Dpo4 in the presence of correct and incorrect incoming substrates in the active site. These simulations have helped determine the order of events, slow reaction coordinates, and key transition state regions in the presence of matched and mismatched base-pairs. We observe that in the presence of mismatched base-pairs, the N-subdomain of pol beta which is believed to be required for catalytic cycling, remains in the "open" conformation, rather than the "closed" conformation observed in the presence of correct base-pair. In contrast to pol beta, in Dpo4 we see the sliding of the DNA template/primer strands in response to the incoming substrate in the active site. Protein subdomains undergo conformational changes that are smaller in magnitude and distinct in identity from pol beta.

COMP 86 [828826]:  Hybrid molecular dynamics-quantum mechanics simulations of solvation dynamics

Matthew C. Zwier, Christopher M. Meeusen, Justin M. Shorb, and Brent P. Krueger, Department of Chemistry, Hope College, 35 East 12th St., Holland, MI 49423,

Solvation dynamics play a large role in chemical processes, whether a traditional small molecule in solution or a cofactor surrounded by protein. Recently, a hybrid molecular dynamics (MD) and quantum mechanical (QM) method (MD/QM) has been developed by Mercer, Gould, and Klug that may be both more applicable to complex systems and more robust than purely classical methods. While it has been used to simulate the (linear) absorption spectra of a number of complex biological systems, to date only limited basic evaluation of the method has been completed. We present the results of MD/QM calculations on an organic dye (oxazine 4) in methanol, compare them to both linear and nonlinear optical spectra, and evaluate a number of critical parameters such as simulation length, QM sampling rate, and QM model chemistry. In particular, a computationally inexpensive semi-empirical QM method gives encouraging results in contrast to previous studies.

COMP 87 [818470]:  Long dynamics simulations of proteins using atomistic force fields and a continuum representation of solvent effects

Xianfeng Li1, Sergio A. Hassan2, and Ernest L. Mehler1. (1) Physiology and Biophysics, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021,, (2) National Institutes of Health, DHHS

Long molecular dynamics (MD) simulations were carried out on the B1 immunoglobulin-binding domain of streptococcal protein G (ProtG) and bovine pancreatic trypsin inhibitor (BPTI) using an atomistic force field and a continuum representation of solvent effects. To mimic frictional and random collision effects, Langevin dynamics (LD) were used. The main goal of the calculations was to explore the stability of tens-of-nanosecond trajectories using a continuum model, and to analyze, in detail, structural and dynamical properties. Conformational fluctuations, order parameters, cross correlation matrices, residue solvent accessibilities, pKa values of titratable groups, and hydrogen-bonding (HB) patterns were calculated from all the trajectories and compared with available experimental data. The simulations comprised 30ns and 40ns for BPTI and ProtG, respectively. For comparison explicit water (EW/MD) of 4 ns and 3 ns, respectively, were also carried out. Two continuum simulations were performed on each protein using CHARMM: one with the all-atom PAR22 representation of the protein forcefield (referred to as PAR22/LD) and the other with the recently developed CMAP potential (CMAP/LD). The continuum model is based on the screened Coulomb potential (SCP) reported earlier, the SCP-based implicit solvent model (SCP-ISM). For ProtG both the PAR22/LD and CMAP/LD 40ns-trajectories were stable, but for BPTI only the CMAP/LD trajectory was stable for the entire 30-ns simulation. The source of the instability of the PAR22/LD simulation of BPTI was explored by an analysis of the backbone torsion angles.

COMP 88 [830533]:  Constant pH molecular dynamics in generalized Born implicit solvent

John T. Mongan, Bioinformatics, Medical Scientist Training Program, NSF Ctr. Theor. Biol. Physics, University of California San Diego, 9500 Gilman Dr. #0365, La Jolla, CA 92093-0365, Fax: 858-534-4974,, David A. Case, Dept. of Molecular Biology, Scripps Research Institute, and J Andrew McCammon, Howard Hughes Med. Inst., NSF Ctr. Theor. Biol. Physics, Dept. Chem. and Biochem., and Dept. Pharmacol, University of California, San Diego

Traditional molecular dynamics (MD) methods employ fixed protonation states and so cannot adequately model the coupling between conformation and protonation state. We have implemented a new method for constant pH MD, employing generalized Born (GB) electrostatics. Monte Carlo (MC) sampling is conducted across discrete protonation states, which are modeled as different sets of partial charges. Use of GB-derived energies for MC allows rapid sampling of protonation states under a potential consistent with that used for MD. Application of the method to hen egg-white lysozyme (HEWL) produces substantially accurate protonation state populations, from which pKa values can be predicted with RMS error of 0.82 from experiment. Results are independent of starting crystal structure. Constant pH trajectories show a strong correlation between conformation and protonation state, underscoring the importance of sampling these properties concurrently.

COMP 89 [832116]:  Constant-pH molecular dynamics simulations for pKa predictions and conformational dynamics studies of proteins

Jana Khandogin, Department of Molecular Biology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, Fax: 858-784-8688,, and Charles L. Brooks III, Molecular Biology, TPC6, Scripps Research Institute

Molecular simulations of pH-dependent biological phenomena require dynamical control of the protonation states. In recent years, several constant-pH molecular dynamics techniques have emerged. In this work, the newly developed constant-pH molecular dynamics technique with continuous titration coordinates based on the lambda dynamics and Generalized Born solvation methods is extended to account for proton tautomerism. In particular, a new dynamic variable is introduced to control the tautomer conversion coordinate in addition to the variable that represents the titration degree of freedom. The potential function that corrects for the arbitrary classical description of the titration pathway of a model compound is analytically derived for two types of titration groups: one with the deprotonated tautomeric states, such as His, and the other one with the protonated tautomeric states, such as Asp or Glu groups.

The new model will be applied for the pKa predictions of several proteins with carboxylic acid groups that exhibit large downward or upward pKa shifts. The accuracy of the current method will be compared to the model that allows only single-site titration. The conformational dynamics of amyloid beta(1-28) under different pH conditions will also be discussed.

COMP 90 [819532]:  Computational studies of chaperonin-mediated protein folding

George Stan1, Bernard R. Brooks1, D. Thirumalai2, and George H. Lorimer2. (1) Laboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health, 50 South Dr. MSC 8014, Bethesda, MD 20892-8014, Fax: 301-402-3404,, (2) Institute for Physical Science and Technology and Department of Chemistry and Biochemistry, University of Maryland

Protein folding mediated by chaperonin molecules is studied by computer simulations. Our focus is on the GroEL-GroES chaperonin complex of the Escherichia coli. The GroEL apical domain fragment (minichaperone) is able to assist folding of non-stringent substrate proteins through a mechanism of binding and unbinding. Molecular dynamics simulations of a peptide interacting with the apical domain show that the annealing efficiency is determined by the interplay between the interactions of the charged and hydrophobic residues in the helices H and I of the apical domain with the peptide. The fundamental requirement of the minichaperone annealing mechanism is a transient interaction of the substrate protein with the hydrophobic surfaces followed by its release by thermal fluctuations. We describe a sequence-based approach to identify the natural substrate proteins (SPs) for GroEL. Our method is based on the hypothesis that natural SPs are those that contain patterns of residues similar to those found in either GroES mobile loop and/or strongly binding peptide in complex with GroEL. The method is validated by comparing the predicted results with experimentally determined natural SPs for GroEL. We have searched for such patterns in five genomes. In the E. coli genome we identify 1422 (about a third) sequences that are putative natural SPs. A limited analysis of the predicted binding sequences shows that they do not adopt any preferred secondary structure. Our method also predicts the putative binding regions in the identified SPs. The results of our study show that a variety of SPs, associated with diverse functions, can interact with GroEL.

COMP 91 [833505]:  Is Poisson-Boltzmann theory insufficient for protein folding simulations?

ThuZar Lwin1, John Lu1, Ruhong Zhou2, and Ray Luo1. (1) Department of Molecular Biology and Biochemistry, University of California-Irvine, Irvine, CA 92697,, (2) Thomas J Watson Research Center, IBM

Computer simulation is an important aspect in solving the protein folding problem. To date, most atomistic folding simulations are performed in GB solvents. However, failures to agree with experiment and with explicit solvents have been observed in GB. Their failures have raised a serious doubt whether the PB theory on which they are calibrated is adequate in treating polar interactions. To address the doubt, we have used our efficient PB implementation to revisit such a failure: beta hairpin folding. In this study, we are able to reproduce the failures in GB as previously reported. However, our PB simulation agrees with experiment as good as explicit solvent simulations when available experimental data, such as room temperature propensity, RMSD to the native structure, and NOE are considered. These data shows that the PB theory is sufficient in modeling polar interactions, at least in the system tested.

COMP 92 [834194]:  Protein folding simulations from first principles by a new molecular dynamics method

Zunnan Huang, Zhanyong Guo, and Ralph A. Wheeler, Department of Chemistry and Biochemistry, University of Oklahoma, 620 Parrington Oval, Rm. 208, Norman, OK 73019, Fax: 405-325-6111,

We have developed a new MD method called trajectory and energy perturbed replica microcanonical search (RMS) for finding global or local energy minima to determine the structures of polypeptides in solvent. Here we present tests of this new simulation method for mapping potential energy landscapes and conformations of an amphiphilic octadecapeptide peptide F (PDB 1PEF) in GB/SA implicit solvent model for water. This de novo designed polypeptide has a high apolar-polar amino acid ratio and can self-associate into hexamers in aqueous solution. The simulations were started from an extended structure. With this method, we find that the x-ray structures (at 1.5 A resolution) of the folded polypeptide can be quickly reproduced after a very short simulation time (backbone RMSD = 1.0 A and all heavy atoms RMSD = 1.5 A in 1.5ns). However, even though many similar folded structures (backbone RMSD between 1 A and 3 A) can be sampled during the simulations, these structures do not correspond to the lowest energy states sampled on the very rugged multi-dimensional potential energy surface. On the other hand, the lowest energy states sampled (backbone RMSD = 5.7 A) are similar to a v-shaped helical conformation. These conformations have approximately 2 kcal/mol lower potential energies than the experimentally derived helical structures. Like those x-ray structures, they also have an apolar hydrophobic interface at one side and a polar hydrophilic interface at another side. However, these v-shaped helical conformations have more intrapolypeptide salt bridges on the hydrophilic side and are able to account for the energy decrease from the helical x-ray structures. Therefore, these conformations reflect the real global minimum energy structures for an isolated polypeptide with water simulated using molecular dynamics, but may deviate from the experimental global structures in a much more complex biological environment.

COMP 93 [832734]:  Catalytic dynamics of Escherichia coli Thioesterase/Protease I

Ching-Yu Chou, Department of Physics, National Taiwan Normal University, No 88 Ting-Chou Road Sec. 4, Taipei, Taiwan, Fax: +886-2-23919098,, Tai-Huang Huang, Institute of Biomedical Sciences, Academia Sinica, and Jung-Hsin Lin, School of Pharmacy, National Taiwan University, 12F No.1 Ren-Ai Road Sec. 1, Taipei, Taiwan, Fax: +886-2-23919098,

Thioesterase I (TEP-I) of Escherichia coli catalyzes the hydrolytic cleavage of fatty acyl-coenzyme A (CoA) thioesters, and it is also a serine protease of the SGNH-hydrolase family. The binding process of TEP-I with its inhibitor DENP (diethyl p-nitrophenyl phosphate) involves a fast formation of the Michaelis-Menten complex (MC) and a subsequent slow formation of the tetrahedral complex (TC). Because of this slow kinetic transition, TEP-I has been recognized as an excellent model system for investigating the fundamental properties of the catalytic intermediate states. However, there is so far no structure of MC solved by X-ray or NMR, and there is no experimental relaxation measurement of MC for other serine protease systems.

We have conducted explicit solvent molecular dynamics simulation of the apo form, MC, and TC of TEP-I with DENP for tens of nanoseconds. To analyze the overall motion and atomic fluctuation in the two-step catalytic process, we have calculated B-factor, dipolar nuclear relaxation order parameters, and the hydrogen bond network in the neighborhood of the oxyanion holes. The calculated B-factor profile of each residue is generally in good accordance with the X-ray result. Based on the molecular dynamics analysis, it is found that the loop near the catalytic triad Ser10 is mostly in disorder in TS, which is confirmed by the NMR nuclear relaxation experiments. We also found that most hydrogen bonds of the neighboring residue of the oxyanion hole Asn73 are rarely formed in the apo TEP-I. Our results indicate that the different serial states of the catalytic process may be characterized by the stability of the catalytic triad and the oxyanion holes.

COMP 94 [829893]:  In silico studies of DNA pol X support an induced-fit mechanism

Benedetta A. Sampoli Benitez, Department of Natural Sciences and Mathematics, Marymount Manhattan College, 221 E 71 st, New York, NY 10021,, Karunesh Arora, Department of Chemistry, New York University, and Tamar Schlick, Department of Chemistry, Courant Institute of Mathematical Sciences, and the Howard Hughes Medical Institute, New York University

DNA repair mechanisms are essential for maintaining genomic integrity. The African Swine Fever Virus (ASFV) polymerase X (pol X) belongs to the X-family of DNA polymerases and seems to be involved in base-excision repair. Kinetics studies have revealed that pol X has low fidelity with a specific preference for five base pairs including the four correct Watson and Crick base pairs and the GG mispair. Besides the NMR structure of the free pol X (with no bound DNA), no other structural data is available for this system. We performed molecular dynamics simulations on a modeled protein/DNA complex, both in the presence and in absence of the incoming nucleotide. When the correct dNTP is present, the protein undergoes a big conformational change, suggesting an induced-fit mechanism. Preliminary results on pol X /DNA complexes with mismatch base pairs (G-G, C-C and A-G) in the active site will be also presented.

COMP 95 [818369]:  Computational studies on biomolecules and reaction mechanisms

Russell J. Boyd, Department of Chemistry, Dalhousie University, Halifax, NS B3H 4J3, Canada, Fax: 902-494 1310,

The inestimable influence of John Pople on the evolution of computational quantum chemistry will be illustrated in the context of some of the recent research interests of my group. In particular, the broad scope and utility of current applications of density functional theory (DFT) methods for the study of the properties and reactions of biomolecules will be illustrated with examples that include, among other topics, model systems for intramolecular catalysis, short-lived radicals and oxidative damage. I will demonstrate that DFT-based methods can be applied successfully to a broad range of problems that remain beyond the scope of conventional electron-correlation methods. Furthermore, I will show that contemporary computational quantum chemistry complements experiment in the study of biological systems.

COMP 96 [818523]:  Alzheimer’s chemistry: Oxidation of methionine by copper(II)?

Arvi Rauk, Patrick Brunelle, Duilio Raffa, Rodolfo Gomez-Balderas, and Gail A. Rickard, Department of Chemistry, University of Calgary, 2500 University Dr. N.W, Calgary, AB T2N1N4, Canada, Fax: 403-289-9488,

The Radical Model of Alzheimer's disease (AD) is a hypothesis that provides a comprehensive description of the chemistry that underlies AD. The premise is that the seminal event leading to the death of neuronal cells is damage to neuronal cell membranes caused by free radicals that initiate lipid peroxidation. In the Radical Model, these radicals are long-lived, hydrophobic glycyl radicals or their peroxy derivatives that are carried into the membrane by oligomers of the amyloid beta peptide (Aβ) in β-sheet form. The glycyl radicals are secondary products of methionine oxidation by Aβ-complexed Cu(II). On the face of it, a cupric ion should not be able to carry out this key first step because of the apparent large disparity in the reduction potentials (E) of Cu(II) ions (E = 0.2 V vs SHE) and dialkyl sulfide radical cations (E = 1.6 V vs SHE). This presentation will examine, by means of high level quantum chemical calculations combined with continuum modeling of the aqueous environment, how the former may be raised and the latter may be lowered.

COMP 97 [845922]:  Lesions in DNA subunits: Radicals derived from the guanine-cytosine base pair

Partha Pratim Bera and Henry F. Schaefer III, Center for Computational Chemistry, University of Georgia, 1004, Sedar Street, Athens, GA 30602, Fax: (706) 542-0406,

The radicals generated by the homolytic cleavage of an X-H bond from the gas phase guanine-cytosine base pair were studied using carefully calibrated theoretical methods. The gradient corrected density functional B3LYP was applied in conjunction with double-zeta plus polarization and diffuse function basis sets, as described in Chem. Rev. 2002, 102, 231. The optimized geometries, energies and harmonic vibrational frequencies were obtained for all the radicals considered, and they were confirmed to be true minima in each case. Structural perturbations along with energy relaxation due to radical formation were investigated. Dissociation energies of the guanine-cytosine base pair and all the radicals are predicted and compared with the dissociation energy of neutral G-C. All the radicals, which are possible outcomes of direct ionizing radiation or oxidizing species, were investigated for the presence of local minima with significant structural changes. Major structural deformations cause strain in the interstrand hydrogen bonding in the DNA double helix. Severe geometry changes were observed when the hydrogen was abstracted from interstrand hydrogen bonding sites, along with sizeable amount of energy changes, indicating the potentially serious consequences to the guanine-cytosine base pair.

COMP 98 [819082]:  New force fields for biomolecular simulations: Better torsions and polarization through QC

Charles L. Brooks III, Molecular Biology, TPC6, Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037,

As a direct result of the many advances stemming from the extremely creative and productive career of John Pople and his collaborators and students over many years, the methods of quantum chemistry now provide practical tools in the development of models to study processes in complex biological systems. In this talk I will focus on two problems that were influenced strongly by my early interactions with John. The first is the development of coupled torsional potentials for the peptide backbone, having its roots in early collaborative studies between John Pople's group and my own. The second is the development of polarizable force fields for biomolecular systems, for which my involvement is also linked to early interactions between our respective groups. The development and implementation of backbone torsional maps based, in part, on energy surfaces computed from high-level quantum chemical models has significantly improved the accuracy of modern force fields. I will briefly review these advances. Similarly, the role of quantum chemical methods in the parameterization of polarizable force fields is critical in advancing modern polarizable force fields. I will describe our efforts in this area, citing examples that demonstrate new phenomena emerging from polarizable force fields for biomolecular systems.

COMP 99 [829323]:  MD simulations of 136 unique tetranucleotide DNA sequences

David L. Beveridge, Department of Chemistry and Molecular Biophysics Program, Wesleyan University, Lawn Avenue, Middletown, CT 06459, Fax: 860-685-2211,

Molecular dynamics (MD) simulations including water and counterions on B-DNA oligomers containing all 136 unique tetranucleotide base sequences obtained from a consortium of researchers. Calculations were carried out on the 136 cases imbedded in 39 DNA oligomers with repeating tetranucleotide sequences, capped on both ends by GC pairs and each having a total length of 15 nucleotide pairs. All MD simulations were carried out with a consensus protocol using the AMBER suite of programs and the parm.94 force field for 15 nanoseconds each. The simulation protocol, informatics issues, organization of the results into a data base, and preliminary results will be presented. of the project involves a total of ~ 0.6 ms of simulation for systems containing roughly 24,000 atoms. The resulting trajectories involve 600,000 coordinate sets and represent roughly 400 GB of data. The results are used to examine the effect of all possible sequence contexts on the dynamical structures of all 10 unique dinucleotide base pair steps. This project was initiated at a workshop meeting in Ascona Switzerland in June 2001 and the group is referred to as the Ascona B-DNA Consortium (ABC). Participants in this phase I project include Gabriela Barriero, K. Suzie Byun, David A. Case, Thomas Cheatham III, Surjit B. Dixit, Emmanuel Giudice, Filip Lankas, Richard Lavery, John H. Maddocks, Roman Osman, Eleanor Seibert, Heinz Sklenar, Gautier Stoll, Kelly Thayer, Péter Varnai, Matthew A. Young and DLB.

COMP 100 [819346]:  QM/MM studies of organic and enzymatic reactions

William L. Jorgensen, Department of Chemistry, Yale University, New Haven, CT 06520-8107, Fax: 203-432-6299,

Combined quantum mechanics and Monte Carlo statistical mechanics simulations are being used to study reaction mechanisms and the origin of solvent effects on reaction rates. The calculations have been highly automated with the BOSS and MCPRO programs; complete free-energy profiles with full sampling of solute and solvent coordinates can be obtained through one job submission. The reacting systems are typically represented using semiempirical PDDG/PM3 calculations and the environment is described by the OPLS-AA force field and TIP4P water model. Illustrative results will be presented for prototypical organic reactions including SN2, SNAr, Menshutkin, elimination, and Diels-Alder reactions, as well as enzymatic reactions catalyzed by chorismate mutase and macrophomate synthase.

Refs: J. Phys. Chem. B 106, 8078 (2002); J. Am. Chem. Soc. 125, 6663, 6892 (2003); 126, 9054 (2004); Org. Lett. 6, 2881 (2004).

COMP 101 [849889]:  Scholarly publishing at the crossroads: An overview of the Open Access publishing movement

Bill Town, Kilmorie Consulting, 24A Elsinore Road, London SE23 2SL, England,

Open Access – free online accessibility of research papers – is already one of the most heated in the field of scholarly communications and was recently the focus of a Parliamentary Inquiry in the UK. Open Access can be achieved in two ways: either author self-, institutional- or subject-based archiving of papers in parallel with publication in traditional subscription-based journals, or the conversion of journals themselves to a free-to-access business model, where costs are covered by payment on behalf of the author rather than on behalf of the reader. A historical overview of developments in Open Access will be given.

COMP 102 [852174]:  Twenty five years of progress in cheminformatics

Wendy A. Warr, Wendy Warr & Associates, 6 Berwick Court, Holmes Chapel, Cheshire CW4 7HZ, United Kingdom, Fax: +44-1477-533837,

Cheminformatics is characterized by a focus on the computer processing of databases of chemical structures, either in 2D or in 3D, but it cannot be studied in isolation from biological data handling systems, especially since the development of combinatorial chemistry and high throughput screening has led to an explosion in the volumes of chemical and biological data to be stored and analyzed. The discipline covers fields such as structure and substructure searching, similarity searching, clustering and diversity analysis, searching databases of reactions, synthesis design, 3D substructure searching, QSAR, and protein-ligand docking. Since he joined the University of Sheffield 25 years ago, Peter Willett has made significant contributions in most or all of these areas. This paper will consider not just his own contributions but the overall development of the discipline, with examples from papers published in the Journal of Chemical Information and Computer Sciences, a journal with which the author has been intimately involved since 1987.

COMP 103 [853125]:  Knowledge based screening

John Delaney, Jealott’s Hill Research Centre, Syngenta, Bracknell, RG42 6EY Berkshire, United Kingdom, Fax: 44 (0) 1344 455629,

This talk will focus on the use of large amounts of prior screen data to direct the acquisition of new high-throughput screen (HTS) compound input. The probabilities of new compounds being active can be estimated from their similarity to known actives and these probability estimates can be used to skew the HTS input towards more active areas of chemistry. The price paid for doing this is a considerable drop in the novelty/diversity of the input as it is dragged towards close analogues of well-worked chemical series. A rational way of trading off enhanced probability of activity against loss of novelty is required, since it is the product of the two that determines the lead generation capacity of the screens. A method for balancing these conflicting issues using the concept of information gain will be presented with an example of its use in a large compound acquisition exercise at Syngenta.

COMP 104 [853133]:  Multi-objective approaches to screening collection design and analysis of HTS data

Stephen Pickett, Cheminformatics, GlaxoSmithKline, Gunnels Wood Road, SG1 2NY Stevenage, United Kingdom, Fax: 01438 768232,

High-throughput screening and library design are the mainstay of lead discovery efforts in the pharma industry and the vast volumes of data generated provide a large resource for data mining. However, high-throughput screening is a highly complex process involving many stages and departments and its success depends critically on successful integration and, ultimately, the content of the screening collection. In this presentation we discuss the whole high-throughput screening process from screening collection design, library design, compound supply through screening to analysis at the chemist's desktop, examining the issues at each stage and some of the solutions put in place at GSK to improve the quality of the high-throughput screening process and the quality of leads that result. A novel approach to determine which compounds should enter the screening collection is presented and examples given of how this methodology can be combined with other design goals using multi-objective optimisation for library design. Methodologies developed to help chemists visualise and interpret the HTS results are discussed and examples from GSK screening campaigns will be used to highlight the specific issues discussed.

COMP 105 [834728]:  Characterization of non-biological antimicrobial polymers in aqueous solution and at water-lipid interfaces from all atom and coarse grained molecular dynamics

Ivaylo Ivanov1, Satyavani Vemparala1, Vojislava Pophristic2, Kenichi Kuroda3, William F DeGrado3, and Michael L. Klein1. (1) Department of Chemistry, University of Pennsylvania, 231 S. 34th Street, Philadelphia, PA 19104,, (2) Department of Chemistry and Biochemistry, University of the Sciences in Philadelphia, (3) Department of Biochemistry and Biophysics, University of Pennsylvania

We have applied molecular dynamics to investigate the structural properties and activity of recently synthesized amphiphilic polymethacrylate derivatives, designed to mimic the antimicrobial activity of natural peptides. The composition, molecular weight and hydrophobicity (ratio of hydrophobic and cationic units) of these short co-polymers can be modulated to achieve structural diversity, which is crucial in controlling the antimicrobial activity. We have carried out all-atom and coarse-grain molecular dynamics on a variety of systems to systematically investigate the conformations adopted by these copolymers in water and at the water-lipid interface as a function of sequence and the chemical nature of the monomers. We have observed the formation of strong interactions between the lipid headgroups and the amino groups of the polymers. Our results indicate sensitive dependence of the overall shape on the sequence, suggesting that experimentally observed changes in activity can be correlated with particular sequences, providing an avenue for rational design.

COMP 106 [833586]:  Coarse-grain molecular dynamics study of peptide nanotube insertion in lipid bilayers

Bernd Ensing, Center for Molecular Modeling, Department of Chemistry, University of Pennsylvania, 231 S. 34th Street, Philadelphia, PA 19104, Fax: 215-573-6233,, Steve O. Nielsen, Department of Chemistry, Center for Molecular Modeling, University of Pennsylvania, Preston B. Moore, Department of Chemistry & Biochemistry, Unveristy of the Sciences in Philadelphia, and Michael L. Klein, Department of Chemistry, University of Pennsylvania

Synthetic peptide nanotubes were recently demonstrated to have strong anti-microbial properties. The mechanism for their anti-bacterial activity is still largely unknown. Nanotubes have been proposed to disrupt the lipid bilayer via a carpet-like mode of membrane permeation. Alternatively, nanotubes can form trans-membrane multimeric entities that form nanopores which conduct water, ions and small molecules. To simulate the slow process of insertion of nanotubes from the aqueous phase into the membrane and the aggregation into multimeric entities, we apply a coarse-grain model. This allows us to study the nanotube behavior as a function of generic properties, such as the size, shape and hydrophobic/hydrophilic matching. We show that there exists a window within the nanotube properties for which it favors a trans-membrane orientation, with a small enough free energy barrier to allow membrane insertion. Lipid bilayer structural factors that play a role for the free energy profile are the alignment of the lipid tail in the neighborhood of the inserting nanotube and the formation of a meniscus in the lipid-water interface.

COMP 107 [832857]:  Dynamics of the full-length P-glycoprotein in the POPC bilayer

Hui-Hsuan Tu, School of Pharmacy, National Taiwan Normal University, Fax: +886-2-23919098,, and Jung-Hsin Lin, School of Pharmacy, National Taiwan University, Fax: +886-2-23919098,

The overexpression of P-glyoprotein (P-gp) is one of the major causes of multidrug resistance (MDR) in cancer chemotherapies. The reversing of the MDR effect has been achieved by designing many P-gp inhibitors, but the structure-based design of "P-gp-ignoring" therapeutic agents is still a remote goal. Until now, it remains very challenging to obtain the high resolution P-gp structure and currently only low resolution electron microscopy structure is available. The recent determination of both open- and close-form X-ray crystal structures of bacterial lipid A transporter, MsbA, has provided good structure templates for homology modeling of P-gp, because the sequence identity between MsbA and P-gp is about 31%.

We have conducted explicit solvent molecular dynamics simulations of the full-length efflux pump, human P-gp, in an excessively hydrated POPC bilayer. Both free and ATP-bound forms of P-gp were simulated. The major part of the starting structure of P-gp was constructed by homology modeling, while the segments of missing residues were predicted by ab initio loop construction methods. It is shown from the molecular dynamics that the overall architecture of P-gp remained very stable for tens of nanoseconds, while the observed membrane undulations were rather large. On the other hand, the root-mean-squared deviations of the final simulated molecular conformations compared to the original homology model were substantial, which indicates that molecular dynamics is capable of refining the homology model efficiently.

The simulation results have allowed us to investigate the conformational changes of P-gp upon ATP binding in the efflux process and to predict the possible binding site of various known substrates and inhibitors. The refined structure models of P-gp by our simulation will be used as the basis for further drug design.

COMP 108 [801417]:  Effects of initial radical damage in molecular dynamics simulations of a 1-palmitoyl-2-linoleyl-sn-glycero-3-phosphatidylcholine (PLPC) lipid bilayer

Patrick Brunelle, Gail A. Rickard, and Arvi Rauk, Department of Chemistry, University of Calgary, 2500 University Dr NW, Calgary, AB T2N 1N4, Canada, Fax: 403-289-9488,

Radical damage to lipids is a very significant biological process and is thought to be involved in Alzheimer's disease. Using high level ab initio calculation, the Gromos forcefield of the 9,12-cis-cis-bis-allylic section of linoleate was reparameterized to a pentadienyl-like radical to be used in molecular dynamics simulations. Thermodynamic perturbation was then used to study the transformation of one linoleic acid side chain of a lipid in a PLPC lipid bilayer to a pentedienyl-like radical. General and regional effects on physical properties of the bilayer will be presented. Environmental effects of the bilayer on the bond dissociation energy of the hydrogen in the 9,12-cis-cis-bis-allylic section of linoleate will also be discussed.

COMP 109 [799621]:  Implicit modelling of heterogeneous biological environments: Applications to integral membrane proteins

Michael Feig, Department of Biochemistry & Molecular Biology, Michigan State University, 218 Biochemistry Bldg, East Lansing, MI 48824, Fax: 517-353-9334,

A critical component in providing realistic simulations of biomolecules is the accurate description of their surrounding environment. Implicit models can account for the physical interactions with the environment based on a mean field approach in a very efficient manner and without the complexity of explicit environments. An extension of the generalized Born method is presented that permits the description of heterogeneous dielectric environments with a continuum model. This novel scheme is used for implicit modelling of biological membranes as a set of layered dielectric media with a low-dielectric hydrophobic core and an intermediate dielectric head-group region surrounded by high-dielectric aqueous solvent. The new method predicts the electrostatic solvation free energy in close agreement with numerical solution of the Poisson equation. The implicit model is tested with membrane insertion of small molecules and compared to explicit membrane simulations and experimental data.Its potential for studying membrane proteins is demonstrated with molecular dynamics simulation of selected integral membrane proteins.

COMP 110 [833095]:  Molecular dynamics simulations of membrane systems using non-additive force fields

Sandeep Patel, Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037,, and Charles L. Brooks III, Molecular Biology, TPC6, Scripps Research Institute

There has been significant progress towards the development of non-additive, or polarizable, force fields for biomacromolecular systems in the recent past. Our lab has been developing a polarizable protein force field which has been shown to be able to allow meaningful molecular dynamics simulations of solvated protein systems. The force field is being extended for application to the study of integral membrane proteins, and membrane systems in general. In particular, ion channels have been singularly pointed out as systems where a self-consistent treatment of non-additive effects of protein, solvent,and translocating ionic species might lead to more quantitative predictions of ion permeation via modeling methods. In this contribution, we will discuss the parameterization of a polarizable force field based on the charge equilibration scheme for the Gramicidin A system. In particular, we will present calculations of ion translocation energetics as embodied in the potential of mean force and compare to results from current non-polarizable (fixed-charge) force fields. We will also discuss properties of pure membrane systems as determined from molecular dynamics simulations of solvated DMPC bilayers; of interest are the prediction of NMR deuterium order parameters, as well characteristics of the interfacial region between lipid headgroup and solvent.

COMP 111 [833525]:  Molecular dynamics simulations of phospholamban: Effects of membrane, phosphorylation and aggregation

Krzysztof Kuczera1, Gouri S. Jas2, and Yao Houndonougbo1. (1) Departments of Chemistry and Molecular Biosciences, University of Kansas, 1251 Wescoe Hall Dr, Lawrence, KS 66045, Fax: 785-864-5396,, (2) Laboratory of Chemical Physics; Bldg. 5, Room 114, NIDDK, National Institutes of Health

We report results of molecular dynamics (MD) simulations of phospholamban (PLB), a 52-residue membrane protein that inhibits calcium ATPase in the cardiac sarcoplasmic reticulum. We have generated a series of 10 ns trajectories of PLB, including explicit solvent, counterions and long-range electrostatic interactions, presenting a microscopic description of PLB behavior under different conditions. Simulations indicate that PLB retains its helical secondary structure in solution and membrane bilayer, with transmembrane helix perpendicular to the bilayer plane. Internal dynamics of PLB involves hinge-bending, twisting and flexing of the two helical domains. Simulations of membrane-bound PLB phosphorylated at Ser-16 and Thr-17 yielded qualitatively similar structure and dynamics as regular PLB. Additionally, we simulated PLB pentamers in a membrane, where transmembrane helices formed stable left-handed coiled-coils. The simulation results are in good qualitative agreement with NMR data and fluorescence experiments, and provide interesting insights into the mechanism of ATPase regulation by the membrane protein.

COMP 112 [823915]:  Simulations of photofacilitated active transport in doubly illuminated photoactive liquid membranes

Teresa Longin1, Teresa Fraterman2, John Terhorst1, and Christopher Lang2. (1) Chemistry Department, University of Redlands, 1200 E. Colton Ave., P.O. Box 3080, Redlands, CA 92373-0999, Fax: 909-335-5312,, (2) N/A

We have conducted a series of simulations of transport in liquid membranes in which the carrier is photoactive, called photofacilitated liquid membranes. In photofacilitated membranes, transport is controlled with light, and such membranes can maintain active transport against a concentration gradient to purify and store solute. Typical photofacilitated membranes are either illuminated on the feed side of the membrane to enhance solute uptake or on the receiving side to speed up solute release. Our theoretical work explores a photofacilitated liquid membrane model in which both sides of the membrane are illuminated. Such doubly illuminated membranes exhibit enhanced solute transport and active transport abilities over singly illuminated membranes and membranes in the dark. In addition, doubly illuminated membranes demonstrate enhanced performance over a broader range of carrier properties than do singly illuminated membranes.

COMP 113 [829804]:  Self-assembly of peptide nanotubes by molecular dynamics study

Ekta Khurana1, Steve O. Nielsen1, Bernd Ensing2, and Michael L. Klein1. (1) Department of Chemistry, Center for Molecular Modeling, University of Pennsylvania, 231 S. 34th Street, Philadelphia, PA 19104-6323, Fax: 215-573-6233,, (2) Department of Chemistry, University of Pennsylvania

Cyclic peptide structures composed of an even number of alternating D- and L- amino acid residues can adopt a flat-ring conformation and stack to form a contiguous hydrogen-bonded hollow tube. Our initial characterization of self-assembly in polar versus non-polar solvents is performed with a dimer of the cyclo (L-Trp-D-Leu)4 rings. Six molecular dynamics simulations were carried out on both the uncapped and the methyl-capped dimers in water, nonane and a hydrated lipid bilayer (DMPC). The dimer remains stable even after a time period of 10 ns in a hydrophobic environment only when it is capped. In all other situations the two rings of the dimer fall apart and the rings no longer assume a flat conformation. The conformation of the rings (torsions) and number of hydrogen bonds between the two rings were analyzed. We also obtained free energy values for the dimerization process by steered molecular dynamics simulations of the capped dimer in nonane.

COMP 114 [826361]:  First-principles Monte Carlo simulations of liquid water in the isobaric-isothermal ensemble

Matthew J. McGrath1, J. Ilja Siepmann2, Will. I-F. Kuo3, and Christopher J. Mundy3. (1) Department of Chemistry, University of Minnesota, 207 Pleasant Street S.E, Minneapolis, MN 55455, Fax: 612-626-7541,, (2) Departments of Chemistry, Chemical Engineering and Materials Science, University of Minnesota, (3) Chemistry and Materials Science Directorate, Lawrence Livermore National Laboratory

The Quickstep energy routines of CP2K were used to perform Monte Carlo simulations of water in the isobaric-isothermal ensemble. Density functional theory (using the BLYP combination of exchange/correlation functionals) was employed using an atom-centered Gaussian basis set to represent orbitals and an auxillary plane wave basis set to expand the electronic density. Standard Monte Carlo moves (conformational changes, molecular translations, molecular rotations around the center of mass, and volume changes) were used to sample phase space. Results are presented for a system of 64 molecules at temperatures ranging from 273K to 323K and at atmospheric pressure. Several issues associated with first-principles simulations in ensembles with fluctuating volumes are also addressed.

COMP 116 [844909]:  The Pople years at Northwestern: A dynamicist learns electronic structure theory

George C. Schatz, Department of Chemistry, Northwestern University, Evanston, IL 60208-3113, Fax: 847-491-7713,

John Pople spent the last part of his career at Northwestern, and although he had few formal students during this period, he had significant influence nevertheless. Indeed, my own research program evolved during this time from a purely dynamics program based on potential energies borrowed from others to one where electronic structure calculations dominate my compute cycles. In this talk I will describe a few of the highlights of this process, including some recent studies of hyperthermal oxygen atom reactions and fracture mechanics where direct dynamics calculations have resolved important questions about problems where there is next to no experimental work.

COMP 117 [818538]:  Molecular potential energy surfaces

Michael A. Collins, Gloria E. Moyano, Christian R. Evenhuis, and Vitali Deev, Research School of Chemistry, Australian National University, Canberra 0200, Australia, Fax: 61-2-61250750,

Molecular potential energy surfaces which describe chemical reactions can now be constructed from ab initio calculations in an automated way, for molecules containing up to several atoms. The method, established and refined over the last decade, relies on interpolation of calculated ab initio data over the whole of the relevant space of molecular configurations. Recently, progress has been achieved on a similar approach to constructing the diabatic potential energy matrix that describes reactions which involve more than one electronic state. The current aim of this work is to develop methods which can produce chemically accurate energy surfaces for reactions of molecules with relatively large numbers of atoms. This talk will present the highlights of recent progress towards this goal.

COMP 118 [844933]:  Thermal reaction rates from higher derivatives of the flux-flux autocorrelation function at time zero

William H. Miller, Department of Chemistry, University of California, Berkeley, CA 94720, Fax: 510-642-6262,

The recent 'quantum instanton' model that has proved quite useful for computing thermal rate constants of chemical reactions is generalized by employing higher order derivatives of the flux-flux autocorrelation function at t = 0. [These are computed using recent developments by Doll and Predescu in Monte Carlo path integration for the Boltzmann operator.] Rate constants are obtained to better than 10% accuracy over a wide range of temperature.

COMP 119 [804637]:  Nakatsuji theorem, Nooijen conjecture, and constrained coupled-cluster theory

Werner Kutzelnigg, Department of Chemistry, Ruhr-Universitaet Bochum, Germany, D 44780 Bochum, Germany, Fax: +49 234 3214045,, and Debashis Mukherjee, Department of Physical Chemistry, Indian Association for the Cultivation of Science

The Hamiltonian H for an n-electron system in a finite one-electron basis of dimension m is characterized by d = O(m4) matrix elements. The eigenstates of this Hamiltonian, i.e. the full-CI states Y depend, however, on the usually much larger set of N= O(mn) parameters. Starting from a theorem by Nakatsuji, according to which it is sufficient for a full-CI wave function to satisfy a d-dimensional set of `contracted Schrödinger equations', Nooijen has proposed a d-dimensional parameterization of a full-CI state in terms of the so-called GCCSD ansatz. This ansatz cannot be exact, if one requires that the parameters in this ansatz are finite. A key feature is that the d-dimensional operator basis does not span a Lie algebra. An analysis of the GCCSD ansatz, including its reformulation to intermediate normalization, and its perturbative analysis, opens the possibility to consider a simplified `constrained' coupled-cluster ansatz, especially to express cluster operators of rank 3 and higher in terms of d parameters only.

COMP 120 [818579]:  Solving the Schroedinger equation for atoms and molecules

Hiroshi Nakatsuji, Department of Synthetic Chemistry and Biological Chemistry, and Fukui Institute for Fundamental Chemistry, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan, Fax: -81-75-383-2741,

To develop a general theory of solving the Schroedinger equation is a central theme of theoretical chemistry: it has a huge scientific and practical importance. Since 2000, we have investigated the structure of the exact wave functions and proposed the methods of solving the Schroedinger equation. For analytical solutions, the singularity problem caused by the nuclear and electron potentials was solved by introducing the scaled Schroedinger equation. We formulate the ICI (iterative CI) method as a general systematic method of calculating the exact wave functions of atoms and molecules in analytical forms. Applications to several atoms and molecules are satisfactory, showing a high potentiality of the proposed method.

COMP 121 [820050]:  Recent developments in geminal model chemistries

Vitaly A. Rassolov, Department of Chemistry and Biochemistry, University of South Carolina, 631 Sumter St., Columbia, SC 29208, Fax: 803-777-9521,

We present the latest developments and investigations of model chemistries based on strongly orthogonal geminals. In particular, we study bonding in transition metal bonds, such as metal hydrides and metal-metal bonds. The spin restricted and spin-unrestricted versions of these models are compared with each other.

COMP 122 [851730]:  Next step in the evolution of molecular alignment tools

Robert D. Clark, Edmond Abrahamian, Alexander Strizhev, Philippa R.N. Wolohan, and Charlene Abrams, Tripos, Inc, 1699 S Hanley Road, St. Louis, MO 63144, Fax: 314-647-9241,

The Genetic Algorithm Superimposition Program was developed a decade ago at the University of Sheffield by G. Jones, P. Willett and R.C. Glen as a deductive pharmacophore elucidation program. GASP used a GA to identify ligand conformations that maximize pharmacophoric compatibility and volume overlap with a template molecule, the end result being an alignment and an associated 3D query suitable for use in flexible pharmacophore searching. We have created a new program based on a new, more powerful GA that incorporates a true multiobjective fitness function rather than the weighted sum used by GASP. Pharmacophore and steric multiplet matching replace feature mapping and volume overlap calculations, which removes the need for any single molecule to serve as template and allows for generation of queries that include partial-match search constraints.

COMP 123 [853124]:  Gold and Silver development

Jason C. Cole1, J. Willem. M. Nissink1, R. Taylor2, and Frank H. Allen3. (1) Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB5 8QD, United Kingdom,, (2) CCDC, (3) Cambridge Crystallographic Data Centre (CCDC)

GOLD is a program for docking small molecules into protein active sites. SILVER is a tool for evaluation of docking results using user-defined sets of requirements. Recent developments to these two programs will be presented. The use of knowledge-based tools for the creation of test sets and for the evaluation of docking plausibility will be discussed.

COMP 124 [852410]:  Contribution of high-throughput docking to the drug discovery process

Eric Vangrevelinghe, Novartis Institute for Biomedical Research, WSJ-350.3.10, Lichtstrasse 35, Basel, Switzerland,

Due to the recent progress in the integration of structural genomics, including homology modeling and experimental 3D structure determination of relevant drug discovery targets, the impact of structure-based in silico screening techniques is increasing rapidly within pharmaceutical industry. In this respect and given the availability of Linux clusters and Grid computing platforms, High-Throughput Docking (HTD) have matured during the last years to become reliable, inexpensive, and fast method for hit and lead finding which complement traditional High-Throughput Screening.

Browsing among compound libraries, HTD aims for the focused selection of hit candidates which most likely bind to the active site of a target, based on the 3D structural hypotheses of ligand-receptor interactions provided by structural biology. Only compounds with the highest docking score, which reflects the complementarity with the active site, are then actually biologically tested for confirmation. There are many possible cases in which HTD can contribute to the drug discovery process, from hit identification in early stage of a project to lead finding when diverse and targeted virtual combinatorial libraries are screened to improve the affinity and/or ADME profile of a known active compound. A review on several different applications of HTD at Novartis will be given.

COMP 125 [852409]:  Molecular similarity approaches for chemoinformatics

Peter Willett, Department of Information Studies, University of Sheffield, Western Bank, Sheffield S10 2TN, United Kingdom,

This paper reviews the author's studies over some three decades into the use of measures of inter-molecular structural similarity in chemoinformatics. The applications that are discussed include reaction indexing, pharmacophore matching, database clustering, diversity analysis and virtual screening; with the similarities involving the comparison of 2D fingerprints, of chemical graphs, of inter-atomic distances, and of molecular field descriptors. The combination of 2D fingerprints with a simple association coefficient, normally the Tanimoto Coefficient, is by far the most commonly used measure of molecular similarity, but is still capable of much further development. Current work in Sheffield on fingerprint-based virtual screening involves the comparison of different similarity coefficients, the use of data fusion to combine database rankings produced by different similarity measures, and similarity measures that are appropriate when multiple bioactive reference structures are available.

COMP 126 [834119]:  A computer-aided molecular design approach for the design of organic molecules (solvents) for crystallization

Arunprakash T. Karunanithi1, Shanthakumar Sithambaram2, Luke E. K. Achenie3, and S. L. Suib2. (1) Department of chemical Engineering, University of Connecticut, 191 Auditorium Road, U-3222, Storrs, CT 06269, Fax: 860-486-2959,, (2) Department of Chemistry, University of Connecticut, (3) Department of Chemical Engineering, University of Connecticut Storrs

Organic solvents play a very important role in many chemical processes. For these processes solvents need to have lot of desirable characteristics (properties) as well as be environmentally benign. Organic chemists play an important role in synthesizing new chemical molecules having desired properties. The experimental approach is very time consuming and expensive. Here we present a computer aided molecular design (CAMD) approach for modeling the solvent design problem. Promising molecules having desired properties are designed which serve as a guide to help the chemists to synthesis these molecules.

Crystallization is one of the key unit operations in the chemical processing industry. For example in the manufacture of pharmaceuticals, the high molecular weight chemicals are recovered as pure solids from impure solutions via crystallization. Solvent plays an important role in the crystallization process and its selection affects the success or failure of the operation. Moreover in the biopharmaceutical industry new drugs are constantly being discovered and a good solvent may not be on the list of common solvents. This paper explores a systematic computer aided design strategy for the design of organic crystallization solvents. The strategy employs molecular structural groups within the mathematical programming model. In our approach, in addition to solubility, many other factors such as solvent effect on crystal habitat, solvent ability to solubilize impurities, solvent inflammability, solvent toxicity and solvent viscosity are considered. In the mixed integer non-linear programming (MINLP) model, the percentage recovery is an appropriate performance objective function. This optimization problem is solved by a decomposition-based methodology to determine the optimal solvent.

Three solvent design case studies involving two different types of crystallization operations, namely cooling crystallization and drowning out crystallization are presented.

COMP 127 [820274]:  CQFF (Consistent Charge Equilibration with general Force Field)

Osamu Kitao, Energy Technology Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba Central 5, 1-1-1 Higashi, Tsukuba 305-8565, Japan, Fax: +81-29-861-4574,, and Tetsuji Ogawa, Center for Collaborative Research, AdvanceSoft

We proposed a concept, consistent charge equilibration (CQEq) [Mol. Phys., 101, 3 (2003)], which uses completely same electrostatic energy expressions for both charge and gradient calculations for all types of atom including hydrogen case. By combining the CQEq method with general force field like AMBER and UFF, we developed the CQFF: CAFF (CQEq with AMBER) and CUFF (CQEq with UFF). We confirmed the CQFF can well describe the several kinds of chemical bonding for large systems like nano-materials and bio-systems with realistic computational time by optimizing atomic parameters for the electrostatic field based on the high-quality ab initio calculations concerning the representative molecules and systems. To accelerate the CQFF calculations, we tried to use Newton-Raphson method and quasi-Newton one to solve the CQEq equation. We report the calculation data, especially computation time and the calculation quality comparing ab initio calculation cases.

COMP 128 [831124]:  Free energy profile along a discretized reaction path: Computational approach and examples

Konstantin N. Kudin, Princeton Institute for Science and Technology of Materials (PRISM), Princeton University, Bowen Hall, Princeton, NJ 08544,

I will discuss the details of the free energy integration along a discretized reaction path specified as a sequence of hyperplanes. The profile is obtained as an integral of two components. The translational component of the free energy is computed by integrating the hyperplane constraint force. The rotational component arises due to the changes in the hyperplane orientation, and is evaluated via the hyperplane torque. Both ingredients - the constraint force and the hyperplane torque - are evaluated independently on each hyperplane. Examples of free energy profiles for chemical reactions obtained via such an approach in constrained Car-Parrinello molecular dynamics simulations are presented.

COMP 129 [827764]:  Interpreting carcinogen benzo[a]pyrene's effects on transcription initiation-required TATA/TBP binding using molecular dynamics simulations

Qing Zhang, Department of Chemistry, New York University, 31 Washington Place, Rm. 1021 Silver, New York, NY 10003, Fax: 212-995-4152,, Suse Broyde, Department of Biology, New York University, and Tamar Schlick, Department of Chemistry, Courant Institute of Mathematical Sciences, and the Howard Hughes Medical Institute, New York University

The TATA-box Binding Protein (TBP) is required by eukaryotic RNA polymerases for correct transcription initiation and binds to an 8-basepair DNA promoter element - TATA box. Benzo[a]pyrene (BP) is a widespread environmental chemical carcinogen which can be metabolically converted to DNA-reactive enantiomeric (+) and (-)-anti-BPDEs. The recent experimental study (Rechkoblit et al. 2001 Biochemistry 40, 5622-5632) of a pair of stereoisomeric adenine adducts, derived from (+) and (-)-anti-BPDEs, has shown how these lesions influence the TATA/TBP binding. Our molecular dynamics simulations reveal that BP's location determines whether the stability of TATA/TBP complexes is increased or decreased. The effect on binding stability can be interpreted in terms of conformational freedom and major-groove space available to BP due to the hydrogen bonds and inserted phenylalanines of the TATA/TBP complex. The unraveled structures and interactions thus suggest how transcription initiation may be affected by the presence of a bulky BP.

COMP 130 [833192]:  Molecular dynamics simulations of DNA/Polyamide complexes in the crystal environment

Anne Loccisano, Center for Computational Sciences, Duquesne University, Department of Chemistry and Biochemistry, 600 Forbes Avenue, Pittsburgh, PA 15282, Fax: (412)396-5683,, Sarah A. Mueller-Stein, Department of Chemistry and Biochemistry, Center for Computational Sciences, Duquesne University, Steven M. Firestine, Mylan School of Pharmacy, Duquesne University, and Jeffrey D. Evanseck, Department of Chemistry & Biochemistry and Center for Computational Sciences, Duquesne University

Minor groove binding polyamides that bind predetermined sequences of DNA offer one approach to artificial gene regulation. However, targeting some sequences is difficult, which is likely due to sequence-dependent structural variations of the minor groove. Molecular dynamics simulations provide a useful method of understanding these structural variations at the atomic level; however, in order to obtain accurate results, the system must be properly equilibrated. We are interested in understanding how to properly equilibrate and treat these types of systems in MD simulations. In order to evaluate our methodology, six simulations in the crystal environment have been performed for 2ns each. The Watson-Crick hydrogen bond distances and the helical parameters have been monitored and compared to the starting X-ray crystal structure in order to determine when these properties converge. The information gained from our simulations will provide a detailed understanding of how to properly treat and equilibrate these types of systems.

COMP 131 [825705]:  Molecular dynamics study of slow base flipping in DNA using conformational flooding

Benjamin Bouvier, Theoretical and Computational Biophysics Department, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Goettingen, Germany, Fax: +49-551-201-2302,, and Helmut Grubmüller, Theoretical molecular biophysics group, Max Planck Institute for biophysical chemistry

Individual DNA bases are known to flip out of the helical stack, spontaneously or under the action of enzymes. Molecular dynamics studies of this process have thus far employed umbrella sampling along a predefined reaction coordinate. In contrast, conformational flooding enables one to predict conformational transitions without prior knowledge of pathways. It identifies possible product states beyond barriers larger than the thermal energy, using a coarse-grained collective coordinate description of the free energy landscape. Transition to these products is facilitated by an artificial destabilizing potential. A flooding potential was devised to drive a single base out of the stack. Local minima (partially open states) were identified along the opening pathway and ‘filled' with additional flooding potentials. Analysis of the pathway provided insight into the underlying driving forces of base flipping and the associated free energy cost.

COMP 132 [834717]:  Monte Carlo simulations of polymer-carbon dioxide phase equilibria

Collin D. Wick, Chemical Sciences Division, Pacific Northwest National Lab, 906 Battelle Blvd., MS K1-83, Richland, WA 99352,, J. Ilja Siepmann, Departments of Chemistry, Chemical Engineering and Materials Science, University of Minnesota, and Doros N. Theodorou, Department of Mat. Sci. and Engineering, National Technical University Athens

Supercritical carbon dioxide has tremendous potential as a versatile, environmentally benign process solvent. The biggest factor hindering its wide use is its low solvent power, requiring the addition of surfactants to enhance the solubility of polar solutes. While partially fluorinated surfactants possess desirable solubility characteristics, their cost is prohibitive and their environmental impact is not fully understood. Therefore, the development of cheaper and more benign hydrocarbon-based polymeric surfactants is highly viable.

Monte Carlo simulations were performed to determine the phase equilibria of both poly(ethylene oxide) and ether-carbonate copolymers with carbon dioxide. The simulations required the parameterization of a carbonate force field, and the use of a combination of advanced Monte Carlo techniques. Results show that Monte Carlo can be used to predict polymer-carbon dioxide phase equilibria, and the data obtained from the simulations can provide valuable microscopic insight.

COMP 133 [832040]:  Relating local energetic roughness and kinetic rates: All-atom accelerated molecular dynamics of cis/trans isomerization of serine-proline motifs

Donald Hamelberg1, Tongye Shen2, and J. Andrew McCammon1. (1) Howard Hughes Medical Institute, Department of Chemistry and Biochemistry, University of California at San Diego, 9500 Gilman Drive, Mail Code 0365, La Jolla, CA 92093-0365, Fax: 858-534-4974,, (2) Department of Chemistry and Biochemistry, University of California at San Diego

Complex systems are often characterized by rough and complicated energy landscapes with high barriers, and the transitions over these barriers are infrequent. Even though they are rare, such transitions play a central role in conformational switching in biomolecules. However, many of these slow transitions cannot be simulated directly using traditional molecular dynamics (MD) because of nanosecond timescale limitations. We show that our MD approach can accelerate the conformational transitions and extend the time scale in all-atom simulations of biomolecules. We also show that this technique allows for the thermodynamic and kinetic rate information to be recaptured. In deducing the kinetic rates, the relationship between the local energetic roughness of the energy landscape and the effective diffusion coefficient is established. We do not only recapture the slow kinetic rate information of the isomerization of serine-proline motifs, but also obtain the underlying local roughness of the energy landscape at atomistic resolution.

COMP 134 [830932]:  Semiclassical scattering on conical intersections

Andrei Piryatinski1, Misha Stepanov1, Sergei Tretiak2, and Vladimir Chernyak3. (1) Theoretical Division, Center for Nonlinear Studies, Los Alamos National Laboratory, MS B258, Los Alamos, NM 87545, Fax: 505- 665-2659,, (2) Theoretical Division, Los Alamos National Laboratory, (3) Department of Chemistry, Wayne State University

The problem of nonadiabatic vibrational dynamics in the vicinity of the electronic energy surface crossing is a key to understanding of variety of fundamental processes in photochemistry including radiativeless energy relaxation and photoisomerization in (bio)molecules. To address the problem, advanced theoretical methods have been developed and implemented as numerical techniques. In this contribution we focus on the photoexcited wavepacket scattering problem in the vicinity of conical intersection, and demonstrate that simple analytical expressions for the scattering matrix can be obtained in the semiclassical approximation. Simplicity of the latter expressions allow us to develop a clear quantitative picture of the photochemical processes taking place near the level crossing surface. This picture is verified using the numerical simulations, and good agreement is found for the realistic set of parameters. Therefore, it is now feasible to implement our computational method into the large scale molecular dynamics simulations significantly reducing the computational costs.

COMP 135 [830557]:  Behavior of a Brownian particle in a nonstationary medium

Alexander V. Popov and Rigoberto Hernandez, School of Chemistry and Biochemistry, Georgia Institute of Technology, 770 State st, Atlanta, GA 30332-0400,

The generalized Langevin equation (GLE) governs the dynamics of particle's motion in liquids in stationary conditions. To include irreversible processes which can take place in a solvent, the GLE was recently extended to its irreversible form, iGLE. The iGLE takes into account the nonstationarity of the solvent response characterized by the multiplier g(t) which defines the amplitude of the random force, thus producing a multiplicative noise. Until now there were neither experimental, nor simulation results confirming the appropriateness of the iGLE. In the present work we perform extensive numerical calculations, including MD and MC simulations, to prove the applicability of the iGLE for thermodynamically equilibrated systems. First of all, we consider the motion of a heavy Brownian particle immersed in a nonstationary colloidal suspension. The latter is represented as a bath of hard spheres which are growing with time. Then we analyse the behaviour of a Brownian particle in a Lennard-Jones fluid with the changing Lennard-Jones radius. The conclusion is that the iGLE in its memory-less form (specific for a Brownian particle) describes the particle's motion correctly. We also found the form of the function g(t) which is shown to be dependent only on the macrostate of the bath. It allowed us to calculate the velocity autocorellation functions directly from the iGLE. This approach is applied to investigate the anomalous properties of the diffusion in changing media.

COMP 136 [810910]:  Melting and superheating of FCC metals at high heating rates

Xin Liu, Changgong Meng, and Changhou Liu, Department of Chemistry, Dalian University of Technology, P.O.Box 288, Dalian 116024, China, Fax: 86-411-84701090,

Melting of solid is one of the most common observations of a phase transformation, but its mechanism is still unknown. In this work, several systems of NPT ensemble were simulated with Molecular-Dynamics method. QSC Force-Field was applied to study the heating-rate induced melting and superheating of Pb, Ag, Cu, Ni, Al, Cu-Ni alloy. Simulations were started from a cubic cell at different heating rates to a temperature higher than the melting point. Results showed the melting of superheated metals are kinetic processes and can be explained with homogeneous nucleation model. The upper-limit of heating-rate-induced superheating is the temperature at which the energy barrier of melting can be overcame by randomization generated during heating. Defects' effect was also studied. And results showed though defect sites exist, the melting temperature rises with increasing heating-rate. This shows apart from defects, heating-rate is still a factor determines the melting temperature of these FCC metals.

COMP 137 [819245]:  Gaussian-weighted RMSD superposition of proteins

Kelly L. Damm and Heather A. Carlson, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, College of Pharmacy, 428 Church St., Ann Arbor, MI 48109-1065,

Superposition of two structures using a simple RMSD fit is a useful tool for comparing protein crystal structures. For proteins with similar conformations, this procedure works well. However, many proteins contain a rigid core region and flexible structures such as loops or even whole domains. Consequently, an alignment can be skewed by the difference between the dynamic regions.

We have developed a novel method to overlay two proteins by their C-alpha coordinates that incorporates a Gaussian-weighting function. The algorithm is based on the Kabsch least-squares method and estimates an optimal transformation between two molecules by minimizing the weighted sum of the squares between the two coordinate sets. Atoms that move only slightly will have a greater weighting than those with larger changes. This method removes the subjective nature of overlaying user-defined core regions of flexible proteins because it does not require any prior knowledge of the protein structure and its dynamic movement. Our superposition tool has been applied to many dynamic proteins for which two conformations are identified and has produced successful alignments. The transformation calculation is heavily weighted by the coordinates of the static region of the two conformations; hence the extent of the motion in the flexible region is more obvious.

COMP 138 [819163]:  Binding MOAD (Mother of All Databases)

Mark L. Benson1, Liegi Hu2, Richard D. Smith3, Michael G. Lerner3, and Heather A. Carlson2. (1) Bioinformatics Program, University of Michigan, Ann Arbor, 2017 Palmer Commons, 100 Washtenaw Ave., Ann Arbor, MI 48109-2218,, (2) Department of Medicinal Chemistry, University of Michigan, Ann Arbor, (3) Biophysics Research Division, University of Michigan, Ann Arbor

We strive to make Binding MOAD (Mother of All Databases) the largest collection of high-quality, protein-ligand complexes available from the Protein Data Bank. At this time, Binding MOAD contains well over 5,300 protein-ligand complexes comprised of ~2100 unique protein families and 2,660 unique ligands. We have searched the crystallography papers for all 5000+ structures and compiled binding data for ~1400 (26%) of the protein-ligand complexes. The binding-affinity data ranges 13 orders of magnitude.

To create a non-redundant dataset, one protein from each of the 2090 protein families was chosen as a representative. Representatives were chosen by tightest binding, best resolution, etc. For the 2090 “best” complexes that comprise the non-redundant version of Binding MOAD, 574 have binding data. This significant collection of protein-ligand complexes will be very useful in elucidating the biophysical patterns of molecular recognition and enzymatic regulation. The complexes with binding-affinity data will help in the development of improved scoring functions and structure-based drug discovery techniques.

COMP 139 [819142]:  Database mining to characterize protein-ligand binding sites

Richard D. Smith, Biophysics Research Division, University of Michigan, Ann Arbor, 4028 Chemistry Building, 930 North University Avenue, Ann Arbor, MI 48109-1055,, Nickolay Khazanov, Bioinformatics Program, University of Michigan, Ann Arbor, and Heather A Carlson, Department of Medicinal Chemistry, The University of Michigan

The biological function of many proteins depends on their ability to recognize and bind small molecules. In addition to natural substrates, many drugs are small molecules that take advantage of binding events to inhibit or activate a protein as necessary. The Carlson group has developed BindingMOAD, a comprehensive database of high-resolution crystal structures of protein-ligand complexes. BindingMOAD contains ~5400 structures, comprised of ~2100 unique proteins. The binding sites have been analyzed for amino acid content, geometry, atomic contacts, ligand volume, binding site volume, and degree of solvent exposure. These are then compared to the large number (1300+) of Ki, Kd, or IC50 values, which are also included in MOAD, to correlate the size and makeup of the binding site with the binding affinity.

COMP 140 [853206]:  Creating a smart virtual screening workflow: Application of E. coli DHFR primary HTS data

Shikha Varma1, Luke S. Fisher2, Teresa A. Lyons2, and Deqi Chen3. (1) Accelrys, Inc, 9685 Scranton Road, San Diego, CA 92121, Fax: 858-799-5100,, (2) Lead Identification and Optimization, Accelrys Inc, (3) Accelrys

Dihydrofolate reductase (DHFR) is a small protein whose activity is critical for DNA synthesis. DHFR is the target for at least four drugs on the market whose benefits range from antibiotic to anticancer. The protein uses a cofactor (NADPH) to accomplish the reduction of dihydrofolate to tetrahydrofolate. Consequently, its binding pocket is large, making it a challenging target for virtual high throughput screening. This study presents a workflow that was developed based on duplicate primary screening inhibition data against E. coli DHFR of a diverse 50,000-compound library containing only 32 active inhibitors. The methods are rapid and work easily with large data files and interpretable descriptors to remove much of the inactive compounds from the dataset. The protocol highlights applications of raw data analysis and recursive partitioning followed by docking and scoring for significantly improved enrichment over docking and scoring alone. In this case, eliminating many false positives prior to vHTS/scoring not only substantially decreases the amount of data analysis required, it also results in almost a half of the actives being represented in the top 1% of the ranked compounds.

COMP 141 [831046]:  Omega2: Conformer generation redux

Matthew Stahl and Geoffrey Skillman, OpenEye Scientific Software Inc, 3600 Cerrillos Road, Suite 1107, Santa Fe, NM 87507,

Reproducing experimentally determined bioactive structures directly from a connection table is a challenging problem. Great care must be taken in representing the chemistry correctly, and choosing an appropriate model environment. This paper will cover a set of validation studies that provide confidence limits and strain energy guidelines when modeling ensembles of conformations. Applications to lead discovery and ligand design are included.

COMP 142 [830037]:  SAESAR: Shape and electrostatics in structure activity relationships

Norah E. MacCuish1, Anthony Nicholls2, and John D. MacCuish1. (1) Mesa Analytics & Computing, LLC, 212 Corona St., Santa Fe, NM 87501, Fax: 509-472-8131,, (2) OpenEye Software

Shape and electrostatics have proven to be integral in understanding activity relationships. We explore a variety of ligand/target complexes and develop strategies for the use of shape and electrostatics in QSAR-like predictive modeling through the software workbench, SAESAR.

We find that careful attention to the details of each complex, such as chemical properties, binding affinities, and tautomers, goes a long way towards developing a successful model. We explore a taxonomy of complexes and the development of their respective models.

COMP 143 [821810]:  Efficient charges: Optimal ligand charges for binding that might actually work

Anthony Nicholls1, Sharangdhar Phatak2, and Glen E. Kellogg2. (1) OpenEye Scientific Software Inc, 3600 Cerrillos Rd., Suite 1107, Santa Fe, NM 87507,, (2) Department of Medicinal Chemistry and Institute for Structural Biology & Drug Discovery, Virginia Commonwealth University

Lee and Tidor have shown how the Linearized Poisson-Boltzmann equation permits the calculation of an "optimum" set of atomic charges for a ligand bound to a protein. Here, the balance between favorable Coulombic attraction and unfavorable ligand/protein desolvation is most shifted towards attraction. In theory, this provides a road-map towards high affinity in ligands of a given shape and binding location. In practise, there are significant issues, including the construction of a real molecule that indeed has these charges. In addition, there is no guarantee that a minimum in the binding potential actually exists. The sum of charges may be absurd. Charges on individual atoms may exceed what is physically possible. Finally, even with the preceding satisfied, the molecule may be too polar to be bio-available. We present a simple, physical, adjustment to the Tidor model that appears to overcome these issues.

COMP 144 [830350]:  Shape and electrostatic similarity across a large-scale database of vendor-available compounds

Robert Tolbert, OpenEye Scientific Software, Suite 1107, 3600 Cerrillos Road, Santa Fe, NM 87507, Anthony Nicholls, OpenEye Scientific Software Inc, Geoff Skillman, OpenEye Software, and Mike Tennant, Pharmix

Finding compounds that exhibit similar shape and electrostatic profiles to an active or set of active compounds is an effective way to extend activity to new chemical classes. We show here that such searches are feasible across a collection of several million compounds and discuss the characteristics of the hits returned from so large a search (2.7M unique compounds, 700M conformations). It is found that, in most cases, between a 100 and a 1000 close morphologs can be found. In addition, the high-degree of shape similarity returned greatly enhances the chances of concomitant electrostatic similarity, which can be enhanced further by local conformational expansion. Given that our database is constructed from readily-available sources, this appears to be a practical strategy for computer-assisted primary or secondary screening.

COMP 145 [835091]:  Structure-based design, molecular modeling and biophysical studies of conformation adopted by tetrapeptides with inhibitory activity for thrombin

Cristina Clement1, Janet Gonzalez1, Rafael Alcantara1, and Manfred Philipp2. (1) Chemistry Department, Lehman College, City University of New York, 250 Bedford Park BLVD West, Bronx, New York City, NY 10468,, (2) Chemistry Department, Lehman College and Biochemistry Ph.D. Program, City University of New York

A structure-based design of a library of tetrapeptides containing the sequence space DPhe/X(P3)-L-Pro(P2)-D-Arg(P1)-P1' was employed to dicover potential inhibitors for thrombin (X= analogs of Phe, such as constrained analogs (L)/(D)-Tic [1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid]). The peptides were docked into active site of thrombin by taking the X-ray coordinates of thrombin template 1ABJ.pdb using the software “SCULPT” provided by MDL and built-in molecular mechanics (MM) force-field to assess the free energy of interaction between the peptides and the protein target. The advanced MM3 force-field was used to minimize individual tetrapeptides and the backbone dihedral angles phi and psi were predicted to favor in most cases beta turns and beta hairpin conformation. Circular dichroism investigations were confirming that the D-Arg- in i+2 position followed by D-amino acids (polar and neutral hydrophobics like D-Thr, D-Gln, D-Ser and D-Ala) or L-Pro in i+3 position favors beta turn structures (I and III) in solution at low and neutral pH. Replacement of D- with L-amino acids in i+3 position was accompanied by a significant lost in the beta turn structure with a shift toward an unorganized or poly-Pro-II helix-like structure. SAR (structure-activity relationship) suggests that tetrapeptides which adopt beta turn or beta hairpin conformation in solution are more active toward inhibiting thrombin.

COMP 146 [818190]:  Rapid evaluation of compound oral bioavailability using in vitro and in silico ADME properties

S. Frank Yan, Kaisheng Chen, Lana Schaffer, Min Wu, and Yingyao Zhou, Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, Fax: 858-812-1570,

The pharmacokinetic (PK) properties of a drug, including absorption, distribution, metabolism, and excretion (ADME), are of critical importance to its bioactivity.  Oral bioavailability (%F) is an important parameter used to evaluate compound pharmacokinetic characteristics.  However, traditional in vivo bioavailability test in lower animals is inherently slow, labor-intensive, and not amenable to automation; this has become the bottleneck of compound PK assessment.  On the other hand, in vitro and in silico studies of compound physicochemical properties (e.g. solubility, pKa, etc.) and ADME properties (e.g. metabolic stability, permeability, etc.) are fast and readily amenable to automation, which is particularly important in the current high-throughput environment of drug discovery.  It has become increasingly important to efficiently predict compound oral bioavailability from in vitro and/or in silico properties using computational methods albeit the complex nature of this in vivo process.  In this study we carried out c2 analyses of various in vitro and in silico properties of ~250 compounds from a number of in-house projects for their filtering power to eliminate compounds with poor oral bioavailability (%F<20).  Decision tree and support vector machine (SVM) methods using those properties were also employed to estimate the bioavailability.  It has been found that the best in vitro/in silico parameter(s) determined for elimination of poorly bioavailable compounds are clearly target-specific, which may indicate certain level of similarity among the compounds in each individual project.  In addition, we noticed that application of multiple in vitro/in silico properties in c2 analysis can improve the filtering power.  We provided a simple statistical method for fast evaluation of in vivo bioavailability of a compound using in vitro and in silico physicochemical and ADME properties.  This may help limit the number of compounds being tested in live animals and improve the pace of drug discovery process. 

COMP 147 [829700]:  Role of quantitative structure activity relationship (QSAR) in understanding HIV-1 binding domain and designing protease inhibitors

Barun Bhhatarai and Rajni Garg, Department of Chemistry, Clarkson University, 8 Clarkson Avenue, Potsdam, NY 13699-5812,

A QSAR study has been made on different series of 4-OH-2-pyranones acting as HIV-1 protease inhibitors. Supported by several QSAR, our results suggests that the inhibitory activity of the compounds has significant correlation with the parabolic ClogP, calculated log of octanol/water partition coefficient, a measure of hydrophobicity of the molecule. Hydrophobic interactions play crucial role in the inhibition of HIV-1 protease enzyme since its binding site has a hydrophobic binding domain. However, the site seems to have an optimum size as indicated by the presence of parabolic ClogP. These new results confirm our earlier findings that the insufficient spread in the substituents' hydrophobicity is one of the reasons for absence of hydrophobic term in many QSAR. Designing molecules with enough wide range of ClogP value would firmly establish the optimum point and help in understanding interactions of these ligands within HIV-1 binding domain.

COMP 148 [803425]:  Three for three: De novo design of multiple novel chemotypes of T-type calcium channel blockers

Daniel L. Cheney1, Jon J. Hangeland2, Todd J. Friends2, and Paul C. Levesque3. (1) Department of Macromolecular Structure, Bristol Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, Fax: 609-818-3545,, (2) Cardiovascular Discovery Chemistry, Bristol-Myers Squibb, (3) Cardiovascular Diseases, Bristol-Myers Squibb Pharmaceutical Research Institute

An increasing body of evidence suggests that selective T-type calcium channel blockers may be clinically efficacious in the treatment of hypertension and angina pectoris while incurring significantly fewer side-effects than current therapies involving blockade of the L-type calcium channel. In this report, we describe the de novo design of novel, selective, and synthetically accessible T-type calcium channel blockers. Prototype molecules are generated by the program Sprout using a pharmacophore model derived from ComFA, small molecule crystal data, and high-quality quantum mechanical conformational energy surfaces. Output structures were iteratively refined into drug-like chemotypes, representatives of which were synthesized and found to exhibit moderate to high potency in in-vitro assays.

COMP 149 [830414]:  Towards the solution structure of a “mini-insulin”

Julien Pecher1, Guillaume Le Flem2, Patrick Bogdanowicz2, Jean-Pierre Pujol2, David A. Case3, Jacques Rochette1, and Francois-Yves Dupradeau4. (1) DMAG EA 3901 INERIS, Faculte de Pharmacie et de Medecine, Amiens, France, Fax: 33-3-22827469, (2) LBTC EA 3214, Faculte de Medecine, Caen, (3) Department of Molecular Biology, The Scripps Research Institute, (4) DMAG EA 3901 INERIS & The Scripps Research Institute, Department of Molecular Biology, 10550 N. Torrey Pines Road, La Jolla, CA, Fax: 1-858-784-8896,

Previous studies in our laboratory have demonstrated that an insulin A-chain analog presents similar functional properties to insulin in vitro. In this derivative, the cysteines 7 and 20 implied in the two interchain disulfide bridges have been replaced by two serines, and the intra-A-chain disulfide bridge has been reconstituted. In aqueous solutions, the structure of this oligopeptide remains unknown because of its aggregation property observed over time. Consequently, the folding and structure of this peptide have been studied by Molecular Dynamics using the Generalized Born implicit solvation model implemented in the AMBER8 program. Starting from an extended conformation, a stable tertiary structure for this A-chain analog close to that observed in native insulin is detected. The disulfide bridge strongly stabilizes the central loop, and the two characteristic alpha helices are formed. These results confirm that the isolated A-chain can spontaneously adopt its tertiary structure. The tridimensional structure observed could be the one which interacts with the insulin receptor and raises the fundamental question of the role of the B-chain in insulin.

COMP 150 [829048]:  Towards validation of a model to identify hERG potassium channel blockers

Laura C. Van Zant, A. Michiel van Rhee, Neil A. Castle, and Christopher P. Silvia, Icagen, Inc, P.O. Box 14487, Research Triangle Park, NC 27709, Fax: 919-941-0813, lvanzant@icagen.comPharmaceutical compounds that block the hERG potassium channel have been associated with an increased risk of adverse cardiac side effects. (Redfern, WS, et al., Cardiovascular Research 58 (2003) 32-45.)Therefore, the identification of likely hERG channel blockers early in the discovery process would be invaluable to the pharmaceutical industry. Herein is described an in silico method based upon recursive partitioning (RP) for the prediction of hERG activity. Using experimental high-throughput screening data (22,299 compounds), an ensemble of RP models was built by varying conditions for the tree generation steps and for the descriptor selection. The predictions from multiple trees were combined to construct consensus models that were used to enhance the predictive power of the models. A validation set of compounds was identified through virtual screening, acquired, and then screened to establish the actual predictive power of the model. Approximately half of the compounds in the validation set were determined to have considerable hERG blocking activities.

COMP 151 [824453]:  A complete model of human type I collagen monomer

Ivan Vinogradov, Darren J. Anderson, and M. Cynthia Goh, Department of Chemistry, University of Toronto, 80 St. George St., Toronto, ON M5S 3H6, Canada, Fax: 416 978 4526,

Collagen is an abundant extra-cellular protein with a unique triple helical structure and an ability to self-assemble into several different aggregates. Understanding this process has been impeded by the lack of a complete 3D structure, which has been impossible to obtain using current experimental techniques. Therefore, a model of human type I collagen was created containing both backbone and side-chain atoms using a reduced rotamer representation derived from a statistical analysis of previously solved structures. Minimization was performed using molecular mechanics and dynamics simulations both in-vacuo and with water as solvent. The final structure provides information about detailed geometry of the monomer unit, determined to within 0.5 A, and other characteristics including bulk properties and surface charge distribution.

COMP 152 [834895]:  Ab initio protein loop prediction in internal coordinate space

Jianghong An1, Maxim Totrov2, and Ruben Abagyan1. (1) Department of Molecular Biology, The Scripps Research Institute, 10550 Torrey Pines Road, La Jolla, CA 92037,, (2) Molsoft LLC

Accurate native conformation prediction of structurally variable regions (SVRs) or loops is a bottleneck of comparative protein structure modeling. There are database (knowledge) based and ab initio approaches for loop prediction. The database-based approach is not suitable for longer loops due to the difficulty of finding the candidate segments. On the other hand, the ab initio approach requires an accurate energy function and an efficient conformational sampling strategy. In this presentation, we will present an ab initio all-atom loop prediction algorithm, optimal-bias Monte Carlo minimization algorithm, which performs local minimization after each random step and uses a priori information about local probability distributions to minimize the number of random steps to the global minimum. A history-feedback mechanism was used during the simulation to enhance the global optimization efficiency. The system is represented in internal coordinates and the implicit solvent method was used. The success of the algorithm is demonstrated by: 1) accuracy of prediction on a benchmark set consisting of 450 loops ( loop length from 4 to 12 residues, 50 loops for each range); 2) comparison with other five recently published methods; and, 3) homology modeling examples in different sequence identities.

COMP 153 [816281]:  Characterization of drug and drug carrier interactions by using computational chemistry and X-ray crystallography

Lingyun Xiao, Department of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin at Madison, 777 Highland Avenue, Madison, WI 53705,, Ronald R. Burnette, School of Pharmacy, University of Wisconsin - Madison, and Ilia A. Guzei, Department of Chemistry, University of Wisconsin-Madison

A methodology combining computational chemistry with X-ray crystallography was developed to characterize the interactions between drugs and drug carriers. The crown ether/metal ion system was selected as an excellent, simple model system representing drug/drug carrier system. In this methodology, the molecular mechanics was employed to generate a conformer distribution, which can serve as a starting point for quantum mechanical simulation and calculation. The complexation energies between crown ethers and lithium ions were computed at HF, DFT and MP2 theory levels. The natural bond orbital (NBO) analysis was applied for orbital interaction study. The experimental verification of the theoretical results was accomplished through X-ray diffraction experiments. The crystal structures of crown ether/lithium perchlorate complexes were achieved, and correlated with the gas-phase calculations. The NBO analysis was also utilized to study the packing forces in crystal unit cells, in order to investigate the differences between crystal structures and gas-phase optimal structures.

COMP 154 [832850]:  Comparative analysis of putative agonist binding modes in the human A1 adenosine receptor

Hugo Gutiérrez de Terán, Cell and Molecular Biology, Uppsala University, Husargatan 3, Uppsala, Sweden, Fax: +46 18 53 69 71,, Johan Ĺqvist, Cell and Molecular biology, Uppsala University, and Ferran Sanz, Research Group on Biomedical Informatics, IMIM / University Pompeu Fabra

A recent study reported a model of the human A1 adenosine receptor and its agonist binding site, proposing two putative binding modes in the same binding site for the natural agonist, adenosine.1 The present work investigates the flexibility of this binding site by exhaustive exploration with the natural agonist and with three other adenosine derivatives: N6-cyclopentyladenosine (CPA), 2-chloro-N6-cyclopentyladenosine (CCPA), and 5'-N-ethylcarboxamidoadenosine (NECA). Our aim was to find a common binding mode for agonists that would explain the role in the binding process of the different substitutions allowed at the 2, N6, and 5' positions of adenosine. This problem was addressed through docking simulations, molecular dynamics studies, and estimations of the ligand-binding free energy with both the AUTODOCK scoring function2 and the linear interaction energy (LIE) approach.3 The results point to a single receptor-binding position that explains the effects of the different chemical modifications on the adenosine derivatives considered here.


1.    Gutierrez de Teran, H, et al. Proteins 2004, 54, 705

2.    Morris, G.M. et al. J. Comp. Chem. 1998, 19, 1639

3.    Ĺqvist, J. et al.. Prot. Eng. 1994, 7, 385

COMP 155 [826531]:  Comparative QSAR as a cheminformatics tool in the design of HIV-1 protease inhibitors

Rajni Garg, Department of Chemistry, Clarkson University, 8 Clarkson Avenue, Potsdam, NY 13699-5810, Fax: 315-268-6610,, and Barun Bhhatarai, Chemistry, Clarkson University

Cheminformatics encompasses the design, organization, storage, management, retrieval, analysis, dissemination, visualization and use of chemical information. Various tasks involved in Cheminformatics are data mining, docking, pharmacophore mapping, structure/sub-structure searching, tools & approaches for predicting activity and never the less defining quantitative structure-activity relationships (QSAR). Comparative QSAR (CQSAR) organizes QSAR from cheminformatics point of view. A new QSAR validated by CQSAR plays important role in predicting the interaction of parameter important in structure modification of drug molecule. Several series of the dihydropyranones, an important class of HIV-1 Protease Inhibitors (HIV-PI) were studied, and QSAR models were developed. Comparative QSAR analyses of these models provide valuable insight in understanding complex receptor-ligand interactions. It is envisioned that the results of this study will also provide important leads in the development of suitable more potent drug candidates and prove the role of CQSAR as cheminformatics tool in the drug design.

COMP 156 [811677]:  De novo structure-based design of ion receptors

Benjamin P. Hay and Alexander A. Oliferenko, Pacific Northwest National Laboratory, PO BOX 999, Richland, WA 99352, Fax: 509-375-4381,

Over the past several years we adapted the concepts embodied in de novo structure-based drug design to allow the computer-aided design of host architectures that are organized for the complexation of cations or anions. This adaptation required methods for (i) building candidate structures and (ii) evaluating and prioritizing these structures with respect to their binding affinity for a specific guest. This poster summarizes recent progress in this area including the creation of a computer software program, HostDesigner, which is capable of generating and evaluating millions of new molecular structures per minute on a desktop personal computer ( Initial screening, which is based on geometric parameters, yields a list of candidates for further evaluation. HostDesigner has been integrated with molecular mechanics software to automate two subsequent screening stages. In stage one, up to 5000 host structures are evaluated and ranked with respect to host-guest binding energies. In stage two, up to 500 host structures are conformationally searched to give a final ranking with respect to both the binding energy and the degree of host preorganization.

COMP 157 [832612]:  DNA and estrogen receptor interaction revealed by the fragment molecular orbital calculation

Toshio Watanabe1, Yuichi Inadomi1, Shigenori Tanaka2, Kaori Fukuzawa3, Tatsuya Nakano4, Lennart Nilsson5, and Umpei Nagashima1. (1) Grid Technology Research Center, National Institute of Advanced Industrial Science and Technology and CREST-JST, 1-1-1 Umezono, Tsukuba 305-8568, Japan,, (2) Kobe University, (3) Mizuho Information & Research Institute, (4) National Institute of Health Sciences, (5) Karolinska Institute

The interaction analysis between the estrogen receptor (ER) and DNA has been carried out by using the fragment molecular orbital (FMO) method. The FMO-HF/6-31G and STO-3G calculations of the complex between the estrogen response element of DNA (DNA-ERE) and the DNA-binding domain of ER (ER-DBD) reveal roles for the Zn-finger motifs in the DNA-binding of the ER-DBD and in the dimerization of ER-DBD. The electrostatic interaction between the positive charges on ER-DBD and the negative charges on phosphate groups is the largest interaction between DNA-ERE and ER-DBD, but analysis of the electrostatic potentials shows the interaction does not concern to the sequence specific binding of ER-DBD. The weaker interaction between the α-helix and the base pairs concerns to them. The drastic changes of the charge distribution on the Zn-finger motifs induced by dimerization and by DNA binding indicate importance of the flexible electronic state on the Zn-finger motifs.

COMP 158 [833261]:  Hierarchical QSAR (HiQSAR) approach to predicting dermal penetration

Brian D. Gute1, James Riviere2, Ronald E. Baynes2, and Subhash C. Basak1. (1) Center for Water and the Environment, Natural Resources Research Institute, University of Minnesota, 5013 Miller Trunk Hwy, Duluth, MN 55811, Fax: 218-720-4328,, (2) College of Veterinary Medicine, North Carolina State University

Since dermal exposure is one of the primary workplace exposures, predictive models for dermal permeability are invaluable. Such models can aid in our understanding of the chemicals that actually penetrate the stratum corneum and become bioavailable after dermal exposure. Riviere et al have developed a new model for skin permeability and the modeling team at NRRI has begun to use their data in developing computationally predictive models for membrane permeability. Exploratory QSAR modeling has been conducted using a series of organochlorines. Membrane permeability is in strong agreement with the lipophilicity of these compounds. Preliminary hierarchical QSAR (HiQSAR) modeling has resulted in adequate models of compound diffusion through the permeable membrane (Q2 = 0.81), but further modeling is being conducted to attempt to refine the models. In addition to various topostructural and topochemical indices, a number of descriptors of molecular shape, size, and electronic character are being examined.

COMP 159 [826746]:  Low-resolution modeling of the ribosome assembly of the 30S subunit by molecular dynamics simulations

Qizhi Cui and David A. Case, Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, Fax: 858-784-8896,

Molecular dynamics (MD) simulations have been performed on the 30S subunit of the ribosome from T. thermophilus in hundred nanosecond time scale with the AMBER8 molecular modeling package. The system is represented in a low resolution level by 4181 pseudoatoms. Each nucleotide is represented by a single pseudoatom (P-atom) centered on the phosphate atom and each amino acid residue is represented by a single pseudoatom (C-atom) centered on the α carbon atom. A number of pseudoatoms (X-atoms) are placed in the middle in the helical regions of the RNA to prevent helix interpenetration.

Our MD simulations provide dynamic views on the assembly of the 30S subunit. The ribosomal protein binding events and the 16S RNA conformational changes are explored. We found that ribosomal proteins play critical roles in the assembly. Protein binding changes the RNA conformation and helps to maintain the RNA around its crystal structure. We observed that at early stage of the assembly, each domain (5', central or 3') is more independently assembled and at a later stage, more domain interactions are involved and help to finalize the assembly. We also observed that the ribosomal proteins bind to the RNA in certain orders as shown in the Nomura ribosome assembly map. Our simulations produce qualitatively consistent results with experimental findings and provide insights on the mechanisms of the ribosome assembly of the 30S subunit.

COMP 160 [827525]:  Modeling and predicting the structure of G-protein-coupled receptors

Mayako Michino, Wonpil Im, Jianhan Chen, and Charles L. Brooks III, Department of Molecular Biology, TPC-6, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037,

G-protein-coupled receptors (GPCRs) are a large and functionally diverse superfamily of integral membrane proteins that play a key role in signal transduction. Their amino acid sequences are characterized by seven hydrophobic segments that are known to form a seven-transmembrane-helix bundle in three-dimensions. Due to the difficulty in crystallizing integral membrane proteins, high-resolution structures exist for only one GPCR, bovine rhodopsin, and there has been much effort in using this structure as a model to predict the structure of other GPCRs. Building such homology models has been limited by the need to represent the membrane environment and the necessity of efficiently sampling alternative conformations in correctly "rebuilding" helix-helix interface regions. To provide a baseline for our homology modeling, we have explored using an implicit membrane generalized Born model together with replica-exchange molecular dynamics simulations with system-specific distance restraints derived from experiments or sequence analysis.

COMP 161 [829278]:  Modeling human K+ channel and exploring ligand binding using molecular dynamics

Fredrik Österberg, Department of Cell and Molecular biology, Uppsala University, Husargatan 3, 75124 Uppsala, Sweden, Fax: (0)18 - 530396,, and Johan Ĺqvist, Cell and Molecular biology, Uppsala University

The potassium hERG channel has become a very important target for drug studies because of its unintended drug interactions. Drugs easily bind the channel and results in blocking the cardiac hERG channel which induces a QT interval prolongation in the electrocardiogram, which can be lethal. The result of blocking the hERG channel has led to an interest of exploring the structure and to be able to design new drugs that don't interact with the channel in an unwanted way. At present state there's no crystallographic structure of the hERG channel so the first step is to make a set of protein models. To these models we have automatically docked a set of ligands with different binding affinity. Finally we run molecular dynamics on the docked complexes to get the relative binding energy. By this we can validate our hERG model against experimental IC50 values and try new drugs against hERG.

COMP 162 [831620]:  Modeling peptide association in amyloid-forming peptides

Ronald D. Hills Jr., Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., TPC-6, La Jolla, CA 92037, Fax: 858-784-8688,, and Charles L. Brooks III, Department of Molecular Biology, TPC-6, The Scripps Research Institute

Serrano et al. designed a series of hexapeptides predicted to form homopolymeric beta-sheets, a subset of which formed amyloid fibrils in vitro [Lopez de la Paz et al. (2002) PNAS 99:16052-7]. Interestingly, peptides that aggregated as beta-sheets did not necessarily form amyloid-like structures. It was found that peptides containing charged residues only formed fibrils in cases where the net molecular charge was +/- 1. In this study, molecular simulations were employed to further rationalize the differences in the abilities of these peptides to form amyloid fibrils. Specifically, molecular dynamics simulations were performed using a generalized Born implicit solvent model in order to study the mechanism and thermodynamics of peptide self-association. Different sized oligomeric complexes of these peptides were simulated to measure the cooperativity in the enthalpy of binding successive peptides.

COMP 163 [833107]:  Modulation of steric forces in the minor groove of DNA

Sarah A. Mueller-Stein, Department of Chemistry and Biochemistry, Center for Computational Sciences, Duquesne University, 600 Forbes Avenue, 308 Mellon Hall, Pittsburgh, PA 15282, Fax: 412-396-5683,, Anne Loccisano, Center for Computational Sciences, Duquesne University, Steven M. Firestine, Mylan School of Pharmacy, Duquesne University, and Jeffrey D. Evanseck, Department of Chemistry & Biochemistry and Center for Computational Sciences, Duquesne University

Free energy perturbation has been applied to study the influence of steric forces in the minor groove of a 15 base pair oligonucleotide, sequence 5' TCGCATCGCATGTAT 3'. The balance between electrostatic effects and steric forces in DNA bending have been investigated previously. Hud et al. showed that ammonium ions were localized in the A-tract of an oligonucleotide. The localization of the ammonium ions occurred at locations of greatest bending in the oligonucleotide. Thus, the coordination of ions in a sequence specific manner may account for A-tract bending. Modification of a central guanine residue allows the insertion of pure steric force in the minor groove, without direct variation in electrostatics. The minimum change in free energy required to bend DNA by steric forces in the minor groove has been calculated.

COMP 164 [830830]:  Molecular dynamics simulations of a RNA-morpholino hybrid

Edmond Y. Lau, Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, 7000 East Ave L-448, Livermore, CA 94550,, and Michael E. Colvin, School of Natural Science and Engineering, University of California

A molecular dynamics study has been performed on a RNA-morpholino hybrid. The hybrid molecule is stable over the duration of the simulation and retains the A-form starting structure. The hydration around this hybrid molecule differs significantly from RNA. The solvent is less structured around the hybrid molecule. Although the average structure of the hybrid molecule is A-form, the morpholino backbone affects the shape and solvent exposure of the minor groove. This work was performed under the auspices of the United States Department of Energy by the University of California, Lawrence Livermore National Laboratory under contract number W-7405-ENG-48.

COMP 165 [809441]:  Molecular dynamics simulations of human tRNALys,3UUU anticodon stem-loop: Determination of the role of nonstandard bases

Nina E. McCrate1, Mychel E. Varner2, Katie L. Schembri2, Amanda E. Combs2, and Maria C. Nagan2. (1) Division of Science, Truman State University, 100 East Normal, Kirksville, MO 63501, Fax: 660-785-4045,, (2) Science Division, Truman State University

Accuracy in translation of the genetic code into proteins depends upon correct recognition of messenger RNA codons by their cognate transfer RNA (tRNA) anticodons. Within tRNAs, incorporation of posttranscriptionally modified bases is common; however, the roles of these chemical modifications are poorly understood. In human tRNALys,3UUU three modified bases, ms2t6A37, mcm5s2U34, and ψ39, contribute to tRNA-mRNA recognition. To gain a better understanding of the biological and structural roles of modified bases in the human tRNALys,3UUU anticodon stem-loop, molecular dynamics (MD) simulations of nine tRNA anticodon stem-loops with different combinations of modified bases were performed. MD simulations were carried out using the SANDER module of AMBER. From analyses of the trajectories, it was found that both ms2t6A37 and mcm5s2U34 contribute as hydrogen-bond donors and acceptors within the loop suggesting that the tertiary structure of the loop may be determined by interactions with these bases.

COMP 166 [827575]:  Predictor@home: A multiscale, distributed approach for protein structure prediction

Chahm An, Michela Taufer, and Charles L. Brooks III, Department of Molecular Biology, TPC-6, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, Fax: 858-784-8688

A multi-step protocol for protein structure prediction including secondary structure prediction, low-resolution conformational sampling, and all-atom structure refinement and scoring has previously been developed. Although the all-atom CHARMM/GBMV force field performs well in the scoring and refinement stages of the protocol, a major bottleneck exists in the limited ability to sample native-like protein conformations. To address this issue, we have assembled a “structure prediction supercomputer” based on volunteer resources and a distributed computing platform over the world-wide-web. With this distributed platform, conformational sampling was increased by 1-2.5 orders of magnitude to generate a wide range of low energy protein folds. Structures generated from the sampling step are further refined and evaluated through the distribution of all-atom CHARMM tasks. The large number of candidate structures are then clustered and scored to determine the best structures. This structure prediction framework, named Predictor@home, was tested on 67 structures in the CASP6 experiment.

COMP 167 [810386]:  Accurate prediction of binding sites for diverse protein targets using fragment-based grand canonical Monte Carlo Simulations

Suo-Bao Rong, Ted Fujimoto, Jennifer Ludington, Brian Alger, Igor Shkurko, Matthew Clark, Jeffery S. S. Wiseman, and Frank P. Hollinger, Locus Pharmaceuticals, Inc, 512 Township Line Road, Four Valley Square, Blue Bell, PA 19422, Fax: 215-358-2020,

The identification of active sites or binding sites of a protein is an essential problem of structure-based drug design. The grand canonical Monte Carlo (GCMC) simulation developed and patented by Locus Pharmaceuticals uses a variety of fragments as probes to identify binding sites of a protein. This approach has been widely applied to identify binding sites in diverse protein targets, including caspase-3/8, EPSP synthase, DNA gyrase, Map kinase P38, and glycogen synthase kinase 3. Several recent examples confirm the ability of the approach to not only accurately identify the binding sites previously reported in crystal structures, but to predict novel binding sites which were not reported, but eventually confirmed by experiment. Generally, ten small hydrophobic and hydrophilic organic fragments and water are used as standard probes. Water mainly functions as a detector of specific highly hydrophilic regions required by the protein for structure or function which may compete with other fragments for binding. The other 10 fragments act as probes to explore hydrophobic and hydrophilic sites to uncover molecular interaction elements. Experiments with different numbers of probe fragments of varied sizes reveal two features of the approach: the number of fragments used to probe does not influence the identified binding sites, whereas the fragment size does change the resulting binding sites if the probe fragments used are too large. Most importantly, this approach creates a functionality map and characterizes the physiochemical property space for further structure-based de novo drug design and ADME(T) optimization.

COMP 168 [819211]:  Incorporating protein flexibility into drug design: HIV-1 protease as a test case

Kristin L. Meagher1, Michael G. Lerner2, and Heather A. Carlson1. (1) Department of Medicinal Chemistry, University of Michigan, Ann Arbor, 428 Church Street, Ann Arbor, MI 48109,, (2) Biophysics Research Division, University of Michigan, Ann Arbor

Traditionally, structure-based drug design (SBDD) is based on a single X-ray structure of a protein target complexed with a known ligand. However, using a single protein conformation provides little information on protein dynamics or the conformational changes of both ligand and protein upon binding. Therefore new techniques are needed to push the frontiers of SBDD by incorporating ensembles of protein conformations to more accurately simulate the inherent motion of the system and the potential induced fit between ligand and protein.

Our method creates receptor-based pharmacophore models based on multiple protein structures (MPS), an ensemble of conformations to represent protein flexibility. To elaborate the generality of this method, we have applied it to unbound structures of HIV-1 protease (HIV-1p). Using molecular dynamics (MD) simulations to generate the MPS, we have developed pharmacophore models of the semi-open, un-complexed HIV-1p. Our models succeed in discriminating known ligands from drug-like non-inhibitors in a system that is highly dependent on protein flexibility. Here, we examine the influence of using MPS from independent MD simulations based on three different apo crystal structures.

COMP 169 [803532]:  Protein ensemble docking: Comparison of fixed charge and polarizable forcefields in scoring

Luciano Mueller and Daniel L. Cheney, Department of Macromolecular Structure, Bristol Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000,

Computational capacity has increased dramatically over the last decade making possible the use of more sophisticated and computationally intensive methods in computer-assisted drug design. As capacity continues to grow and algorithms become more efficient, those in the molecular computational community are faced with the enviable challenge of how to best to utilize this new potential. In this report, we show that existing docking programs generally perform poorly in terms of binding pose prediction in real-world settings, i.e., cross-docking multiple ligands into a single rigid protein. For example success rates even for relatively easy targets such as thrombin and factor Xa were typically 50% or less. We explore a general strategy for lead docking which utilizes representative conformational ensembles of target proteins. The docked poses are further refined and re-scored using fixed charge or polarizable forcefields in the presence of a solvent model. We show that this protocol can lead to dramatic improvements in both sampling and scoring over conventional single rigid protein docking, regardless of the docking program or target.

COMP 170 [827057]:  Strategies for efficient ligand-receptor docking: Typical case studies

Akbar Nayeem and Stanley Krystek Jr., Computer-Assisted Drug Design, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, NJ 08543-5400, Fax: 609-818-3545,

Flexible ligand docking requires thorough sampling of the conformational space of the ligand in the context of the receptor binding site. This often results in docked poses that are conformationally unrealistic. For example this is true when the ligand to be docked involves rings which the docking program cannot treat flexibly. Most of the computational efforts to date have been aimed at improving the ligand conformational sampling. We propose here a novel protocol whereby a multi-conformational database of plausible ligand conformations is rigidly docked to protein receptor. Comparison of the rigid versus fully flexible ligand docking will be discussed.

COMP 171 [830909]:  Virtual screening approach: Application of a hydropathic forcefield to 3D database searches

Micaela Fornabaio1, Fraydoon Rastinejad2, Shilpa Kharalkar1, Martin Safo1, Donald J. Abraham1, and Glen E. Kellogg1. (1) Department of Medicinal Chemistry and Institute for Structural Biology & Drug Discovery, Virginia Commonwealth University, Box 980540, Richmond, VA 23219-1540, Fax: 804-827-3664,, (2) Department of Pharmacology, University of Virginia Health Sciences Center

The aim of our work is to develop new computational tools for virtual screening. We have been using pharmacophoric generation/3D database searching tools in combination with the HINT (Hydropathic INTeractions) software in a number of studies. Because the HINT score is based on experimentally determined partition coefficients between 1-octanol and water, LogPo/w, it is directly related to DG of binding. We have shown that 1 kcal mol-1 corresponds to about 500 HINT score units. The search for i) new and innovative ligands that bind to the nuclear hormone receptor FXR (farnesoid X receptor), a bile acid sensor coordinating cholesterol metabolism, and ii) novel selective effectors for RPK (human erythrocyte pyruvate kinase), an allosteric glycolytic enzyme, will be presented. Results obtained by applying the HINT scoring function to evaluate the interaction between the proteins and the small molecule hits from the 3D database searches against the NCI database will be shown.

COMP 172 [819199]:  Docking studies and ligand recognition in folypolyglutamate synthetase

Xiao-Jian Tan and Heather A. Carlson, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, College of Pharmacy, 428 Church St., Ann Arbor, MI 48109-1065,

In both bacteria and eukaryotes, folypolyglutamate synthetase (FPGS) catalyzes the addition of the glutamate to folate, forming gamma-linked polyglutamate folates of different lengths. In the X-ray crystal structure of the L. casei FPGS complex, only part of 5,10-methylenetetrahydrofolate (TMF) ligand has been determined, and it is in a non-productive binding mode. Additionally, there is no structural evidence of where the attacking L-glutamate is bound. To understand how this protein is capable of accommodating ligands of different length and net charge, we have performed docking studies for folate substrates and glutamate based on the X-ray crystal structure of L. casei FPGS. Our docking results suggest two possible locations for folate binding in the active site, the one seen in the complex structure and another distinct cavity. According to our model and experimental studies, it is highly probable that folate can bind in both sites, and we suggest that binding in the new pocket would be especially meaningful for the initial addition of the first glutamate residue. The binding site for the attacking glutamate was also found by docking glutamate to the structure. The location we have determined is consistent with several mutagenesis studies. Another interesting result is that both diglutamate and triglutamate folates can dock in similar conformations that imply a common transition state. The transition-state like conformation may help us to understand the mechanism of the ligation reaction. However, it is still not clear how longer polyglutamate folates are bound, and further studies are needed.

COMP 173 [834034]:  Docking to large ensembles of homology models reliably explains the substrate binding differences in Cytochrome P450 1As of human and fish species

Jahnavi C. Prasad, Bioinformatics, Boston University, 48 Cummington Street #110/117, Boston, MA 02215, Fax: 617-353-4814,, Carlos J. Camacho, Center for Computational Biology and Bioinformatics, University of Pittsburgh, John J. Stegeman, Department of Biology, Woods Hole Oceanographic Institute, and Sandor Vajda, Department of Biomedical Engineering, Boston University
Experimental evidence suggests that 3,3'-4,4'-TetraChloroBiphenyl (TCB) is metabolized 50-300 times faster in human Cytochrome P450 1A1 than in the fish CYP 1A. In order to understand the structural basis of this difference, TCB was docked to large numbers of homology models of the two enzymes, retaining multiple ligand conformations from each model. We observed with very high statistical significance that TCB tends to dock closer to the Heme ring in human CYP1A1 than in fish CYP1A. This may explain the observed difference in the metabolic rates as well as the release of reactive oxygen species (ROS) observed in the fish when metabolizing TCB. Further analysis identified the putative residues and the structural reasons determining this specificity. When another compound Benzo[a]pyrene (BAP) was docked, the numbers of BAP orientations agreed remarkably well with the experimentally determined ratios of corresponding metabolites. Such an application of docking to study metabolite distributions is novel.

COMP 174 [832988]:  Computational prediction of structure, substrate binding mode, mechanism and rate for a malaria protease with a novel type of active site

Sinisa Bjelic, Dept. of Cell & Molecular Biology, Uppsala University, Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden, and Johan Ĺqvist, Cell and Molecular biology, Uppsala University

Starting from the primary amino acid sequence we homology modeled the 3D structure of a histo-aspartic protease from the malaria parasite Plasmodium falciparum against plasmepsin II. With this model structure, a peptide substrate is docked in the active site and through molecular dynamics simulations together with the empirical valence bond method the postulated reaction mechanism is verified.

Understanding enzyme catalyzed reaction mechanisms is invaluable for efficient drug design and our studies show that when there is no known structure the vast amount of data generated from genome sequencing projects can be used with available computational methods to predict both structure and function of enzymes.

COMP 175 [833844]:  A structure-based approach to Akt/PKB inhibition

Dawoon Jung, Martino Forino, and Maurizio Pellecchia, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037,

In order to identify potential PKB inhibitors, we adopted a structure-based approach that takes advantage of the available 3D structure of PKB and virtual docking techniques. Initially, we docked the entire Chembridge (San Diego, CA, USA) collection (50,000 compounds, Diverse Set) by using the software FlexX (Biosolve, Sankt Augustin, Germany). The top 4,000 scoring compounds (using drug-score) were selected and further examined using several strategies that included the use of additional scoring functions, such as Gold-score and Chemscore (CSCORE, Sybyl, Tripos). For each strategy, 100 to 200 compounds were selected and experimentally tested for PKB inhibition in an enzymatic assay. Results will be presented in terms of hit rate and the inclusion of H-bonding properties in the selection process. Three compounds with IC50 values comparable to the only known inhibitor (H-89) were obtained and their potencies confirmed in a number of different assay.

COMP 176 [833451]:  Docking of phthalate monoesters to PPAR-ă

Taner Kaya, Bioinformatics Prog, Boston University, RM 107, 44 Cummington St, Boston, MA 02215, Fax: 617-353-4814,, Scott C. Mohr, Department of Chemistry, Boston University, David J. Waxman, Department of Biology, Boston University, and Sandor Vajda, Department of Biomedical Engineering, Boston University

Phthalate esters, ubiquitous environmental contaminants used as plasticizers, exert toxicity toward various tissues by processes involving peroxisome proliferator activated receptors (PPARs). Molecular docking and free energy calculations were performed to identify novel phthalate ligands of PPAR-γ. The method was validated by docking known ligands and the calculations correctly reproduced the binding orientations of several full agonists of PPAR.Results were improved introducing a more accurate scoring function based on the all-atom molecular mechanics potential CHARMM and a Generalized Born/Surface area solvation term (ACE). Comparison of the lowest CHARMM/ACE energy of each phthalate vs. the logarithm of the EC50 value for PPAR trans-activation, determined experimentally, yielded a good correlation. Thus, we can distinguish PPAR-γ non-binding phthalates from PPAR-γ binding phthalates. A screen of mono-ortho phthalates represented in the ACD identified several putative binders, including known PPAR agonists. These findings support the use of computational methods to identify environmental chemicals.

COMP 177 [818347]:  Quantitative structure–activity relationship analysis of pyridinone HIV-1 reverse transcriptase inhibitors using the k nearest neighbor method and QSAR-based database mining

Jose Luis Medina-Franco1, Alexander Golbraikh2, Rafael Castillo1, and Alexander Tropsha2. (1) Department of Pharmacy, Universidad Nacional Autonoma de Mexico, Avenida Universidad 3000, Mexico City 04510, Mexico, Fax: (+5255)-5622-5329,, (2) Laboratory for Molecular Modeling, School of Pharmacy, University of North Carolina at Chapel Hill

We have developed validated quantitative structure-activity relationship (QSAR) models for 44 non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) of the pyridinone derivative type. The k nearest neighbor (kNN) variable selection approach was used. This method utilizes multiple descriptors such as molecular connectivity indices, which are derived from two-dimensional molecular topology. QSAR models with high internal accuracy were generated, with leave-one-out cross-validated R2 (q2) values ranging between 0.5 and 0.8. The best models were used to search the National Cancer Institute database. Derivatives of the pyrazolo[3,4-d]pyrimidine and phenothiazine type were identified as promising novel NNRTIs leads. Several candidates were docked into the binding pocket of nevirapine. Docking results suggested that these types of compounds could be binding in the NNRTI binding site in a similar mode to nevirapine.

COMP 178 [828896]:  QSAR study of hemostatic labdane diterpenoids

M. A. Turabekova, U. N. Zainutdinov, and Sh. I. Salikhov, Chemistry Department, National University of Uzbekistan named after Mirzo Ulugbek, Vuzgorodok, Tashkent, 700174, Uzbekistan, Fax: +998-71-1206475,

Molecular modeling investigations and QSAR analysis have been performed for a series of potential hemostatic drugs – labdane diterpenoids recently isolated from Central Asian Lagochilus plant species. The geometry of each molecule was fully optimized using semiempirical approach AM1 and a set of quantum-chemical parameters (atomic charges, HOMO and LUMO energies, dipole moment, electrostatic potential etc.) has been obtained. Multiple linear regression analysis (MLRA) combined with the genetic algorithm (GA) was applied for the selection of the variables that resulted in the best fitted models. Several equations describing hemostatic activity as a function of physicochemical, 3D and theoretically derived descriptors have been established and described. Good statistical quality models and their relevance to possible modes of action exerted by labdane diterpenoids are also discussed.

COMP 179 [833471]:  2-Pyrimidinethiol and methyl-2-pyrimidinethiols: A computational study of tautomers and dimers

Fillmore Freeman, Department of Chemistry, University of California, Irvine, Irvine, CA 92697-2025, Fax: 949-824-2210,, and Henry N. Po, Department of Chemistry and Biochemistry, California State University, 1250 Bellflower Blvd, Long Beach, CA 90840, Fax: 562-985-8557,

Ab initio theory, MŘller-Plessett second order perturbation theory (MP2), and density functional theory (DFT, BLYP, B3LYP) with the 6-31+G(d,p) and 6-311+G(d,p) basis sets have been used to calculate the vibrational spectra, structures, and relative energies of 2-pyrimidinethiol (2-mercaptopyrimidine) and its dimer, 2(1H)-pyrimidine-thione and its dimer, and 4-methyl-2-pyrimidinethiol, 5-methyl-2-pyrimidinethiol, 4,5-dimethyl-2-pyrimidinethiol, 4,6-dimethyl-2-pyrimidinethiol, and 4,5,6-trimethyl-2-pyrimidinethiol and their tautomers.

COMP 180 [832815]:  A crystal force field: Evaluation of short-range intermolecular interactions for representation of X-ray crystal structures in Cambridge Structure Database

Hitoshi Goto, Shigeo Obata, and Naofumi Nakayama, Department of Knowledge-based Information and Engineering, Toyohashi University of Technology, Toyohashi 441-8055, Japan, Fax: 81-532-48-5588,
The Cambridge Structure Database (CSD) of X-ray crystal structures provides an immense treasure-house of non-covalent intermolecular interactions. One way of making wise use of the unprecedented situation that over hundred thousands high-quality data on the crystal packing of molecular solids can be readily retrieved at our fingertips, will be to re-formulate classical intermolecular potential functions: weak interactions of van der Waals, short-range interactions like a hydrogen bonding, and electrostatic interactions. In this session, as a part of our long-standing project towards the goal of “constructing the next generation of molecular force field for the reliable and multi-scalable molecular simulations”, we will introduce our recent approach to evaluation of short-range intermolecular interactions using a combination of the modified Lippincot-Schröder (short-range) function, Buffered 14-7 (MMFF vdW) function, and charge equilibration (QEq) approach.

COMP 181 [833859]:  A theoretical study of active site proton swapping in Subtilisin Carlsberg during catalysis

Marc D. Legault, Department of Physics, University of Puerto Rico at Bayamon, #170, Carr. 174 Parque Industrial Minillas, Bayamon, PR 00959,
The objective of this research is to investigate the proton swapping that occurs between the active site residues of the serine protease Subtilisin Carlsberg during catalysis. The movement of these protons will show how charge is transferred between the aspartic residue and the serine/tetrahedral intermediate residue and substantiate a charge buffering mechanism. Accurate quantum mechanical calculations were performed on a very restricted part of the enzyme: the catalytic triad and one residue of the oxyanion hole. By performing partial geometrical optimizations on this small system one can determine the most energetically favorable position of these protons with and without the presence of tetrahedral intermediates. These positions will indicate if the interactions between residues of the catalytic triad are mediated by short strong hydrogen bonds.

COMP 182 [833704]:  A theoretical study of the enantioselectivity of Rhizomucor Miehei lipase during catalysis

Brenda De Leon Rivera1, Marc D. Legault1, and Gabriel L. Barletta2. (1) Department of Physics, University of Puerto Rico at Bayamon, 170 Road 174 Minillas Industrial Park, Bayamon, PR 00959,, (2) Department of Chemistry, University of Puerto Rico at Humacao
The objective of this research is to study the interactions between different substrates and the active site of the Rhizomucor Miehei lipase and to relate the above interactions to the activity and enantioselectivity. The configuration energy of the enzyme-substrate system was determined using combined quantum/molecular mechanics methods such as the ONIOM methodology. The system was partitioned into two layers. The first layer, consisting of the most significant residues of the active site of the enzyme and substrate was treated using quantum mechanics. The energy of this layer was computed at the DFT level using the three-parameter Becke hybrid with the Lee, Yang and Parr electron correlation functional (B3-LYP) and using the 6-311G* basis set. The second layer consisting of all other residues of the active site and the rest of system was treated using the OPLSAA molecular mechanical approximation. The ONIOM energy of sterically different chiral tetrahedral intermediates and enzyme was used to calculate ΔΔG* in order to determine the enantioselectivity E=exp(-ΔΔG*/RT) of these different enzyme-intermediate systems.

COMP 183 [832647]:  A theoretical study on fragmentation pathways and mechanisms of protonated β-alanine

Man Kit, Jackie Cheng1, On Ying, Onyx Chan1, S. Abirami2, N. L. Ma3, and C. W. Tsang4. (1) Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, Hong Kong SAR, Hong Kong, Fax: 852-23649932,, (2) Institute of High Performance Computing, (3) Novartis Institute for Tropical Diseases Pte Ltd, (4) Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University
β-alanine is the only β-amino acid found in naturally occurring β-peptides with high biomedical and therapeutic values, such as carnosine (β-Ala-His), anserine (β-Ala-1-methyl-His) and pantothenic acid (vitamin B-5). Studies on the fragmentation pathways and mechanisms of protonated (H+) β-alanine versus that of α-alanine serve as the basis for understanding the mass spectra of protonated α/β-peptides, which are useful in the differentiation of isomeric α/β-peptides. Our mass spectrometric studies revealed that H+-(β-alanine) dissociates mainly by loss of H2O to yield a stable b1 ion (a protonated 4-membered β-lactam ring, m/z=72), whereas H+-(α-alanine) yields a major fragment ion arising from the concerted loss of (H2O + CO). In conjunction with the experimental studies, the potential energy surfaces for dissociation of H+-(β-alanine) and H+-(α-alanine), including the transition and intermediate structures involved, were theoretically calculated using density functional theory at the B3-LYP/6-311+G(3df,2p)//B3-LYP-6-31G(d) level. The theoretical study shows that for β-alanine, the loss of H2O (β-lactam) pathway has a significantly lower energy barrier (53 kJ mol-1) than that of α-alanine associated with formation of protonated 3-membered α-lactam ring, but the loss of (H2O +CO) pathway could not be found as in α-alanine. Another dissociation pathway, found for H+-(β-alanine) only, is the loss of ketene (CH2CO) leading to the formation of a methaniminium ion (CH2=NH2+, m/z=48) with a low energy barrier of 167 kJ mol-1.

COMP 184 [808027]:  Ab initio genetic algorithm based elucidation of multiply aromatic clusters

Anastassia N. Alexandrova, Department of Chemistry and Biochemistry, Graduate Student, Utah State University, 0300 Old Main Hill, Logan, UT 84322-0300, Fax: 435-797-3390,, Alexander I. Boldyrev, Department of Chemistry and Biochemistry, Utah State University, Hua-Jin Zhai, W. R. Wiley Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, and Lai-Sheng Wang, Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory and Washington State University
The Ab Initio Gradient Embedded Genetic Algorithm (GEGA) program for elucidation of the global minima of clusters was developed. The global minimum structures of small clusters of boron, lithium and magnesium were found, and the analysis of chemical bonding was performed for every found global minimum. Multiple aromaticity and antiaromaticity (of both σ- and π-types) govern the shape of the considered species and play a major role in their stabilization. A series of neutral and anionic clusters from B3 to B9, discovered theoretically and observed by photoelectron spectroscopy, have unexpected planar shapes and multiple (anti-)aromatic character. B8, B8-, B9 and B9- clusters are remarkable, smallest discovered molecular wheels, containing hepta- and octo-coordinated boron atoms. We proposed a series of pure boron clusters, which potentially could be used as new ligands and building blocks. A new family of inorganic compounds – planar, aromatic, highly-charged boranes B6H66-, B5H56-, B7H76-, B10H88- was also discovered.

COMP 185 [832854]:  Absolute and relative entropies from computer simulation with applications to ligand binding

Jens Carlsson, Department of cell and molecular biology, Uppsala University, Uppsala biomedical centre, Box 596, 75124 Uppsala, Sweden, Fax: +46-18-536971,, and Johan Ĺqvist, Cell and Molecular biology, Uppsala University
A comparison between two related methods, Schlitter's formula and quasiharmonic analysis, for calculating absolute entropies from the covariance matrix of atomic fluctuations using MD simulations is presented. Encouraging agreement is obtained for translational entropies, but for the rotational contribution both methods fail to reproduce theoretically calculated values. Absolute and relative vibrational entropies are found to be better reproduced using quasiharmonic analysis compared to Schlitter's formula. For rotational entropies we propose a method based on the variances in Euler angles, which gives good agreement with theory. Alternative methods for estimating translational entropies based on principal RMS fluctuations of the center of mass are also presented and these reproduce theoretically calculated values well. These methodologies are applied to the binding of benzene to T4-lyzozyme, where close agreement with literature is obtained for translational and rotational entropies.

COMP 186 [832853]:  Accurate predictions of protein-protein binding free energies

Martin Almlöf, Department of Cell and Molecular Biology, Uppsala University, BMC, Box 596, 75124 Uppsala, Sweden, Fax: +46 18 53 69 71,, Bjřrn Brandsdal, The Norwegian Structural Biology Center, University of Tromsř, and Johan Ĺqvist, Cell and Molecular biology, Uppsala University

Here we present LIE (Linear Interaction Energy) calculations which accurately predict binding free energies of three protein-protein systems: bovine pancreatic trypsin inhibitor (BPTI) in complex with trypsin, the third domain of the turkey ovomucoid domain inhibitor (OMTKY3) in complex with chymotrypsin, and OMTYK3 in complex with human leukocyte elastase. The LIE method is a semi-empirical method to predict the free energies of binding of ligands to their receptors utilizing MD or MC simulations. It has previously been used successfully to accurately predict small ligand - protein binding free energies using one free parameter. Here we find that the intrinsic properties of these protein-protein interactions requires modification of a previously established parameter of the LIE method to accurately predict the binding free energies.


COMP 187 [819226]:  Automatic clustering of probe molecules to define surface complementarity: Applications to protein-protein interfaces

Michael G. Lerner, Biophysics Research Division, University of Michigan, Ann Arbor, 4028 Chemistry Building, 930 North University Avenue, Ann Arbor, MI 48109-1055,, and Heather A. Carlson, Department of Medicinal Chemistry, University of Michigan, Ann Arbor
Previous work in the Carlson group has focused on using small molecule probes to develop receptor-based pharmacophore models for structure-based drug design. To expand the utility of this method, we have developed new procedures to place the chemical probes and employed both RMSD and Jarvis-Patrick based methods for automatic probe clustering. This extended method has been tested through a study of protein-protein interfaces. These automated methods are robust, deterministic, faster and less subjective than previous methods. Results for both protein-protein interfaces and structure-based drug design will be discussed.

COMP 188 [825452]:  Binding affinity studies of Plasmepsins from Plasmodium falciparum

Martin Nervall, Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, Box 596, S-126 53 Uppsala, Sweden, Fax: +46-18-536971,, and Johan Ĺqvist, Cell and Molecular biology, Uppsala University
In drug design two major goals are high potency and good selectivity. A method to explain and predict both potency and selectivity would be very valuable in the field of drug discovery. In the present study we use molecular dynamics (MD) in conjunction with the linear interaction energy (LIE) method to investigate the properties of a number of inhibitors of plasmepsin II (PlmII) from Plasmodium falciparum. LIE is a semi empirical method for determination of binding free energy of a ligand to a receptor. The calculated binding affinity can be directly compared with experimental data.The studied compounds have been proved experimentally to comprise a remarkable selectivity towards PlmII over the highly homologous human aspartic protease cathepsin D. By using LIE to reproduce experimental binding affinity data we aim to explain the selectivity of these ligands from the obtained trajectories.

COMP 189 [827820]:  Binding energy calculation for theophylline-RNA aptamer with generalized BAR method

Yoshiaki Tanida1, Masakatsu Ito1, Hideaki Fujitani1, Michael R. Shirts2, Christopher D. Snow3, Guha Jayachandran4, and Vijay S. Pande2. (1) Fujitsu Laboratories Ltd, 10-1Morinosato-Wakamiya, Atsugi, Kanagawa, Japan, Fax: +81-46-250-8844,, (2) Department of Chemistry, Stanford University, (3) Biophysics Program, Stanford University, (4) Department of Computer Science, Stanford University
Recent advances in the generalized Bennett acceptance ratio (BAR; M. Shirts et al. 2003) method enable us to obtain the binding energy of realistic complex systems interacting with the explicit waters. In order to suit the generalized BAR method, we develop a massively parallel simulation server, BioServer, consisting of 1280 processors to efficiently perform the independent molecular dynamics (MD) calculation. In this report, we apply the generalized BAR method to estimate the binding energies for an RNA aptamer with theophylline and its analogs. MD simulations are carried out using the amber force field for an RNA aptamer and using the general amber force field (GAFF; J. Wang et al. 2004) for the theophylline molecule. The comparison of this work with the previous work (H. Gouda et al. 2003) is investigated.We also discuss in detail the results obtained within our framework.

COMP 190 [833097]:  Comparison of arbitrary versus tailored similarity spaces in property estimation

Brian D. Gute1, Subhash C. Basak1, Denise Mills1, and Douglas M. Hawkins2. (1) Center for Water and the Environment, Natural Resources Research Institute, University of Minnesota, 5013 Miller Trunk Hwy, Duluth, MN 55811, Fax: 218-720-4328,, (2) School of Statistics, University of Minnesota
Quantitative molecular similarity analysis (QMSA) methods using a variety of calculated molecular descriptors and experimental properties have been used to select analogs and estimation a wide variety of properties pertaining to chemistry, drug discovery, and environmental toxicology. Traditionally, descriptor sets have been selected either arbitrarily, intuitively by an expert, or through the use of a variety of data reduction techniques. 'Tailoring' is a new approach to the QMSA method that seeks to use indices that are strongly correlated with the property of interest. Studies have been carried out on two very different databases to examine the effectiveness of tailored vis-ŕ-vis arbitrary similarity spaces. The spaces are all derived from the same set of topological indices, only the selection methods vary. Results show that the tailored method outperforms the non-tailored techniques in estimating hydrophobicity for a set of 213 chemicals and Ames' mutagenicity for 95 aromatic amines.

COMP 191 [821150]:  Computation of the absorption spectrum of green fluorescent protein

Steven Trohalaki, Soumya S. Patnaik, and Ruth Pachter, Air Force Research Laboratory, Materials & Manufacturing Directorate, AFRL/MLPJ, Building 651, 3005 Hobson Way, Suite 1, Wright-Patterson Air Force Base, OH 45433-7702, Fax: 937-255-3377,
Green Fluorescent Protein (GFP) is a widely used fluorescent marker exhibiting two excitation peaks – a strong peak at 398 nm and a second at 475 nm, with the fluorescence at ca. 510 nm. Its molecular structure consists of a ß-barrel composed of 11 ß-strands and a central helix containing the fluorophore. Two different forms of the fluorophore – a protonated/neutral fluorophore and a de-protonated/anionic fluorophore – are thought to be responsible for the two distinct spectroscopic states, which are followed by a significant conformational change. Notably, the isolated fluorophore in solution is efficiently quenched. Conformational flexibility of the fluorophore within the protein cavity therefore appears to be an important factor governing the photochemistry of GFP. Simultaneous deformation of the fluorophore's two exocyclic dihedral angles, φ and τ, about the adjacent single and double bonds, respectively, has been termed a “hula twist.” In this work, we incrementally vary φ and τ and perform constrained geometry optimizations of GFP with both neutral and anionic fluorophores using ONIOM – a quantum mechanics/molecular mechanics method. We then perform time-dependent density functional theory (TD-DFT) calculations to determine the absorption spectrum of each of the conformations that compose the hula twist. The TD-DFT results will be discussed in comparison to experimental spectra.

COMP 192 [834005]:  Computational approaches to MEK1 and MEK2 structure determination and inhibitor design

Huifen Chen1, Jeffrey F. Ohren2, Christopher E. Whitehead1, Alexander Pavlovsky2, Erli Zhang2, Peter Kuffa3, Chunhong Yan2, Patrick McConnell2, Amy Delaney4, David T. Dudley4, and Charles Hasemann2. (1) Computer Assisted Drug Discovery, Discovery Technologies, Pfizer Global Research and Development, Ann Arbor Labs, 2800 Plymouth Rd, Ann Arbor, MI 48105, Fax: 734-622-2782,, (2) Discovery Technologies, Pfizer Global Research and Development, Ann Arbor Labs, (3) Department of Chemistry, University of Michigan, (4) Molecular Sciences and Technologies, Pfizer Global Research and Development, Ann Arbor Labs
MEK1 and MEK2 are closely related, dual-specificity, tyrosine/threonine protein kinases found in the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway. Approximately 30% of human cancers have a constitutively activated MAPK pathway and constitutive activation of MEK1 results in cellular transformation. Novel and ATP non-competitive MEK1 and MEK2 inhibitors were discovered through a high-throughput screen. The compounds were found to be highly potent and exquisitely selective for MEK1 and MEK2. To understand the structural basis for the inhibition of MEK1 and MEK2 and to enable structure-based design of improved compounds, we applied computational techniques to predict the inhibitor binding site and design protein constructs to facilitate the crystallography efforts. The X-ray structures of both MEK1 and MEK2 were successfully determined in complexes with ATP and inhibitor. The structures revealed a novel mechanism of protein kinase inhibition and have been used in the structure-based design of improved MEK inhibitors.

COMP 193 [829265]:  Computational investigation of structural and electronic characteristics of a series of glycosidase inhibitors and their relationship to experimental activity data

Robert D. Anderson and M. C. Milletti, Department of Chemistry, Eastern Michigan University, 225 Mark Jefferson, Ypsilanti, MI 48221, Fax: 734-487-1496,

Molecular orbital calculations are used to investigate the interaction of a series of sugar mimics with α-glycosidase. The compounds of interest are mono- and disaccharides and they include glucose, a group of hyacinthacines, a number of alexines, several aminocyclopentitols, nojirimicin with several of its analogs, and castanospermine. The structure of all molecules and their protonated analogs have been optimized at the B3LYP/6-311G* level of theory using the Gaussian'03 suite of programs. The structures of the compounds, both in the neutral and the protonated forms, are analyzed for similarities to the glycosyl ester intermediate proposed in the catalytic mechanism for glycosidases. In addition, charge distributions are compared to that of the oxycarbenium ion intermediate. The energy and location of the LUMO are considered as possible predictors of site of nucleophilic attack. Trends in LUMO energy, charge distribution and molecular shape are correlated to experimental activity data.

COMP 194 [835058]:  Computational modeling study of the C-terminal RING-finger domain of HDM2

Zengjian Hu1, Tangayi Githu2, Donnell Bowen3, and William M. Southerland1. (1) Department of Biochemistry and Molecular Biology, Howard University College of Medicine and the Howard University Drug Discovery Unit, 520 West Street, Northwest, Room 324, Washington, DC 20059,, (2) Howard University College of Medicine, (3) Department of Pharmacology, Howard University College of Medicine
The HDM2 oncoprotein plays a critical role in regulating cell proliferation and apoptosis. While the crystal structure of the HDM2 N-terminal domain which binds to the transactivation domain of p53 was determined, the 3D structural information of its RING-finger domain has not been available to date. Since the RING-finger domain of HDM2 is responsible for its E3 ligase activity which promotes p53 degradation, it represents an alternative molecular target to activate p53 in tumors. In this paper, we report computational homology modeling of the HDM2 C-terminal RING-finger domain based upon the 3D structures of other RING-finger related families and extensive structural refinement. The 3D models proposed here provide a novel mechanism for a further understanding of HDM2 function and the relationship between HDM2 and its binding partners. They also provide a point of departure for the design of HDM2 inhibitors using structure-base drug design method and the development of new chemotherapeutics for the treatment of human cancers.

COMP 195 [835063]:  Computational studies of the potential inhibitors of the copper-containing enzyme lysyl oxidase

Faina Ryvkin, Department of Chemistry, Emmanuel College, 400 The Fenway, Boston, MA 02115,, and Marina Dang, Department of Chemistry, Brandeis University
Lysyl oxidase (protein-6-oxidase; EC is the key-enzyme in elastin and collagen maturation. It initiates the formation of the crosslinks that provide the required strength and flexibility of these important structural proteins. Biochemical studies of this enzyme showed its requirement for Cu (II), which explains some of the pathologies where the inhibition of LOX is directly or indirectly involved. To clarify the mechanism underlying the inhibitory effect on LOX, the mixed quantum mechanics/molecular mechanics methodology was applied using Qsite program (Schrödinger Inc.). An earlier proposed structural model of Cu (II) binding site indicates at least one coordinated water molecule. Our studies show that several potential inhibitors, such as azide, thiocyanide and cyanide displace the solvent-derived water molecule in the copper coordination sphere, but no major structural rearrangement of the copper binding site is associated with this ligand substitution.

COMP 196 [834719]:  Computational studies of the structure and bonding of sulfur and phosphorous ylides

Jean M. Standard, Beth A. Copack, and Rebecca J. Steidl, Department of Chemistry, Illinois State University, Campus Box 4160, Normal, IL 61790-4160, Fax: 309-438-5538,

Ylides are useful synthetic intermediates that are formed from the interaction of singlet carbenes with heteroatom-containing molecules. Double bond character in sulfur and phosphorous ylides frequently has been proposed as a contributor to their stabilities. In this work, ab initio studies of the structure and bonding of sulfur and phosphorous ylides were carried out at the MP2 and CCSD(T) levels of theory using correlation-consistent basis sets. Results were compared with calculations performed using density functional theory. The sulfur and phosphorous ylides were found to have bonds significantly shorter than typical single bonds and binding energies ranging from about 40-70 kcal/mol. To characterize the bonding of the ylides, charge distributions were determined using Natural Population Analysis, and Natural Bond Orbital and Natural Resonance Theory analyses were employed to examine the extent of double bond character. The charge transfer is significant in both the sulfur and phosphorous ylides, ranging from 0.6-0.7 electrons. Natural Resonance Theory analysis indicates that both sulfur and phosphorous ylides possess approximately 20-25% double bond character. The origin of the short ylide bonds is attributed primarily to a strong electrostatic attraction between the highly oppositely charged C and S atoms or C and P atoms rather than to any significant double bond character.

COMP 197 [833888]:  Conformational interconversion of alanine dipeptide from 100 nanosecond molecular dynamics simulations by implicit and explicit solvation methods

Ryan A. Newton, Department of Chemistry and Biochemistry and Center for Computational Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282,, and Jeffrey D. Evanseck, Department of Chemistry & Biochemistry and Center for Computational Sciences, Duquesne University
The Generalized Born (GB), Analytical Continuum Electrostatics (ACE2), and Generalized Born using Molecular Volume (GBMV) implicit solvent models have been compared against a 519 explicit water simulation of the alanine dipeptide using the CHARMM program. Five 5 ns simulations have been conducted at 300 K using the NVE ensemble for each solvent model for a total of 100 ns. This study compares the preference of the alanine dipeptide (N-acetyl-L-alanine-N'-methylamide) in each type of solvent environment for each of its seven conformations: C7ax, C7eq, áR, áL, C5, â, and PII. Reaction path following techniques were employed to determine the lowest the energy paths between the different conformations. The paths and the computed barriers between conformations are compared for the different solvent models. We discuss the ability of each model to sample conformational space and compare the findings against experimental results and explicit solvent simulations.

COMP 198 [826546]:  Conformational isomerization kinetics of a dipeptide, N-acetyl - tryptophan methyl amide (NATMA): A non-RRKM approach

Johnson K Agbo and David M. Leitner, Department of Chemistry, University of Nevada, Reno, MS 216, Reno, NV 89557, Fax: 775-784-6804,

Rice - Ramsperger - Kassel - Marcus (RRKM) statistical theory of the determination of the reaction rate often overestimates the rate of conformational isomerization of fairly large molecules with low barriers to isomerization. A dynamical correction to the RRKM rate coefficient can incorporate the influence of intramolecular vibrational energy redistribution (IVR) on the reaction rate. We have calculated the IVR threshold, the RRKM rate and the dynamical correction to estimate the isomerization rate of the dipeptide NATMA.

COMP 199 [833502]:  Conformational study of small molecules in crystallographically determined structures

Rajeshri G. Karki, Laboratory of Medicinal Chemistry, National Cancer Institute, National Institute of Health, Building 376, Boyles Street, Frederick, MD 21702, Fax: 301-846-6033,, and Marc C Nicklaus, Laboratory of Medicinal Chemistry, National Institutes of Health
In a previous study (Bioorg. Med. Chem. 3, 1995, 411-428), we have looked at the conformational changes of small molecules when binding to proteins, using molecular mechanics analysis on a small number of compounds present both as pure material in the Cambridge Structural Database (CSD) and in protein-bound complexes in the Protein Data Bank (PDB). Crystallographically determined coordinates of protein-ligand complexes are often used as reference structures for algorithms in 3D structure generation and database searches, docking, molecular mechanics force field development etc. However, accurate understanding of the quantitative aspects of the conformational changes a ligand undergoes when it binds to a protein is still surprisingly elusive, and, as a consequence, so is the amount of ligand strain energy that can be tolerated in the computational approaches. We have therefore revisited this question at a higher level of accuracy and sample size, by analyzing strain energies at the ab initio level for approximately 200 small-molecule ligands present both in the CSD and the PDB, with one inclusion criteria being a crystallographic resolution of 2Ĺ or better.

COMP 200 [834403]:  Constructing irregular surfaces to enclose macromolecular complexes for mesoscale modeling using the discrete surface charge optimization (DiSCO) algorithm

Qing Zhang, Department of Chemistry, New York University, 31 Washington Place, Rm. 1021 Silver, New York, NY 10003, Fax: 212-995-4152,, Daniel A. Beard, Department of Bioengineering, University of Washington, and Tamar Schlick, Department of Chemistry, Courant Institute of Mathematical Sciences, and the Howard Hughes Medical Institute, New York University
Salt-mediated electrostatic interactions play an essential role in biomolecular structures and dynamics, but are computationally expensive. To approximate electrostatic interactions in models on the polymer level simulated over long times, Beard and Schlick have developed the DiSCO (Discrete Surface Charge Optimization) algorithm (Beard & Schlick 2001 Biopolymers 58, 106-115). DiSCO represents a macromolecule by a few hundred discrete charges on a regular-shape surface enclosing the system modeled by the Debye-H¨šckel approximation to the Poisson-Boltzmann equation, and treats the salt solution as continuum solvation. Here we generalize DiSCO by developing an irregular surface building method. Results indicate that irregular surfaces lead to a more accurate approximation, surface smoothing is important, and charge optimization by the TNPACK minimizer is efficient and does not depend on the initial assigned values. The new DiSCO algorithm has been successfully applied to the chromatin fiber and the supercoiled DNA bound to Hin and Fis proteins.

COMP 201 [797051]:  Potential ligand design for Dengue virus using high throughput screening, binding affinity evaluation and pharmacophore/scaffold identification

Zhigang Zhou and Carol Post, Dept. of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 201 S. University Rd., 1333 Hans Hall, box #154, West Lafayette, IN 47907, Fax: 765-496-1189,

Dengue virus is imposing high threat to human health. An effective inhibitor is yet to be developed. The structure of Dengue E protein reveals that a binding pocket at the area between domain 1 and 2 could be a drug target. In order to initiate the rational drug design project, a virtual screening of potential candidates against the protein has been carried out using High Throughput Screening (HTS) of docking. A strategy of 3-layer of screening is suggested and followed in the virtual screening. First, 1500 molecules are screened out based on two scores from three libraries with totally about 143,000 molecules. 150 molecules are then selected using high-accuracy protocol of docking. The structures of complexes of hits/protein are finally minimized and scored. Binding energies are calculated and analyzed. 3 type of binding modes have been recognized from binding structure analysis. Based on pharmacophore/scaffold identification, it is realized that hydrogen bond, aromatic area and hydrophobic areas are common features on these hits. It indicates that they may be important for ligands of E protein. 25 final hits have been selected from the final hit list and the biological activity of these compounds is scheduled to be evaluated against Dengue virus.

COMP 202 [796779]:  Design and conformational analysis of paclitaxel derivatives of nitroimidazole

Iwona Weidlich and S. Sobiak, Department of Chemical Technology of Drugs/Faculty of Pharmacy, University of Medical Sciences, Grunwaldzka 6, 60-780 Poznań, Poland, Fax: (61)8-659-566,

Paclitaxel was subject to detailed analysis using semiempirical method PM3 by HyperChem 7.0 Professional. The vacuum domination structure of conformer B (HC2'C3'H=173,40°; DH=-439,07 kcal/mol) and the stable conformer A (HC2'C3'H=74°; DH=-438,6 kcal/mol) were obtained.

Low toxicity of paclitaxel prodrugs can be achieved by blocking the C2'-OH group, which is important for anticancer activity. Also the C2'-OH position was blocked by nitroimidazole ester groups and calculated. Summing up five compounds were subject computational analysis: paclitaxel, 2'-(4-nitrocinnamylcarbonate) paclitaxel, 2'-O-(5-methyl-nitro-1H-imidazol-2-yl) methyloxycarbonyl) paclitaxel, 2'-O-(5-(4-chlorophenacyl)-nitro-1H-imidazol-2-yl) methyloxycarbonyl) paclitaxel, 2'-O-(5-(4-chlorophenacyl)-3-nitro-4-[bis (2-chloroethyl) amino]-1H-imidazol-2-yl) methyloxycarbonyl) paclitaxel (scheme).

The results of the calculations of title compounds were correlated with those of the screening study (1). The flexibility of acetoxide groups probably allows adjusting to an active site of tubuline.

  1. E.W.P.Damen, J.Tapio, “Synthesis of novel paclitaxel prodrugs designed for bioreductive activation in hypoxic tumour tissue”, Bioorg.Med.Chem., 10(2002) 71-77.

COMP 203 [815567]:  Development of a special purpose parallel computer for the first principles DVXƒż calculations

Umpei Nagashima, Grid Technology Research Center, National Institute of Advanced Industrial Science and Technology, 1-1-1 Umezono, Tsukuba 305-8568, Japan, Fax: +81-29-862-6601,, and Tohru Sasaki, Keio Leading-edge Laboratory of Science and Technology, A-Priori Microsystems, Inc
We developed a special purpose parallel computer: Embedded High Performance Computer (EHPC) for the first principle DVXa calculations, which realizes super high performance and cost-down for large scale first principle material simulation. An EHPC unit consists of one host-board (Pentium III 400MHz) and 7 acceleration-boards. Four general purpose processors (SH4 200MHz) are equipped on a board. The EHPC unit has 28 processors connected to each other by Compact PCI-bus. A program for the first principles DVXacalculations has been developed on the EHPC using an object-oriented programming language C++ and message passing interface: MPI. The step of matrix elements generation where more than 90% computation time is required was efficiently parallelized on the system. In the case of Si78B6H53 cluster was shown, the special purpose computer with four EHPC units is almost 100 times faster than a lone Pentium III processor. Super-linear speed up has been observed at the matrix elements generation step.

COMP 204 [832263]:  Docking studies and 3D-QSAR analysis for inducible nitric oxide synthase inhibitors

Yoko Kyoya1, Shigeo Ueda1, Akihiro Yano2, Yukio Tominaga1, Motoharu Ido2, Motoji Kawasaki1, and Iwao Fujiwara1. (1) Chemistry Research Laboratories, Dainippon Pharmaceutical Co., Ltd, Enoki-cho 33-94, Suita, Osaka 564-0053, Japan, Fax: +81-6-6338-7656,, (2) Pharmacology & Microbiology Research Laboratories, Dainippon Pharmaceutical Co., Ltd

Inducible nitric oxide synthase (iNOS) catalyzes the generation of cellular messenger nitric oxide (NO) by oxidation of substrate L-arginine. The rational design of iNOS inhibitors is of therapeutic interest in regulating pathological NO levels associated with various diseases. We have previously discovered a novel class of iNOS inhibitor, a series of 2-imino-1,3-thiazolidine derivatives1. To understand the binding modes of this series of compounds as well as to get a deeper insight into the structure-activity relationships, we performed docking studies and comparative molecular field analysis (CoMFA). Docking experiments suggested the importance of hydrogen bonds between the imino moiety of inhibitors and the both of the carboxyl group of Glu371 and the carbonyl oxygen on the main chain of Trp366 of iNOS. Based on this binding mode, we successfully developed a predictive CoMFA model with r2 and q2 values of 0.86 and 0.55, respectively.

[1]Bioorg. Med. Chem. 2004, 12, 4101.

COMP 205 [834265]:  Effect of glycosylation on a model peptide

Sarah M Tschampel, Department of Chemistry, Complex Carbohydrate Research Center, 220 Riverbend Road, Athens, GA 30602,, and Robert J. Woods, Complex Carbohydrate Research Center, University of Georgia

Asparagine-linked glycosylation, the co-translational covalent attachment of carbohydrates to asparagine side chains, has a major effect on the folding, stability and function of many proteins. Despite the diversity of these carbohydrate structures, the core Β-D-(GlcNAc)2 remains conserved in all N-linked glycoproteins. Experimental nuclear magnetic resonance data illustrates that although two glycopeptides, which differ only in the stereochemistry of the carbohydrate-peptide linkage, have a different overall conformation for the peptide. Investigation of these systems with empirical computational methods confirms the role the natural saccharide plays in the overall conformation of the peptide.

COMP 206 [832622]:  Efficient linear-scaling Ewald method for combined QM/MM calculations: Development and comparison with stochastic boundary and spherical cut-off methods

Kwangho Nam, Jiali Gao, and Darrin M. York, Department of Chemistry, University of Minnesota, 207 Pleasant St. SE, Minneapolis, MN 55455-0431, Fax: 612-626-7541,

In order for an efficient evaluation of long-ranged electrostatic forces during molecular dynamics, an extension of Ewald summation method in the scheme of combined QM/MM method employing semiempirical Hamiltonian is presented. The method is based on splitting of total Ewald potential into short-range interaction and long-range pair-wise periodic correction that interacts with electrons and nucleus at quantal atom sites under monopolar approximations and on the Mulliken charge representation of QM charge distribution in image cells. The serial and parallel implementations and performance of current method is tested by computing potential of mean force (PMF) under periodic boundary molecular dynamics (PBMD) simulations in a series of simulations of the ionic association of 1) ammonium chloride and 2) ammonium metaphosphate, and the dissociative phosphoryl transfer mechanism of 3) methyl phosphate and 4) acetyl phosphate. The computed PMFs are compared with the corresponding PBMD simulations using electrostatic cut-offs, and with results from non-periodical stochastic boundary molecular dynamics (SBMD) simulations, with electrostatic cut-offs and with full electrostatics. In addition, a similar approach employing ab initio quantum method is also presented, in which Ewald correction is included into ab initio QM/MM Hamiltonian.

COMP 207 [833110]:  First-principles calculation of the binding free-energy landscape of a trypsin-ligand complex

Olgun Guvench, Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Rd, TPC-6, La Jolla, CA 92037, Fax: 858-784-8688,, and Charles L. Brooks III, Department of Molecular Biology, TPC-6, The Scripps Research Institute

To further basic knowledge about free-energy landscapes of protein — ligand binding and also to generate benchmarks for assessment of simplified energy functions used to search and score protein — ligand complexes, we have undertaken binding free-energy landscape calculations for a trypsin — ligand complex using an atomic level-of-detail model with explicit solvent molecules. The ligand, benzamidine, is a small molecule competitive inhibitor, and binds strongly (Ki 0.018 mM) despite its small size (C7H9N2). In the range of 3-7 Ĺ from its bound position, benzamidine undergoes a combined desolvation, loss of orientational entropy, and induction of internal geometric strain, all without an energetic barrier to binding. A possible explanation is that unfavorable contributions to the free energy from these three factors are more than compensated for by the favorable liberation of water molecules that had been surrounding benzamidine's phenyl ring and bound in trypsin's binding pocket.

COMP 208 [834250]:  Forcefield parameterization of inhalational anesthetics, halothane and isoflurane: An ab initio study

Satyavani Vemparala, Ivaylo Ivanov, and Michael L. Klein, Department of Chemistry, University of Pennsylvania, 231S, 34th Street, Philadelphia, PA 19104,

Reliable forcefield parameters are an essential ingredient in the molecular dynamics simulations to study the effects of inhalational anesthetics on lipid membranes and membrane proteins. In this study we have undertaken detailed ab initio calculations to obtain an accurate forcefield for halothane and isoflurane. After performing initial unconstrained geometry optimizations using both HF and DFT, several constrained DFT calculations were done to determine torsional barriers. Hessian frequency calculations were also performed to determine bond and bend parameters. The merits of three charge partitioning schemes (Mulliken population, ESP and RESP) were explored, and we found RESP charges to be most appropriate. Car-Parinello molecular dynamics calculations were also performed with the molecules in a 64-water molecule box for 10ps each, to investigate the structural properties. Finally to validate the forcefield developed, classical molecular dynamics simulations were performed for 5ns each to compare with available experimental data.

COMP 209 [832507]:  Fuzzy relational clustering of molecular conformations using novel features based on DNA base-pair step parameters

Milind Misra1, Deepa Pai2, Rohan Woodley2, Amit Banerjee3, Rajesh N. Davé3, Liang-Yu Shih2, Xiang-Jun Lu4, A. R. Srinivasan4, Wilma K Olson4, and Carol A. Venanzi1. (1) Department of Chemistry and Environmental Science, New Jersey Institute of Technology, 323 King Boulevard, Newark, NJ 07102, Fax: 973-596-3596,, (2) Department of Computer Science, New Jersey Institute of Technology, (3) Department of Mechanical Engineering, New Jersey Institute of Technology, (4) Department of Chemistry and Chemical Biology, Rutgers University

Six rigid-body parameters (Tilt, Roll, Twist, Shift, Slide, Rise) are commonly used to describe the relative orientation and positioning of any two base pairs in a nucleic acid structure. The present work generalizes the algorithms of the 3DNA software package (Nucleic Acids Res., 31, 5108-21, 2001) to describe the relative orientation of any two planes in a molecule--for example, planes which contain important pharmacophore elements. Fuzzy relational clustering is used to classify molecular conformations using the six "base-pair step" parameters as features. This approach is applied to an analog of GBR 12909, a flexible inhibitor of the dopamine transporter potentially useful in the treatment of cocaine abuse. The results of this approach provide representative conformers for future 3D-QSAR analyses.

COMP 210 [826417]:  How does autophosphorylation modulate catalysis function and regulation in cAMP-dependent protein kinase?

Yuhui Cheng, Department of Chemistry and Biochemistry, UC, San Diego, 9500 Gilman Dr. MC 0365, La Jolla, CA 92093-0365,

Many protein kinases are activated strongly by the phosphorylation of a polypeptide region (activation loop) that lies outside the active-site cleft. A prototypical example is provided by cyclic AMP-dependent protein kinase (PKA). Here we use both two PKA-Mg2ATP-substrate complexes, the wild type and dephosphorylated mutant T197A to perform computational studies. Classical molecular dynamics clearly identifies two side-chain conformations of the P-site serine in both the wild type and T197A mutant. The reactive conformation dominates in the wild type while the non-reactive conformation dominates in the T197A mutant. Consistent result are yielded with umbrella sampling in both two complexes. Density functional theory QM/MM studies on the reactive conformations in both two complexes indicate the trivial reactive barrier difference for the phosphoryl transfer step. Our findings suggest that the main role of autophosphorylation in PKA may be to adjust the substrate orientation and not to substantially modulate catalytic potential.

COMP 211 [825575]:  Investigating targets of antibacterial cysteine protease inhibitors

Leslie A. Vogt and Jeffrey P. Wolbach, Department of Chemistry, Juniata College, 1700 Moore St., Huntingdon, PA 16652,

Streptococcal pyrogenic exotoxin B (SpeB), a highly conserved cysteine protease secreted by Streptococcus pyogenes, is inhibited by several peptidic compounds. Some, but not all, of these compounds also exhibit anti-bacterial activity against S. pyogenes, suggesting that SpeB is not the only target of inhibition. Required features in the active site of other targets are hypothesized from molecular dynamics studies using the x-ray crystal structure of SpeB to compare the binding modes of inhibitors with and without anti-bacterial activity. The crystal structure is also used to construct model structures for homologous protein sequences obtained from the genome of S. pyogenes, assuming the target is also a cysteine protease with a conserved active site. Binding modes of models exhibiting the hypothesized features and inhibitors with anti-bacterial activity can be examined using docking and molecular dynamics simulations.

COMP 212 [818535]:  Kinetic and geometrical isotope effects in hydrogen-atom transfer reaction: Application of multi-component MO method

Takayoshi Ishimoto, National Institute of Advanced Industrial Science and Technology, Grid Technology Research Center, Umezono 1-1-1, Tsukuba, Ibaraki 305-8561, Japan, Fax: +81-29-862-6611,, Masanori Tachikawa, Graduate School of Science, Yokohama-city University, Quantum Chemistry Division, and Umpei Nagashima, Grid Technology Research Center, National Institute of Advanced Industrial Science and Technology

To estimate the kinetic isotope effect (KIE) for hydrogen (or deuterium) abstraction from H(D)OR (R = H, CH3, and CN) by an OH radical, we have analyzed the mechanical feature from a viewpoint of the quantum nature of the proton and deuteron with the multi-component MO method which can determine both nuclear and electronic wavefunctions simultaneously. The geometrical isotope effect, induced by the replacement from the hydrogen atom to deuterium, is clearly demonstrated. The difference of the nuclear wavefunction of the proton and deuteron affects the changes of geometry and electronic charge density. The ratio of the rate constant of the reaction for R = H by our calculation is reasonable agreement with experimental result. The difference in activation energy and the ratio of the rate constant for the chemical reaction as affected by the R group is controlled by the wavefunctions of the proton and deuteron.

COMP 213 [829427]:  Modeling of triclosan analogs for enoyl reductase inhibition

Jonilyn G. Longenecker, Paul D. Schettler Jr., Richard R. Hark, and Jeffrey P. Wolbach, Department of Chemistry, Juniata College, 1700 Moore Street, POB 394, Huntingdon, PA 16652,

Triclosan is an effective antibacterial agent, acting by breaking the bacterial synthase cycle through inhibition of enoyl reductase. However, recent wide-spread use of triclosan has raised concerns about the possibility of development of triclosan-resistant strains of bacteria. In this work, we have used molecular dynamics to study the binding of 20 triclosan analogs to E. coli enoyl reductase (1QSG). Free energies of binding were determined by modifying the triclosan molecule in the X-ray crystal structure of 1QSG to form each analog and by using a solvent-cap MM/PBSA procedure. Automated docking studies were also conducted on each analog and additional MD simulations were run on the seven analogs with suggested alternative, lower-energy poses than the ″triclosan-like″ configuration. Comparison of experimental binding energies for a subset of the analogs is used to verify the accuracy of the method. Results of this study will be used to suggest alternative anti-bacterial agents to triclosan.

COMP 214 [833605]:  Molecular simulations of model Langmuir monolayers

Leslie V. Villalobos-Rivera and Gustavo E. López, Departmant of Chemistry, University of Puerto Rico, Mayagüez Campus, Mayagüez, PR 00681,

The study of the liquid-liquid and vapor-liquid equilibrium of surfactant molecules forming an interface between water and air has been considered using two types of Monte Carlo computer simulations. First, a simulation box was defined such that the monolayer was exposed to an externally applied lateral pressure in a modified isothermal-isobaric ensemble, whereas the water bath was modeled in the canonical ensemble. The applied lateral pressure-surface area phase diagrams clearly showed the coexistence of two liquid phases, denominated as liquid expanded state (LES) and liquid condensed state (LCS). Also, distribution functions of enthalpies for the monolayer were computed to clearly identify each liquid phase and the coexistence range. The phase transitions between the liquid state and vapor state have been considered using Monte Carlo computer simulations in the Standard Virtual Gibbs Ensemble. We have identified the coexistence between the LES and the LCS, in agreement with the experimental and theoretical evidence existing in the literature. Furthermore, we have successfully identified the critical temperature and critical density for the liquid expanded-liquid condensed and for the liquid expanded-vapor equilibrium of the monolayer.

COMP 215 [834902]:  Nitrosation of melatonin

Jamie M. Rintelman, Department of Chemistry, Iowa State University, 201 Spedding Hall, Ames, IA 50011, Fax: 515-294-5204,, Mark S. Gordon, Chemistry Department and Ames Laboratory USDOE, Iowa State University, and Julia E. Rice, IBM Almaden Research Center

Melatonin is present in many organisms including many very primitive organisms. Humans produce it in the pineal gland and it plays a role in regulating the body clock. It has also been shown to act as a radical scavenger. The antioxidant/prooxidant balance in the body is very complex and involves many competing reactions. The nitrosation of melatonin is one of the most important reactions in understanding melatonin's role in helping to regulate the antioxidant/prooxidant balance in the human body. Because these reactions occur in the body, it can be important to include solvent effects. Both implicit and explicit solvent calculations have been performed to determine the impact of solvent on the reaction profile. This also helps to determine the level of theory at which the solvent effects must be represented.

COMP 216 [812945]:  On the convergence of a hybrid parallel tempering Tsallis statistics Monte Carlo algorithm

Hanbin Liu, Dept of Chemistry and Center for Molecular and Materials Simulations, University of Pittsburgh, Pittsburgh, PA 15260, and Kenneth D. Jordan, Dept. of Chemistry and Center for Molecular and Materials Simulations, University of Pittsburgh
In the present study we explore a procedure in which parallel tempering Monte Carlo simulations are carried out using the Tsallis generalized ensemble (PTTS). The PTTS algorithm is compared with traditional parallel tempering Monte Carlo (PTMC), Metropolis Monte Carlo (MMC) and Tsallis statistics Monte Carlo (TS) simulations for a one dimensional model potential. The LJ38 cluster which is known to be especially difficult to equilibrate at low temperature is examined using PTMC and PTTS algorithms. It is found that convergence of both the PTMC and PTTS algorithms are appreciably poorer, particularly at temperatures in the vicinity of the Oh --> C5v transformation, when starting from the C5v structure than from the Oh global minimum. It is also found that although it is harder to locate the Oh than the C5v minimum, it is easier for the simulation to escape from the former. The PTTS algorithm is more effective at dealing with this situation than is the PTMC algorithm, achieving convergence with about one-third as many moves (equilibration plus production) than required with the PTMC algorithm.

COMP 217 [819468]:  Pharmacophore identification and antidiabetic activity prediction in the class of guanidino- and aminoguanidinoacetic acid compounds

Aleksandr V. Marenich, Isaac B. Bersuker, and James E. Boggs, Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712,

The pharmacophore of a set of antidiabetic agents was revealed and a formula for quantitative prediction of their activities was derived using the electron-conformational method (I. B. Bersuker, Current Pharmaceutical Design, 2003, 9, 1575-1606). Conformational analysis and electronic structure calculations for the training set of 50 molecules were carried out by semi-empirical and ab initio methods. An electrostatic field of water molecules was modeled to account for the solvation influence on conformations. The pharmacophore consists of four sites with specific reaction indices which may be occupied by carbon, nitrogen, and oxygen atoms as shown below, or by any other atoms which have the same electronic structure characteristics and geometry positions within the limits of tolerances. The quantitative activity prediction has an accuracy of more than ~90%.

COMP 218 [832910]:  Q: A novel method to simulate the solvation of hydrophobic surfaces by water and its application to the estimation of protein-ligand binding constants

Arthur M. Doweyko, Pharmaceutical Research Institute, CADD, Bristol-Myers Squibb, Rte. 206 and Provinceline Road, Princeton, NJ 08543, Fax: 609-252-6030,, and Stephen R Johnson, Computer-Assisted Drug Design, Bristol-Myers Squibb

Solvent entropy change is the single greatest factor in driving the association of hydrophobic species in aqueous solution. We have developed a novel methodology which simulates the solvation of hydrophobic surfaces by water. A system of virtual solvent particles surrounding the solute governed by arbitrarily applied rules provides a means to estimate the degree of order (Q) imposed by such solvation. Computed changes in Q (dQ) upon complex formation have been found to correlate well with observed binding affinities of host-guest complexes in aqueous solution. Examples are described which illustrate the ability of dQ calculations to identify the correct ligand pose from a set of decoy complexes, as well as provide rank ordering of a set of highly diverse ligand-protein complexes. Comparisons to surface area-based calculations are discussed. The Q methodology holds great promise in the development of predictive structure-based approaches to drug design, as it provides a relatively simple means to estimate the hydrophobic effect.

COMP 219 [810526]:  Rare gases inserted into biological building blocks: A theoretical study of glycine - Rg compounds (Rg=Xe, Kr, Ar)

Galina M. Chaban, NASA Ames Research Center, Mail Stop T27B-1, NASA Ames Research Center, Moffett Field, CA 94035-1000, Fax: 650-604-1095,

Compounds formed by insertion of rare-gas atoms (Xe, Kr, and Ar) into glycine molecule are investigated using accurate ab initio computational methods. Identification of such insertion compounds may open new frontiers in the field of rare-gas chemistry, such as possible existence of biological molecules that include chemically bound rare gas atoms. The most stable glycine-Rg configuration is found to correspond to insertion of Rg atoms into the O-H bond of glycine. These NH2CH2COORgH compounds are metastable , but separated by sizable potential barriers from the Rg + glycine dissociation products. Preliminary calculations show that NH2CH2COOXeH compound is energetically stable with respect to another (3-body) dissociation channel (NH2CH2COO + Rg + H), while the corresponding Ar species is not stable in this respect. The compound with the inserted Kr is a borderline case, with the 3-body dissociation products being close in energy to the NH2CH2COOKrH minimum.

COMP 220 [831757]:  Rate constant calculation of ligand binding with solvation force determined by boundary elementary method

Ben Zhuo Lu1, David Zhang1, and Andrew J. McCammon2. (1) Department of Chemistry and Biochemistry, University of California at San Diego, Gilman Dr. 9500, San DIego, CA 92093,, (2) Department of Chemistry and Biochemistry, University of California-San Diego

The electrostatic interaction has been demonstrated as a main factor to affect the diffusion-influenced rate constant of ligand-protein,or protein-protein encounter. However, the electrostatic solvation effect from the moving ligand was traditionally ignored in the simulation, such as in UHBD program. The boundary elementary method (BEM) is used for the Poisson-Boltzmann (PB) force updating for the protein-ligand, or protein-protein interaction in the binding process. A fine surface triangular mesh is used to improve the accuracy of the calculation. And, because the BEM solver for PB equation mainly depends on the molecular surface geometry, for rigid binding case, the surface information could be used in each step of force updating. This makes the BEM approach to be fast compared with the finite difference or finite element method. A test is performed, and the analysis are also made on the substrate solvation effect on binding, and on the computational speed of this approach.

COMP 221 [834454]:  Sila-Pummerer rearrangement of cyclic sulfoxides: A computational study of sulfonium ylide intermediates

Fillmore Freeman1, Svetlana V. Kirpichenko2, and Bagrat A. Shainyan2. (1) Department of Chemistry, University of California, Irvine, Irvine, CA 92697-2025, Fax: 949-824-2210,, (2) A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Division of the Russian Academy of Sciences

The 2,5-boat conformer (3) of the oxasila derivative of 1-methylenehexahydrothiopyran (1-methylenethiacyclohexane), which is a minimum, has been implicated as an intermediate in the thermal sila-Pummerer rearrangement of axial 3,3-dimethyl-3-silathiacyclohexane 1-oxide (1) to the O,S-acetal 4,4-dimethyl-3-oxa-4-silathiacyclo-heptane (2). B3LYP and MP2 with the 6-31+G(d,p) and 6-311+G(d,p) basis sets have been used to calculate the structures, relative energies, and relative thermodynamic parameters of the chair, twist, boat (3), half-chair, and sofa structures of the oxasila derivative of 1-methylenehexahydrothiopyran .

COMP 222 [833187]:  Similarity-based chemical clustering techniques

Brian D. Gute, Subhash C. Basak, and Denise Mills, Center for Water and the Environment, Natural Resources Research Institute, University of Minnesota, 5013 Miller Trunk Hwy, Duluth, MN 55811, Fax: 218-720-4328,

This study proposes the use of clustering techniques within a chemical similarity space derived using calculated molecular descriptors to identify related groups of chemicals and to choose representative chemicals from these groups for testing. These techniques are as applicable to drug discovery or industrial chemical development, i.e., data mining, as they are to toxicity estimation and address possible issues of mixture toxicity. Through the use of these techniques it is possible to use a minimalistic approach to testing rather than full factorial design analysis. The results reported here will focus on clustering a large library of psoralen derivatives, a family of chemicals used to treat both psoriasis and leukemia, and clustering a set of 228 chemicals that have been identified as components of JP-8 (jet propellant formulation #8), a fuel mixture that is in widespread use by the United States military and is known to cause immunosuppression.

COMP 223 [831003]:  Tautomerization of the HBO base pair model in the DNA major and minor grooves

Francois-Yves Dupradeau1, Chengzhi Yu2, Ralph Jimenez2, Floyd E. Romesberg2, and David A. Case3. (1) DMAG EA 3901 INERIS, Amiens, France & The Scripps Research Institute, Department of Molecular Biology, La Jolla, CA, Fax: 1-858-784-8896,, (2) Department of Chemistry, The Scripps Research Institute, (3) Department of Molecular Biology, The Scripps Research Institute

The 2-(2'-hydroxyphenyl)benzoxazole derivative (or HBO) has been developed to experimentally study base pair tautomerization within DNA duplexes. This base pair model presents an enol-imine moiety, where tautomerization may be photochemically induced, leading to the corresponding keto-amine tautomer by Excited-State Intramolecular Proton Transfer (ESIPT). When correctly positioned into the DNA 5'-CGTTTC(HBO)TTCTC-3' dodecamer, opposite an abasic site, it has been shown that HBO is a good mimic of Watson-Crick base pairs. When oriented so that the tautomerization probes the major groove, ESIPT was observed and the duplex environment found to stabilize the keto-amine tautomer. However, when incorporated into DNA with the enol-imine moiety positioned in the minor groove, no ESIPT is observed. To study this tautomerization difference and a putative solvent effect, molecular dynamics (MD) simulations have been conducted in a box of explicit water molecules using the AMBER8 program. MD clearly show no major difference of solvation of the enol-imine in the DNA grooves. However, different hydrogen-bonding patterns are observed between the HBO enol-imine (residue i ‰) and the deoxyribose endocyclic oxygen of thymine-8 (residue i+1 ‰). Thus, we propose that at least for the HBO base pair model, a nucleobase-ribose hydrogen-bond, unique in the minor groove, disrupts the enol-imine hydrogen bond and prevents its ESIPT. These studies demonstrate that the HBO base pair model is a sensitive probe of its DNA duplex environment and should be capable of characterizing the duplex environment in other sequences or when bound to different DNA-binding proteins.

COMP 224 [835093]:  Theoretical study on glucose polysaccharides

Jen-Shiang K. Yu, Department of Biological Science and Technology, National Chiao Tung University, No. 75, Po-Ai Street, Hsinchu 300, Taiwan, Fax: +886-3-5729288,
Abstract text not available.

COMP 225 [833403]:  Unbinding study of edema factor-calmodulin complex using steered molecular dynamics

Kristine A Baker, Department of Chemistry and Biochemistry, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, Fax: 412-396-5683,, Jeffrey D. Evanseck, Department of Chemistry & Biochemistry and Center for Computational Sciences, Duquesne University, and Steven M. Firestine, Mylan School of Pharmacy, Duquesne University
Steered molecular dynamics (SMD) induces unbinding of ligands and conformational changes in biomolecules on time scales accessible to molecular dynamics simulations. SMD has been used to study the unbinding of the signaling protein calmodulin from anthrax edema factor. The applied forces are sufficiently large to reduce the overall binding energy enough to yield unbinding within one nanosecond. The simulations were carried out using the less reactive, two Ca2+ ion bound form of calmodulin. The simulations were run using NAMD, using periodic boundary conditions and include approximately 22,000 water molecules and seven chlorine ions to neutralize the charge on the EF-CaM-2 Ca2+ complex. Time-dependent external forces have been applied to the system and the elastic responses have been analyzed to determine the unbinding mechanism of the complex and investigate the possible use of strategically placed small molecular weight compounds to act as inhibitors to prevent EF-CaM binding.

COMP 226 [830137]:  Unintended consequences of periodic boundary conditions: Particles of different mass have different effective temperatures

Randall B. Shirts, Scott R. Burt, and Aaron M. Johnson, Department of Chemistry and Biochemistry, Brigham Young University, C100 Benson Building, Provo, UT 84602, Fax: 801-422-0153,

Most molecular dynamics simulations are performed with periodic boundary conditions. Because of non-Boltzmann velocity distributions, standard procedure has been to regularly resample the Boltzmann distribution. One reason for this is that the center-of-mass constraint on the momentum causes the effective temperature for particles of different mass to be slightly different. In addition, a finite-size system has a non-Boltzmann equilibrium velocity distribution anyway. Therefore, non-Boltzmann velocity distributions seen in simulations are not necessarily a result of poor sampling statistics, but an artifact of small system size and periodic boundary conditions. These effects are inversely proportional to the size of the system. We demonstrate these results in hard sphere simulations in 1, 2 and 3 dimensions. One may avoid regular velocity resampling by applying small-system corrections for the differences between ensembles. This is more efficient than simulating larger systems. These small-system corrections should be understood when extrapolating bulk behavior from microcanonical molecular dynamics simulations.

COMP 227 [824805]:  Predicting chemical shielding in proteins: A QM/MM study combined with MD simulations

Seongho Moon and David A. Case, Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037,

Chemical shielding parameters in a protein are analyzed using a hybrid quantum mechanics and molecular mechanics (QM/MM) method in combination with molecular dynamics (MD) simulations in order to include the conformational averaging and solvent effects and long-range electrostatic interactions. Here, the QM domains are embedded in the MM electric fields and the frontier bonds are truncated by the quantum capping potentials (QCP). The main advantage of this method is that the QM and MM regions are divided transparently without any structural distortion in the boundary regions from MD snapshots. We have studied the amide and carbonyl groups in the oxidized thioredoxin for which well defined X-ray and NMR structures are available, and also polypeptide model systems to scrutinize the conformational effects on chemical shielding. The results show that this combined method provides much better results than static QM calculations and enables us to do a realistic study on chemical shielding in proteins.

COMP 228 [833770]:  Understanding C2-substituent effects of bis(oxazoline) copper(II) catalyzed Diels-Alder reactions by density functional computation

Edward G. Franklin1, Jason DeChancie1, and Jeffrey D. Evanseck2. (1) Department of Chemistry and Biochemistry, Duquesne University, 600 Forbes Ave., 308 Mellon Hall, Pittsburgh, PA 15282,, (2) Department of Chemistry & Biochemistry and Center for Computational Sciences, Duquesne University

Large-scale density functional investigations of C2-substituent effects of bis(oxazoline) copper(II) catalyst complexes on the rate and selectivity of Diels-Alder reactions were performed. Using Becke's three-parameter density functional theory with the nonlocal correlation of Lee, Yang, and Parr and the 6-31G(d) basis set, the steric and electronic effects of tert-butyl, isopropyl, and phenyl substituent substitution are reported with regard to the Diels-Alder reaction of cyclopentadiene and acrylate imide. Consistent with experimental studies, the computed ground state structures and rates of reaction are in good agreement. The computed transition structures provide an understanding of how the C2-subtituents modulate the copper(II) catalyst, which ultimately impact the catalytic power of the system. The balance between steric and electronic effects is discussed in rationalizing the observed rate and selectivity enhancements of the Diels-Alder reaction.

COMP 229 [834338]:  Understanding the proficiency of OMP Decarboxylase: An ab initio study

Courtney L Stanton, Department of Chemistry and Biochemistry, UCLA, University of California Los Angeles, Los Angeles, CA 90095,, and K. N. Houk, Department of Chemistry and Biochemistry, University of California Los Angeles

Since 1995, when orotidine 5'-monophosphate decarboxylase (ODCase) was declared nature's most proficient enzyme, it has come under intense scrutiny both experimentally and computationally. Despite this attention, the mechanism of ODCase catalysis remains unsolved. The various proposed mechanisms for the decarboxylation of ODCase have been explored with density functional theory, to determine the types of chemical catalysis that can explain the activation barrier lowering found with the enzyme. In addition, crystal structures of the active site have been explored to determine the geometrical feasibility of various types of catalysis, including general acid catalysis at O-2, O-4, C-5 or C-6, as well as iminium ion formation at O-4.

COMP 230 [827011]:  A computational study of the competing pathways of rearrangement, HF and HCl elimination reactions of CF3CF2CH2Cl and CF3CHClCF3

William C. Everett, Bert E. Holmes, and George L Heard, Department of Chemistry, University of North Carolina at Asheville, CPO # 2310, One University Heights, Asheville, NC 28804, Fax: 828-232-5179
DFT calculations have performed on CF3CF2CH2Cl and CF3CHClCF3 to examine several competing elimination and rearrangement pathways. Transition geometries for 1-2,HX eliminations for both molecules were considered as well as 1,2-FCl interchanges and subsequent HF and HCl eliminations. Characterization of transition geometries by vibrational frequency calculations leads to sets of vibrational frequencies, threshold energies and moments of inertia that are used as input for RRKM rate constant calculations. Using a range of basis sets it is discovered that there is little change in geometry, moments of inertia and vibrational frequencies for transition geometries, however there is a significant variation in threshold energies. This leads to a large uncertainty in the calculation of rate constants from this data, but a consistency in the prediction of product ratios. A comparison with experimental results is made where data is available.

COMP 231 [827459]:  A QM/QM’ approach to modeling the Zn(II)/Cu(I) core of a protein

Melinda A. Harrison1, Llaria Ciofini2, Jeffrey D. Evanseck3, Carlo Adamo2, and Charles T. Dameron1. (1) Department of Chemistry and Biochemistry, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, Fax: 412-396-5683,, (2) Laboratoire d’ Electrochimie et de chimie Analytique (UMR 7575), ENSCP, (3) Department of Chemistry & Biochemistry and Center for Computational Sciences, Duquesne University
A copper model, Enterococcus hirae (E. hirae), has been developed which regulates the copper uptake, availability, and export in bacteria. The repressor protein, CopY, controls the regulation of E. hirae, through its binding/release of the DNA in the promoter region of the cop operon. This operon encodes four proteins: copA, copB, copZ and copY. CopA and CopB are involved in the import and export of Cu(I) into and out of the cell. CopZ delivers Cu(I) to the Zn(II)CopY protein bound to the operon where the Zn(II) is displaced and the Cu(I) is accepted. Cu(I)CopY is unable to bind DNA, thus the protein is released from the operon and transcription of the cop genes occurs. CopY binds each metal in a CxCxxxxCxC motif (C= cysteine) in the C-terminal end of the protein. The protein is ligated to Cu(I) via the cysteinyl sulphurs in a trigonal planar coordination and Zn(II) via a tetrahedral coordination. Modeling of the Cu(I)/Zn(II) core of the protein was undertaken by the means of Density Functional Theory. Next the optimized Cu(I)/Zn(II) cores were embedded in the protein environment attached by 19 residues of the protein backbone. Mixed QM/QM' calculations using the ONIOM approach were performed.

COMP 232 [833663]:  Ab-initio fragment orbital theory: Application to the excited states of some organometallic compounds

Guru P Das, MLBP, Air Force Research Laboratory, Wright Patterson Air Force Base, OH 45433,, and Jean-Philipe Blaudeau, ASC/HP, Air Force Research Laboratory

An approach (known as ab-initio fragment orbital theory (AFOT)) recently formulated to compute ground and excited states of large molecules is described. The approach is based on treating a large molecule in terms of identifiable building blocks (e.g. the functional groups), to be generally called fragments. Application to some interesting excited states of some ethynyl compounds of Platinum is described.

COMP 233 [826883]:  Application of variational reduced-density-matrix theory to organic molecules

Gergely Gidofalvi, Department of Chemistry, The University of Chicago, 5735 S. Ellis Ave, Chicago, IL 60637, Fax: 773-702-0805,, and David A Mazziotti, Department of Chemistry and the James Franck Institute, University of Chicago
Variational calculation of the 2-electron reduced-density matrix (2-RDM), using a new first-order algorithm [Mazziotti, Phys. Rev. Lett. (in press)], is applied to medium-sized organic molecules. The calculations reveal systematic trends in the accuracy of the energy with well-known chemical concepts such as hybridization, electronegativity, and atomic size. Furthermore, correlation energies from hydrocarbon chains indicate that the calculation of the 2-RDM subject to two-positivity conditions is size extensive, that is the energy grows linearly with the number of electrons. Because organic molecules have a well-defined set of functional groups, we employ the trends in energy accuracy of the functional groups to design a correction to the 2-RDM energy for an arbitrary organic molecule. We apply the 2-RDM calculations with the functional-group correction to a large set of organic molecules with different functional groups. Energies with milli-Hartree accuracy are obtained both at equilibrium and non-equilibrium geometries.

COMP 234 [831109]:  Bonding or antibonding, an overlap population study

Xin Liu, Changgong Meng, and Changhou Liu, Department of Chemistry, Dalian University of Technology, P.O.Box 288, Dalian 116024, China
Overlap population (OP) analysis is a common method to study the bonding characteristics, especially bond strength, between a pair of atoms. With this method it would be possible to single out the contribution to the total overlap population between 2 atoms made by each molecular orbital. The overlap population between 2 atoms depends upon the total number of occupied molecular orbitals. In order to study the bonding characteristics, a series of OP analyses were carried out on the overlap matrixes generated during single point calculations of hundreds of selected chemicals with G98w software. All these structures were optimized and testified with frequency calculations to be the minimum point with the corresponding theoretical methods and basis-sets first. It is found that for a certain molecule, calculations with various levels of theories and various basis-sets will produce similar structural, orbital and energy results, but these OP analyses may give different results. Bonding characteristics for a certain molecule resulting from the OP analysis results may vary with the level of theories and the size of basis-sets used for calculation, or even become unpredictable. This shows that OP analysis is not a golden rule for bonding characteristic study.

COMP 235 [824749]:  Calculating low energy reaction pathways in proteins and RNA: A QM/MM implementation of the Nudged Elastic Band (NEB) method

Ross C Walker1, David H. Mathews2, and David Case1. (1) Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Rd., San Diego, CA 92122,, (2) Biochemistry & Biophysics, University of Rochester, Rochester, NY 14642,

We have implemented a simulated annealing based version of nudged elastic band (NEB) within an early version of AMBER 9 and successfully used it to find low energy pathways for conformational changes in protein and RNA based systems. In the NEB method the minimum energy path for a conformational change is quantified as a series of images of the molecule describing the path. The images at the end points of the path are fixed in space while the intervening structures are connected to their neighbours by "springs" that keep each image from sliding down the energy landscape onto adjacent images. By implementing a coupled QM/MM potential model that combines a region of chemical interest, described quantum mechanically, with a classical region, described by the AMBER force field equation, we have been able to find low energy reaction pathways involving bond breaking and formation for protein and RNA systems.

COMP 236 [834957]:  Computational studies of the phosphorylation reaction in protein kinase A: Ab-initio QM/MM approach

Marat Valiev, EMSL, Pacific Northwest National Laboratory, P.O. Box 999, MS K8-91, Richland, WA 99352, Fax: 509-376-0420,, and John H. Weare, Department of Chemistry & Biochemistry, University of California at San Diego
Abstract text not available.

COMP 237 [834391]:  Computational study of epoxide ring-opening reactions of 2,3-anhydrosugars

Peng Tao1, Raghavan B. Sunoj1, Matthew P. DeMatteo1, Todd L. Lowary2, and Christopher M. Hadad1. (1) Department of Chemistry, Ohio State University, 100 West 18th Avenue, Columbus, OH 43210,, (2) Department of Chemistry and Alberta Ingenuity Centre for Carbohydrate Science, University of Alberta

Density functional theory (DFT) methods, along with molecular dynamics simulations, have been applied to study the mechanism of epoxide ring opening for the stereoselective synthesis of functionalized glycosides from 2,3-anhydroglycosides. The relative C2 and C3 selectivity was determined based on complete transition state searches in the gas phase as well with continuum dielectric methods to compare the calculations to the experimental results. Extended molecular dynamics simulations (up to 2 ns) have been performed on selected systems to investigate the dynamical interactions and coordination of the experimental catalysts, such as sparteine, with the 2,3-anhydrosugar. The simulation results reveal that sparteine is strongly coordinated to the Li+ counterion, and provides significant stability to hold the Li+ in close proximity for the epoxide oxygen to facilitate ring opening. In addition, CPMD (Car Parrinello Molecular Dynamics) simulations have been applied to visualize the detailed ring-opening process for the anhydrosugar.

COMP 238 [826718]:  Computational study of the reaction mechanism of ethylenimine with DNA

Patricia M. Todebush, Department of Natural Sciences, Clayton College and State University, 5900 North Lee Street, Morrow, GA 30260, Fax: 770-960-4335,
Computational chemistry methods have been used to study the interactions between aziridine (and other small alkyl substituted ethylenimines) and the viral DNA backbone specifically looking to understand and possibly predict the correct mechanism for viral inactivation by electronically studying the ring opening mechanism to understand its biological activity. Density Functional Theory (B3LYP 6-31G**) calculations have been completed to study the reaction mechanism for the interaction of ethylenimine as a DNA cross linking agent via nucleophilic ring opening of the ethylenimine by nitrogen on the purine ring system. This work is extremely relevant since determining the mechanism of action for ethylenimine will lead to a better understanding of how to create vaccines, while also opening the possibility for future studies of ethylenimines as anti-cancer and antibiotic agents.

COMP 239 [815401]:  Computational study of twisted intramolecular charge transfer (TICT) characteristics of substituted pyrrolyl pyridines

Jessica L. Menke and Eric V. Patterson, Department of Science, Truman State University, 100 E. Normal, Kirksville, MO 63501, Fax: 660-785-4045,
4-(1-pyrrolyl)-pyridine was investigated for the presence of TICT (twisted intramolecular charge transfer) characteristics. This molecule was studied using quantum mechanical molecular orbital and density functional calculations. The ground state energy surface for the rotation about the central axis was obtained at the B3LYP/6-31G* level. The effect of polar (acetonitrile) and non-polar (cyclohexane) solvent was accounted for through the integral equation formalism polarizable continuum model (IEF-PCM). TD/SCRF single point calculations were computed at each point along the scan to obtain approximate surfaces for the first six excited states. Excited state optimizations were then performed at the CIS/6-31G* level. Trends for 4-(1-pyrrolyl)-pyridine will be compared to the previously studied 2-(1-pyrrolyl)-pyridine and three of its methylated derivatives, 3-methyl-2-(1-pyrrolyl)-pyridine, 2,4-dimethyl-6-(1-pyrrolyl)-pyridine, and 5-methyl-2-(1-pyrrolyl)-pyridine which have been shown to possess TICT characteristics.

COMP 240 [828741]:  Determination of the conformation of 2-hydroxy, 2-amino and 2-fluoro benzoic acid dimers in CDCl3 using 13C NMR and DFT/NBO analysis: The central importance of the carboxylic acid carbon

Ronald R. Burnette, School of Pharmacy, University of Wisconsin - Madison, 777 Highland Avenue, Madison, WI 53705-2222, Fax: 608-262-3397,, and Frank Weinhold, Theoretical Chemistry Institute and Department of Chemistry, University of Wisconsin

DFT (B3LYP/6-31+G*) structure optimization and subsequent Natural Bond Orbital (NBO) analysis with B3LYP/6-311+G(2d,p) characterization of the conformations and 13C chemical shifts of 100 mM, 2-hydroxybenzoic acid, 2-aminobenzoic acid and 2-fluorobenzoic acid in CDCl3 at 250C is performed. Two primary minimum energy conformations each are found for 2-fluorobenzoic acid, 2-aminobenzoic acid and 2-hydroxybenzoic acid. Concentration dependent shifts in the 1H and 19F NMR spectra suggest dimerization of benzoic acid derivatives occurs in CDCl3 but not for fluorobenzene. The hydrogen bonding interaction between carboxylic acid groups was demonstrated to be resonance-assisted and is stabilized primarily by overlap between the carbonyl oxygen's lone pairs and the adjacent hydroxyl antibonding orbital as determined by second order perturbation analysis. The average absolute value of the spectral shift differences between conformations, for theory versus experiment, is found to be directly proportional to the relative energy difference between the respective conformations. In all cases, the anisotropic spectral shift of the carboxylic carbon is strongly affected (deshielded) by characteristic resonance-type delocalization within the carboxylic moiety. The most important are the two competing vicinal NBO delocalizations from the carbonyl oxygen p-type lone pair into the hydroxyl CO and ring CC antibonds, with the former type dominating.

COMP 241 [852924]:  DFT and ONIOM studies on the oxalate oxidase (Oxo) catalytic mechanism

Tomasz Borowski1, Arianna Bassan2, Nigel G.J. Richards3, and Per Siegbahn1. (1) Department of Physics, Stockholm Center for Physics, Astronomy and, Stockholm University, S-106 91, Stockholm, Sweden, Fax: 46 8 55378601,, (2) Department of Physics, Stockholm University, (3) Department of Chemistry, University of Florida

Density Functional Theory (DFT) methods have been used to discern the molecular mechanism of the catalytic reaction of oxalate oxidase (Oxo). The study has been done in two steps. First, various reaction mechanisms have been analyzed with standard DFT methods applied to relatively small model system comprising the active site Mn ion, the groups modeling the first-shell ligands and the reactants. At this stage, the environmental effects of the remaining part of the enzyme were accounted for using the SCRF approach. Out of the mechanisms tested, only one involved an acceptable activation barrier. Secondly, the structure and energetics of the key intermediates (for example see figure) found in the favorable catalytic mechanism were refined with the QM/MM methods (ONIOM) applied to models comprising 900 atoms in total and ca. 70 atoms in the QM region. The results of these calculations are presented in the poster.

COMP 242 [820434]:  Energetics and barriers of pericyclic reactions involving alkene analogues R2BPR'2 and R2AlNR'2

Thomas M. Gilbert and John M. Bailey, Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115, Fax: 815-753-4802,

Although physical studies of phosphinoboranes R2BPR'2 suggest that some contain weak B=P double bonds, computational studies of their pericyclic reactions disagree with this view. For example, the [2+2] cyclization of (F3C)2B=P(t-Bu)2, 1, and ethane exhibits a very small barrier, in contrast to the analogous organic reaction. Pericyclic reactions between 1 and alkenes are more exothermic than its dimerization, making it an interesting synthetic target. Related aminoalanes R2AlNR'2 exhibit planar geometries around nitrogen, yet show physical behavior inconsistent with the presence of an Al=N double bond. Reactivity computations confirm that dimerization is energetically favored over crossover pericyclic reactions for aminoalanes with small R, R'. Dimerization is disfavored for those with large R, R', but these distort from planarity, confirming the weak π interaction. When one enforces a planar geometry by linking large R, R' peripheral groups, the aminoalane exhibits a decreased tendency toward dimerization and enhanced pericyclic reactivity.

COMP 243 [817192]:  Large-scale molecular orbitals based on fragment molecular orbital method solved by projection method

Yuichi Inadomi1, Hiroaki Umeda1, Toshio Watanabe1, Tetsuya Sakurai2, and Umpei Nagashima1. (1) Grid Technology Research Center, National Institute of Advanced Industrial Science and Technology, 1-1-1 Umezono, Tsukuba 305-8568, Japan, Fax: +81-29-862-6601,, (2) Institute of Information Science and Electronics, University of Tsukuba

We have been developing the computational tool to obtain the molecular orbitals for large molecules such as proteins and molecular clusters without excessive calculation costs. In our method, the entire Fock matrix is generated by the technique based on the fragment molecular orbital method, which is applicable to large systems and suitable for the parallel processing. To solve the large scale generalized eigenproblem, we use the projection method with the preconditioning because this method works effective in using the computers of the distributed memory parallel architecture and is favorable to calculate only a small number of eigenvalues and corresponding eigenvectors of the large scale Fock matrix. Our method has high parallelization efficiency and the communication cost is negligible to the total calculation costs. Thus, this is one of the right applications for using the Grid technology.

COMP 244 [833943]:  ONIOM computations of the water dimer structure and thermodynamics

Stephen Arnstein, Department of Chemistry and Biochemistry, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282,, and Jeffrey D. Evanseck, Department of Chemistry & Biochemistry and Center for Computational Sciences, Duquesne University

Nine water dimer configurations have been evaluated with the ONIOM method. Eight quantum chemical methods combined with 21 basis sets have been tested to predict properties of the water molecule and compare to experiment. The most promising levels of theory have been coupled to two semi-empirical methods and the AMBER force field. Convergence of computed structure, dipole moment, vibrational frequencies, quadrupole moment and polarizability for the water molecule occurs when using the 6-311+G(3d2f,2p) basis set. The efficiency and accuracy of the ONIOM method is assessed in the modeling of the hydrogen bond in the water dimer and can be applied to hydrogen bonding in other biological and chemical systems. For ONIOM calculations on the water dimer, we find that the lower level of theory dominates the computed structural and energetic properties.

COMP 245 [828861]:  Parallel Fock matrix construction on layered multi-processor system

Hiroaki Umeda1, Yuichi Inadomi1, Hiroaki Honda2, and Umpei Nagashima1. (1) Grid Technology Research Center, National Institute of Advanced Industrial Science and Technology, 1-1-1 Umezono, Tsukuba, Japan, Fax: +81-29-862-6611,, (2) Mizuho Information & Research Institute

Fock matrix construction routine for a RHF calculation has been parallelized on a multi-processor system with layered-structure, which consists of 3 host PCs (level 0; Pentium3 400MHz, 256Mbytes memory), and 21 controller- and 63 worker-SH4 processors (level 1 and 2; Hitachi SH4 200MHz, 64Mbytes memory). On this system, worker processor cannot communicate with the other worker processors nor host PCs, it can only communicate with the controller processor directly connected. We have developed multi-level dynamic load-balancing routine of Parallel Fock matrix construction to drive worker processors, and introduced it into GAMESS program on host PCs. Speedup of the routine shows 62.5 when HF/STO-3G calculation of (Gly)15 is performed using 63 worker-SH4 processors even on the layered multi-processor system. Acknowledgments: This work was partially supported by CREST, JST, and also supported by Special Coordination Funds for Promoting Science and Technology, “EHPC Project”, from MEXTs Grant.

COMP 246 [823727]:  Modeling MAO (methylaluminoxane) formation

Lacramioara Negureanu, Randall W. Hall, and Les G. Butler, Department of Chemistry, Louisiana State University, Baton Rouge, LA 70820, Fax: 225-578-3458,

Ab initio MP2 molecular dynamics simulations have been used in order to model MAO formation through what we consider elemental steps starting with the reaction of trimethylaluminum and water. A building molecule in MAO formation has been identified and a general formula, answering to some of the most crucial questions regarding MAO structure and catalytic activity ( Al:CH3 ratio higher than 1, its ability to methylat the matallocene catalyst and its role in the formation of the olefin polymerization active species) has been proposed. For the proposed MAO formation steps activation barriers have been calculated for DFT/6-31g** chemistry model. For the proposed models NMR properties are calculated for the comparison with the experiment.

COMP 247 [823037]:  Local electron correlation models

Martin Head-Gordon, Department of Chemistry, University of California Berkeley and Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720,

Progress on the development and implementation of efficient local correlation models will be reported, with particular emphasis on second order Moller-Plesset perturbation theory, as the simplest wave-function based approach. Examples will be given, and prospects for the future discussed, as part of overviewing our progress in the following areas: 1) Using auxiliary basis expansions, we have achieved an efficient implementation of the local triatomics-in-molecules (TRIM) model, which scales only 4th order with molecule size. 2) We are developing single parameter opposite-spin correlation models that offer improved statistically improved accuracy relative to MP2 theory, as well as permitting faster computation. 3) We are exploring localized orbitals that are in a sense optimal for describing electron correlation in local terms. 4) Modifications of the auxiliary basis approach that are particularly tailored for exploiting sparsity are in progress.

COMP 248 [818568]:  Correlation energy extrapolation by intrinsic scaling

Klaus Ruedenberg and Laimutis Bytautas, Ames Laboratory USDOE and Department of Chemistry, Iowa State University, Ames, IA 50011, Fax: 515 294 0266,

Remarkably accurate scaling relations have been shown to exist between correlation energy contributions from various excitation levels in the CI approach, when these contributions are considered as functions of the size of the correlating orbital space. On the basis of these relationships, a new method has been developed for accurately extrapolating sequences of smaller CI calculations to the full CI energy. The method has furthermore been combined with the appropriate extrapolation of the FCI energies to the complete basis set limit. Using this approach, the ground states of the atoms Ne, F, O, N, C as well as the molecules H2O, F2, O2, N2, C2 and, hence, the respective binding energies have been recovered to millihartree accuracy. The method also operates successfully for systems with strongly multi-configurational zeroth-order wavefunctions, where coupled-cluster approaches encounter problems. For instance, the entire dissociative potential energy curve of F2, has been determined with millihartree accuracy.

COMP 249 [818484]:  Use of quantum Drude oscillators in describing dispersion interactions between weakly bound electrons and polar molecules

K. D. Jordan, Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260,, and Feng Wang, The Henry Eyring Center for Theoretical Chemistry, University of Utah

Electron correlation effects play an important role in the binding of excess electrons to polar molecules and their clusters. Both second-order dispersion interactions and high-order correlation effects make important contributions to the electron binding as described by traditional electronic structure methods. We have recently developed a method using quantum Drude oscillators for describing these correlation effects. In this approach the excess electron is treated explicitly, and all other electrons of the molecule or cluster are modeled using Drude oscillators. The approach is illustrated with applications to water clusters.

COMP 250 [807552]:  John Pople's interpretive work

Richard F. W. Bader, Department of Chemistry, McMaster Univeristy, 1280 Main St. W, L8S 4M1 Hamilton, ON, Canada, Fax: 905-522-2509,
I met John Pople when I arrived in Cambridge in 1958 for a year of postdoctoral studies. In addition to having the opportunity of speaking with John, I read the papers that he co-authored with Sir John Lennard-Jones, particularly those describing the development of equivalent orbitals. John Pople's early work stressed the interpretive side of theoretical chemistry. He used equivalent orbitals to obtain understanding of numerous problems including the structure of liquid water, stressing the role of ‘lone pairs' that emerged from the equivalent orbital approach. He approximated the electron density distributions in simple hydride molecules, using the observed geometries and dipole moments as input, work that we later emulated using the forces on the nuclei to parameterize the equivalent orbitals. His interpretive work extended into the early sixties when he proposed a method for expressing the diamagnetic susceptibility as a sum of atomic contributions, foreshadowing another of my research interests.

COMP 251 [811538]:  Some interesting features of gas-phase reactions involving metal dications

Manuel Yáńez, Departamento de Química, C-9, Universidad Autónoma de Madrid, Cantoblanco, 28049-Madrid, Spain, Fax: +34-91-497-5238,

The development of electrospray ionization techniques has opened up the possibility of producing clusters involving metal dications in the gas phase, and the interest in dication-molecule reactivity grew significantly. The first studies of reactions between metal dications and organic bases reveal a clear distinction between transition metal and alkaline-earth metal dications. In the latter case, [base-M]2+ cations could be isolated in the gas phase and their unimolecular reactivity could be investigated. For transition metals, only monocations produced after the loss of a proton from [base-M]2+ could be detected. One peculiarity of gas-phase reactions involving dications is the possibility of observing coulomb explosions, that may compete with unimolecular decompositions leading to the loss of a neutral molecule from the [base-M]2+ adduct. This will be illustrated for urea + Ca2+ and glycine-Ca2+ reactions, through an analysis of the topology of the corresponding potential energy surfaces obtained at the B3LYP/cc-pWCVTZ level of theory.

COMP 252 [817549]:  Network topology of protein structures

Saraswathi Vishveshwara and K.V. Brinda, Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India, Fax: +91-80-23600535,

It is well known that the three dimensional structural information of proteins is encoded in its sequence. However, the code is a subtle balance among a number of factors such as the geometrical properties, energetics, and conformational entropy of the constituents of the polypeptide chain. Such factors collectively determine the folding of the protein into its unique three dimensional structure. The problem of protein folding has been addressed from various points of view. One approach involves the study of the vast amount of structural data that are available on proteins and the understanding of the rules that govern their structure.

Recently, proteins are being viewed as graphs and the protein structure graphs have been constructed from the available crystal structure data. A distinct advantage of the graph representation is that it takes into account the global topology of the protein structure. Such graphs have been investigated in order to gain insights into the structure, stability, and folding of proteins. We have constructed the protein structure graphs and have studied their properties utilizing the techniques of graph spectral analysis. The graphs are converted to Laplacian matrices and their important eigenvalues and the corresponding eigenvector components have been analyzed to gain information on clusters of interacting residues in proteins. The eigenvector components corresponding to the top eigenvalues are also used to identify cluster centres. This has enabled us to identify a variety of clusters within the protein, which are important from the structure, stability and folding points of view. The cluster centres are recognized as amino acid residues in the proteins, which are crucial for the integrity of the protein structure. Furthermore, we have studied the weighted protein structure graphs from the perspective of network topology. The basic principles that have emerged from these investigations will be discussed.

COMP 253 [821011]:  Diffusion in liquids: Breakdown of Stokes-Einstein relationship

Yashonath Subramanian1, Pradip Kumar Ghorai1, and Srikanth Sastry2. (1) Solid State & Structural Chemistry Unit, Indian Institute of Science, Sir C.V. Raman Avenue, Bangalore 560 012, India, Fax: +91-80-23601310,, (2) Theoretical Sciences Unit, Jawaharlal Nehru Centre for Advanced Scientific Research

We show that the well known Stokes-Einstein relationship between the the self diffusion coefficient and the size of the solute breaksdown when the size of the solute is comparable to that of the void existing amidst the solvent in which it is diffusing. The size of void is proportional to the size of the solvent and therefore the regime where it breaksdown depends on the ratio of the solute to the solvent radius. This interesting behaviour has its origin in Levitation effect and occurs due to mutual cancellation of forces on the guest. The associated properties such as the potential energy landscape, behaviour of intermediate scattering function and k dependence of the self part of the dynamic structure factor are reported. They are significantly different for the linear regime and the anomalous regimes of the Levitation effect.

COMP 254 [832403]:  Assembling phenomena of water-containing clusters and the design of ion selective receptors

Kwang S. Kim, Department of Chemistry, Pohang University of Science and Technology, San 31, Hyojadong, Namgu, Pohang 790-784, South Korea, Fax: +82-54-279-8137,

To better understand water, we begin with studying the intrinsic nature of water clusters. An excess electron changes certain water cluster structures drastically, resulting in the magic numbers for the anionic water clusters. By interaction with halide ions followed by laser excitation, neutral water clusters can form anionic water clusters. This dynamics is investigated with ab initio molecular dynamics simulation of the excited state. We discuss the association and dissociation phenomena of acids, bases, and salts by water clusters, and the molecular assembly phenomena to form water-bridging organic nanotubes along with the short hydrogen bonding in the contiguous one-dimensional hydrogen bond relays of the nanotubes. Finally, we highlight our recent efforts on designing ion selective receptors as nanosensors. We show how a design strategy based on quantum mechanical calculations of molecular clusters enables us to design a wide range of receptors exhibiting excellent affinity for the biologically important ions.

COMP 255 [813998]:  Car-Parrinello and classical molecular dynamics simulation studies of supercritical carbon dioxide

Balasubramanian Sundaram and Moumita Saharay, Chemistry and Physics of Materials, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O, Bangalore 560064, India, Fax: 91-80-22082766, BALA@JNCASR.AC.IN

We have performed Car-Parrinello molecular dynamics (CPMD) simulations of supercritical carbon dioxide, in order to understand its microscopic structure and dynamics. Atomic pair correlation functions and structure factors have been obtained and good agreement has been found with experiments. Neighboring pairs of CO2 molecules are present in the distorted T-shaped geometry. The intramolecular vibrations of CO2 reveal a red shift in the frequency spectrum relative to that of an isolated molecule, consistent with experiments.

The distribution of the magnitude of instantaneous dipole and quadrupole moments of individual molecules were found to be asymmetric with long tails, with mean values of moments as 0.85 Debye and 6.1x10-26 esu, respectively.

The solvent structure of CO2 molecules around an ethanol molecule (solute) has also been obtained using classical and CPMD simulations. The structure and lifetime dynamics of the hydrogen bond between the alcohol and carbon dioxide has been characterized.

COMP 256 [815114]:  Characterization of interfacial n-octanol and 3-octanol with molecular dynamic simulations

Preston B. Moore, Department of Chemistry & BIochemistry, University of the Sciences in Philadelphia, 600 South 43rd Street, Philadelphia, PA 19104, Fax: 215-596-8543,, and Raeanne L Napoleon, Department of the Sciences in Philadelphia, Department of Chemistry

Molecular Dynamic (MD) computer simulations of interfacial n-octanol/water and 3-octanol/water were investigated. The octanol systems were simulated at the vapor interface, at the water interface, and in the bulk for comparison. This systematic study was intended to understand octanol/water interfaces on the atomic level. After equilibration, in which an interface formed via phase separation, the intefacial propers were investigates for structural and dynamical properties. Our results supports the idea of order interface only 1-2 molecular layers deep before bulk properties are reached for water and 3-octanol, but we find surface effects for the n-octanol interface well over 30 Ĺ. Our simulations of the orientation's dynamics suggest frustration at the surface. The octanols form a hydrogen bonded network with the water ordering the surface molecules, creating a hydrophilic -hydrophobic layering, consistent with recent experiments.

COMP 257 [834359]:  Simulation of fluorinated ionic liquids: From ab initio to classical model

Christian Simon, Pierre Turq, and Mathieu Salanne, Laboratoire Liquides Ioniques et Interfaces Chargées, Université Pierre et Marie Curie, 4 Place Jussieu, Case courrier 51, Paris Cedex 05 75252, France, Fax:,

Hydrogen fluoride based liquid solutions (like ethyl-methyl-imidazolium fluoride in solution in HF, or water-HF mixtures), or fluoride salts melts (like LiF-CaF2 or LiF-ThF4) are difficult to study experimentally because of their high corrosivity and toxicity. Chemical-physics data are much less available than for aqueous systems for example.

Interactions in these systems are quite complex since their constituents can form either hydrogen bonds either semi-covalent bonds: simple pair potentials from quantum mechanics do not capture these features. Ab initio molecular dynamics simulations are therefore the only starting point to devise classical models. We will present different approaches, including systematic parametrization of polarizable models. The qualities and limits of the models obtained will be discussed regarding the thermodynamical or dynamic properties of the liquids compared to the few available experimental data.

COMP 258 [797636]:  Flexible “Induced Fit” docking of ligands to enzyme active sites

Shashidhar N. Rao1, Ramy Farid1, Hege Beard1, Tyler Day1, Mee Shelley1, Jason Perry1, Stanley Krystek Jr.2, and Akbar Nayeem2. (1) Application Science, Schrodinger, 120 W. 45th Street, New York, NY 10036-4041,, (2) Computer-Assisted Drug Design, Bristol-Myers Squibb

Conventional docking methods employing a rigid protein may not identify active ligands due to lack of consideration of associated conformational changes in the protein binding site (induced fit). These changes can range from subtle backbone movements to dramatic side-chain and loop movements. To enhance the utility of virtual screening, we have derived a general protocol using our docking and protein structure prediction programs, Glide and Prime, which produces induced-fit models with accurately predicted binding site conformational changes. This paper focuses on three X-ray structures of human liver X receptor beta (LXR-beta PDB IDs 1PQC, 1PQ6 and 1P8D) each of which was induced to fit the ligands from the other two structures. For example, 1PQC with a small ligand T0901317 (43 atoms) was induced to fit the much larger ligands from 1PQ6 (GW3965, 74 atoms) and 1P8D (epoxycholesterol; 73 atoms). All the six induced fit models "trained" to bind the three ligands show remarkable similarity to the corresponding X-ray structures in terms of ligand poses and positions of protein backbone and side-chain atoms. These models accurately predict key protein/ligand interactions observed in the X-ray structures. Thus, each of the native protein structures in 1PQC, 1P8D and 1PQ6 was produced starting from the X-ray structures of the other two complexes. Enrichments in virtual HTS studies carried out using the induced fit models and comparison to enrichments obtained using the rigid X-ray structures will also be presented.

COMP 259 [830064]:  Family 6 glycosyl hydrolases: Automated docking and phylogenetic analysis

Blake Mertz, Robert S. Kuczenski, Robert T. Larsen, Anthony D. Hill, and Peter J. Reilly, Department of Chemical Engineering, Iowa State University, 2114 Sweeney Hall, Ames, IA 50011-2230, Fax: 515-294-2689,

Glycosyl hydrolase Family 6 members, key enzymes in cellulose hydrolysis, are found in eight subfamilies: 1) mainly actinobacterial endoglucanases (EGs); 2) ascomycotal proteins, mainly of unknown function (UPs); 3) chytridiomycotal cellobiohydrolases (Cel6As) and EGs; 4) actinobacterial and proteobacterial Cel6As and UPs; 5) chytridiomycotal Cel6As and UPs; 6) ascomycotal UPs; 7) basidiomycotal Cel6As and UPs; and 8) ascomycotal Cel6As and UPs. Cellooligosaccharides were computationally docked into the active site of Hypocrea jecorina (formerly Trichoderma reesei) Cel6A, a Subfamily 8 member, to determine the extent of its processive action in binding and attacking cellulosic substrates. β-Glucosyl residues of substrates bound in the –1 subsite are in the skew-boat conformation and are much more strongly bound than when they are in the chair conformation. Docking allowed the identification of subsites –3 and +3. This computational work adds an important tool to research into the technologically and economically feasible breakdown of cellulose to glucose.

COMP 260 [819445]:  Protein-protein docking methods used to study complex protein interactions

Dana Haley-Vicente, Accelrys Inc, 10188 Telesis Court, Suite 100, San Diego, CA 92121,, and Tim Glennon, Life Science, Accelrys

There are an estimated 15,700 known protein-protein interactions in humans (BIND, Understanding these interactions is important for insights into molecular recognition and networks such as signal transduction pathways in cells. One such interaction is between the interleukin-1 (IL-1) receptor and an IL-1 agonist, which mediate of inflammation response. The binding of an agonist such as IL-1 alpha to the IL-1 receptor is the initial step in IL-1 signal transduction and therefore is a tempting target for anti-inflammatory therapeutics. To assist in studying protein interactions, we have used ZDOCKpro for protein-protein docking as well as complementary tools, Evolutionary trace, Profiles-3D, and DelPhi, to study and validate the IL-1 receptor antagonist and agonist system. Results reveal the ease of docking the unbound (non-complex structure) form of the protein ligands, IL-1 beta and IL-1 receptor antagonist, to the bound (complex structure) of the IL-1 receptor. In contrast, docking of a bound 21-residue peptide antagonist to two forms of the bound IL-1 receptor proves difficult possibly due to the intrinsic flexibility of the protein receptor upon binding of the peptide. Overall, we find protein-protein docking and complementary tools are useful to study protein-protein interactions of unknown complex assemblies.

COMP 261 [833601]:  Structure-based design of focused drug-like combinatorial libraries

Leah L. Frye1, Robert B. Murphy2, T. Mark Reboul2, Peter S. Shenkin2, Daniel T. Mainz2, Evelyn W. Chambers1, D. Quentin McDonald2, and Richard A. Friesner3. (1) Schrodinger, LLC, 1500 SW First Ave., Suite 1180, Portland, OR 97201, Fax: 503-299-4532,, (2) Schrödinger, LLC, (3) Department of Chemistry, Columbia University

In recent years, combinatorial library design has shifted toward small focused libraries that are biased toward a specific target and exhibit optimal drug-like physiochemical properties. Structure-based design strategies can be implemented in focused library design when a 3D structure of the target is available. We will describe the development of a new computational tool based on our docking algorithm, Glide, that performs rapid virtual screening of combinatorial libraries to eliminate unpromising compounds before they are synthesized. The methodology involves: 1) definition of core positions, 2) evaluation of the best substituents at each site of diversity, 3) rational selection of which fully substituted cores to evaluate further, 4) docking of the selected fully substituted cores, and 5) utilization of various strategies for the selection of the optimal reagents for use in library synthesis based on the docking results and predicted ADMET properties (QikProp). A number of case studies using this tool will be presented.

COMP 262 [823533]:  Testing compounds for selectivity: Docking helps to find relevant proteins

Sukjoon Yoon, Andrew Smellie, David S. Hartsough, and Anton Filikov, Informatics and Modeling, ArQule, Inc, 19 Presidential Way, Woburn, MA 01801, Fax: 781-376- 6019,,

At the stage of optimization of a chemical series, the compounds are normally assayed for binding or inhibition on the target protein as well as on several proteins from a selectivity panel. These proteins are identified from sequence homology and/or experimental selectivity data, which are usually very limited or not available. Here we present a computational method of identification of selectivity panel proteins. It is based on evaluation of binding site similarity to the target protein using docking and scoring of target-optimized small molecular probes. Docking scores of these probes to other proteins measure the binding site similarity to the target. Validation of the method includes re-discovery of non-homologous proteins that bind common ligands, like estradiol, tamoxifen or riboflavin. Given three-dimensional structures, the method can effectively discriminate proteins with binding sites similar to the target from random proteins independently of sequence homology.

COMP 263 [831654]:  Using physics-based energy functions to estimate the binding free energy of docked complexes

Deepak Singh, Nan-jie Deng, C. M. Venkatachalam, and Marguerita Lim-Wilby, Accelrys, Inc, 10188 Telesis Court, Ste 100, San Diego, CA 92121,

Virtual screening protocols in the search of lead candidates are increasingly sophisticated and efficient. With increasing availability of good 3D structures of receptors, screening for good binders by application of docking enables attempts at predicting experimental binding affinity. Docking of known and random ligands to a receptor target can thus provide a good method for prioritizing compounds for synthesis and assay. However current docking and scoring approaches are unable to accurately rank hits on the basis of experimental binding affinity. Molecular mechanics energy functions combined with molecular dynamics simulations and continuum electrostatics have shown considerable promise in providing reasonable estimates of the binding free energy of protein-ligand complexes. In this study three different physics-based methods to estimate the absolute binding free energy of a set of known ligands of the thymidine kinase receptor are compared. All calculations were performed on docked conformations identified as part of a virtual high throughput screening protocol. The advantages of using physics-based methods following the application of a vHTS approach for more focused discovery efforts are discussed.

COMP 264 [831218]:  A natural amino acid classification scheme derived from multiple sequence alignments

Eric B. Fauman, Computer Assisted Drug Discovery, Pfizer Global Research & Development, 2800 Plymouth Rd, Ann Arbor, MI 48105, Fax: 734-622-2782,

A protein structure defines a series of functional requirements necessary for generating that structure. A multiple sequence alignment provides a number of solutions to these requirements. By comparing thousands of positions across hundreds of multiple sequence alignments, one can derive a small number of discrete functional classes, and a fitness of each amino acid for each class. Bayesian inference from these classes reproduces standard substitution matrices when applied to pair-wise amino acid comparisons, but extends naturally to conservation analysis of multiple residues observed at a specific position in a multiple sequence alignment.

COMP 265 [834625]:  Algorithmic complexity of protein structure alignment

Greg Dewey and Yuting Jia, Applied Life Sciences, Keck Graduate Institute, 535 Watson Drive, Claremont, CA 91711, Fax: 909-607-8086,

Structural information can identify common functional and evolutionary relationships in proteins with low sequence similarity. Consequently, structural alignments often reveal commonalities not seen by sequence alignment. Despite this important role in bioinformatics, structural alignment algorithms, scoring systems and significance testing are not at the level of sophistication of their counterparts in sequence alignment. We propose a new alignment method in which one protein structure is related to a second by the number of operations that must be performed to make the protein isomorphic with the first. Group operations about internal coordinates are used to transform one protein's coordinates into another. The similarity of two proteins can be described as the minimal number of operations in this transformation. This definition of protein similarity is closely related to the algorithmic complexity of the alignment and provides an information metric of structural similarities. Results on lattice proteins are discussed using this general method.

COMP 266 [814480]:  Information theory and macromolecular structure

Irwin D. Kuntz, Department of Pharmaceutical Chemistry, University of California San Francisco, 600 16th St., San Francisco, CA 94143-2240,, and Tiba Aynechi, Graduate Program in Biophysics, University of California San Francisco
I will explore applications of Shannon information theory to problems in macromolecular structure. Specifically, I am interested in the efficiency of structural constraints, molecular force fields and sequence alignment procedures in clustering sequence-structure spaces.

COMP 267 [804242]:  Shannon entropy as a local surface property

Tim Clark, Friedrich-Alexander-Universität Erlangen-Nürnberg, Computer-Chemie-Centrum, Nägelsbachstrasse 25, D-91052 Erlangen, Germany, Fax: +49-9131-8526565,
Molecules convey information in nature. The most common, and possibly the only, mechanism by which molecules pass on their information are intermolecular interactions. The information content of a molecule must therefore be encoded in its ability to enter into interactions with other molecules. We have recently shown that this ability can be represented well by four local properties, the molecular electrostatic potential, the local ionization energy, the local electron affinity, and the local polarizability. We now present a theoretical framework that allows the values of these four local properties at a molecular surface, which may be van der Waals, solvent-excluded or isodensity, to be used to calculate the information content of the molecule. The locality of Shannon entropy is an important property because it allows us to assign noise levels to different regions of the molecular surface. Regions of low Shannon entropy must be involved in specific binding.

COMP 268 [826129]:  Group Entropy analysis and hybrid Quantum Mechanical/Molecular Mechanical simulations for elucidation of enzyme function

Troy Wymore1, Hugh B Nicholas1, John Hempel2, and David W Deerfield II1. (1) Biomedical Initiative Group, Pittsburgh Supercomputing Center, 4400 Fifth Avenue, Pittsburgh, PA 15213, Fax: 412-268-8200,, (2) Department of Biological Sciences, University of Pittsburgh
We will describe our research that has lead to a successful integration of sequence-based bioinformatics and atomic scale simulation on the Aldehyde Dehydrogenase (ALDH) family. This integration has resulted in compelling hypotheses concerning the molecular basis for two metabolic diseases as well as a novel enzyme mechanism. We developed and applied analyses that identify residues in biological macromolecules that confer specificity of interaction on the members of a paralogous family of molecules. The analysis uses the Kullback-Leibler (KL) distance; an information theory measure of entropy. Residues that have a high KL distance represent positions in the alignment where there are large systematic differences in the kinds of residues present in the two subfamilies (i.e., the defined subfamily under investigation and the rest of the alignment). This KL distance corresponds to the biological question of “What columns in an alignment most completely discriminate the subfamily or group from the rest of the alignment?” We also sought to better understand how these residues impact on the ALDH chemical mechanism. Therefore, we employed molecular dynamics (MD) simulation methods using both Molecular Mechanical (MM) potentials for studies of substrate binding and hybrid Quantum Mechanical (QM)/MM potentials for the subsequent reactions. The results suggest that the intermediate formed upon nucleophilic attack of the enzyme on the substrate is stabilized by a proton transfer from a mainchain amide. This proton transfer is supported by interactions with a residue with high group entropy. Mutating residues that disrupt this “second sphere” interaction could be the molecular basis behind two metabolic diseases.

COMP 269 [817992]:  Real-space post-Hartree-Fock correlation models

Axel D. Becke, Department of Chemistry, Queen's University, Kingston, ON K7L 3N6, Canada, Fax: 613-533-6669,
The latest developments in our continuing efforts to model post-Hartree-Fock correlation energies will be reported. In particular, a novel and simple DFT model of the dispersion interaction between non-overlapping systems will be presented which works surprisingly well.

COMP 270 [824921]:  Addition via subtraction in coupled cluster theory? A reconsideration of the CC and CI interface

Rodney J. Bartlett and Monica Musial, Quantum Theory Project, University of Florida, Gainesville, FL 32611,

Today, Coupled-cluster (CC) theory has almost entirely eclipsed configuration interaction as the optimum, high-level correlated approach to molecular structure and spectra. This follows because of its size-extensivity and vastly better convergence to the full CI limit. However, one might argue that CC theory is potentially overkill for many problems. John Pople addressed this issue when he introduced quadratic configuration interaction, but that was fundmentally flawed. However, there is a related path that offers simpler calculations than CC theory, but has most of the essential advantages, including size-extensivity. Furthermore, this route might suggest ways to benefit from the cancellation of connected and disconnected cluster operators and to provide more accurate potential energy surfaces. We will present the theory and numerical illustrations.

COMP 271 [819444]:  A generally applicable relativistic methodology based on the regular approximation to the exact relativistic Hamiltonian: Theory and applications utilizing both DFT, many body perturbation and coupled cluster theory

Dieter Cremer, Department of Theoretical Chemistry, University of Göteborg, Reutersgatan 2, Göteborg S-41320, Sweden, Fax: +46-31-7735590,, and Michael Filatov, Department of Theoretical Chemistry, Göteborg University

A hierarchy of generally applicable relativistic methods is presented, which enables one to obtain quantum chemical descriptions of atoms and molecules with increasing accuracy at the all-electron level. [1,2] The new methods (ZORA-GDF, IORAmm, NESC-ZORA, NESC-SORA) are based on the regular approximation to the relativistic Hamiltonian and solve the problems connected with this approach (gauge-invariance problems, problems with the applicability to correlation-corrected wave function methods) in a simple way so that relativistic corrections for a broad spectrum of molecular properties of medium-seized and larger molecules become possible. The new methods are applied with both Hartree Fock, DFT, and correlation corrected wavefunction methods such as MBPT or CCSD(T). Relativistically corrected NMR chemical shifts, NMR spin-spin coupling constants, and other molecular properties are discussed.

1) Filatov, M.; Cremer, D. J. Chem. Phys. 2003, 119, 11526 - 11540. 2) Filatov, M.; Cremer, D. J. Chem. Phys. 2004, 121, 5618 - 5622.

COMP 272 [824122]:  Theoretical studies of second row molecules

Thom H. Dunning Jr., Joint Institute for Computational Science, University of Tennessee, Oak Ridge National Laboratory, Oak Ridge, TN 37831, Angela K. Wilson, Department of Chemistry, University of North Texas, and David E. Woon, Molecular Research Institute

During the past decade, there has been remarkable progress in the quantitative calculation of molecular properties. It is now possible to calculate many properties with an accuracy that rivals that of all but the most sophisticated experimental measurements. However, molecules containing atoms from the second row, aluminum–argon, present a special challenge. The basis sets used to describe second row atoms must be augmented with functions to describe inner polarization effects. In addition, second row atoms can expand their valence shell, leading to unusual bonding situations. We will review results of recent theoretical studies of molecules containing second row atoms with the goal of better understanding how to describe such molecules.

COMP 273 [827200]:  New assessments of quantum chemical methods using G2 test sets

L. A. Curtiss, Materials Science Division, Argonne National Laboratory, 9600 S. Cass. Ave., Argonne, IL 60439,, Krishnan Raghavachari, Department of Chemistry, Indiana University, and Paul C Redfern, Chemistry Division, Argonne National Laboratory

The assessment of quantum chemical methods using well-established test sets of experimental data is important for establishing the reliability of new methods. In the past we have developed test sets of energies (enthalpies of formation, ionization potentials, electron affinities, and proton affinities) including the G2, G2/97, and G3/99 test sets [J. Chem. Phys. 106 1062 (1997); 109 42 (1998); 112 7374 (2000)]. These test sets have been used to assess ab initio as well as density functional methods. In this paper we review these test sets and assessments that have been done with them. An expanded test set that includes larger molecules and third-row elements is presented and results for G3 theory and associated methods on this test set are presented. In addition, a selection of density functional methods, including ones that have appeared since our original papers, are assessed on this new test set.

COMP 274 [825316]:  BMK, a novel density functional for thermochemical kinetics

A. Daniel Boese and Jan M.L. Martin, Department of Organic Chemistry, Weizmann Institute of Science, P.O. Box 26, 76100 Rechovot, Israel, Fax: +972(8)934-4142,,
The prediction of reaction barrier heights is a known weakness of most DFT exchange-correlation functionals. We propose a new density functional, denoted BMK (Boese-Martin for Kinetics), which has an accuracy in the +/- 2 kcal/mol range for reaction barrier heights. Unlike previous attempts at such a functional, this improved accuracy does not come at the expense of equilibrium properties: general thermochemistry is comparable in quality to the best existing hybrid GGA functionals, while geometries and vibrational frequencies are between GGA and hybrid GGA functionals in quality. Initial tests for electrical properties are very encouraging. BMK is thus not a specialized 'kinetics' functional, but rather a general-purpose functional whose area of applicability has been extended to transition states.

COMP 275 [825830]:  Electron tunneling through molecular media

Q. Sun1, J. Liang1, A. Selloni1, and G. Scoles2. (1) Department of Chemistry, Princeton University, Washington Road, Fax: 609-258-6746,, (2) Princeton University and SISSA (Trieste, Italy), Fax: 609-258-6665,

We discuss an experimental and theoretical study of the electronic properties of dithiols sandwiched between two, parallel, Au(111) sufaces. The influence of the distance between the two surfaces and of the chemical nature and length, tilt angle, and coverage of the thiols on the local density of states (LDOS) at the Fermi energy (Ef) has been explored. For alkylthiols, we calculate that the value of the LDOS at Ef near the center of the molecular wires ( a quantity that is related to the tunneling current near zero bias ) is mainly determined by the length of the alkane chains. The tilt angle of the molecular wires with respect to the surfaces ( and , therefore, the distance between the surfaces ) has a very small influence on the LDOS at the center of the molecule, while the effect of coverage can be completely ignored. Experimentally we have carried out differential tunneling current measurements of different thiol monolayers using conductive-tip AFM and nanografting. Whenever possible the experimental results shall be compared with the results of the theoretical study.

COMP 276 [820813]:  Mechanism underlying the product distribution of 1,3-butadiene absorbed on the Si(100)2x1 surface probed by ab initio molecular dynamics

Mark E. Tuckerman, Department of Chemistry and Courant Institute of Mathematical Sciences, New York University, 100 Washington Square East, New York, NY 10003, Fax: 212-260-7905,

The chemistry of hybrid structures composed of organic molecules and semi-conductor surfaces is opening up exciting new avenues of development in molecular electronics, nanoscale devices, and surface lithography. Covalent attachment of organic molecules to such a surface can yield active devices, such as molecular switches, or passive insulating layers. Moreover, the reactions can be controlled by tailoring specific organic molecules, suggesting possible new lithographic techniques. Despite recent experimental and theoretical investigations of the covalent attachment process, a detailed understanding of the chemistry is needed before it can be exploited for such novel purposes and is currently lacking. In this talk, we report on the results of a set of forty finite temperature ab initio molecular dynamics trajectories, which is employed to investigate the distribution of addition products and underlying microscopic mechanism of the addition of 1,3-butadiene to the Si(100)2x1 surface. The product yields are in good agreement with recent STM measurements and include a Diels-Alder [4+2] adduct with a surface dimer acting as the dienophile, a [4+2]-like adduct which bridges two dimers within a row, a [4+2]-like adduct which bridges two dimers in adjacent rows, and an interdimer [2+2] adduct. The trajectories indicate that a common mechanism underlies the distribution and is predominantly a non-concerted stepwise mechanism that proceeds via an intermediate zwitterion composed of a carbocation bonded to a negatively charged surface dimer.

COMP 277 [832653]:  Multimillion atom simulations of dynamics of oxidation of an aluminum nanoparticle and hypervelocity impact damage in aluminum nitride ceramic

Priya Vashishta, Rajiv K. Kalia, and Aiichiro Nakano, Collaboratory for Advanced Computing and Simulations, University of Southern California, 3651 Watt Way, VHE 606, Los Angeles, CA 90089-0242, Fax: 213 821-2664,

Atomistic mechanisms of oxidation of an Al nanoparticle has been studied using large-scale molecular dynamics simulations on parallel computers to study, which has applications in high-energy density materials. Simulation involving several hundred million atoms has been performed on parallel computers to study hypervelocity impact damage of high-strength aluminum nitride ceramic. Results reveal an atomistic mechanism of damage initiation, i.e., the phase transformation wave front acts as a source of dislocations and micro-cracks upon the arrival of an elastic rarefaction wave. A multi-resolution and probabilistic visualization algorithm has been developed to interactively analyze massive datasets from these simulations.

COMP 278 [828641]:  Chemical bonding and properties of high pressure solids

John S Tse, Physics and Engineering Physics, University of Saskatchewan, 116 Science Place, Saskatoon, SK S7N 1A5, Cayman Islands, Fax: 306-966-6400,

Recent experimental studies have revealed many exotic structures of simple elemental solids at high pressure. Instead of adopting progressingly dense pack structures, such as FCC or HCP, very often open and very complex structures indciative of directional bonding were observed. Some of the structure types are unprecedented and not observed in any elments or alloys under ambient conditions. We attempted to rationalize these novel structures and structural transitions employing the concept of chemical bonding. Furthermore, we will correlate the structural features to superconductivity property observed in some of the high pressure polymorphs.

COMP 279 [815811]:  Close-packing and H-bonding in ice and water under extreme conditions

A. Marco Saitta, Physique des Milieux Condensés, Université Pierre et Marie Curie, Campus Boucicaut, 140 rue de Lourmel, 75015 Paris, France, Fax: +33-1-44274469,
The structure of amorphous ice under pressure has been studied by molecular dynamics and in-situ neutron diffraction. The starting low-density phase undergoes significant changes as the density increases, and at ρ=1.51 g/cm3 our calculated gOO(r) is in excellent agreement with our experimental data obtained at 1.8 GPa and 100 K on very high density amorphous ice (VHDA) made at 150K. The analysis of orientational distributions reveals that dense amorphous ice is characterized by major distortions of the tetrahedral geometry, and that the structural changes on densification can be interpreted as a trend towards a disordered closed packed structure. The onset of the angular distortions is driven by temperature and explains the existence of two high-density forms of amorphous ice, HDA and VHDA. A similar study, although very difficult from the experimental point of view, has been conducted on hot liquid water up to 700 K and 6.5 GPa. A preliminary analysis of the experimental data and of the classical and Car-Parrinello simulations shows that water under these conditions behaves more and more as a simple liquid.

COMP 280 [806383]:  Modeling allosteric inhibition of LFA-1/ICAM-1 interaction using normal mode analysis

Kiyean Nam, Molecular Systems, Merck & Co., Inc, RY50SW-100, P.O. Box 2000, Rahway, NJ 07065, Fax: 732-594-4224,
Recently, significant progress has been made in the binding free energy (BFE) calculation methods between proteins and small molecules. However, in many cases, the data that molecular modeling needs to correlate with are not necessarily the direct measure of BFE. Assays often measure the functionality of the ligand that represents the secondary or tertiary effect of ligand binding to the target. Assays that measure the protein-protein interaction upon ligand binding at an allosteric site are good examples. In these cases, BFE calculations tend to be less informative as a predictive parameter for the assay readout, such that careful visual inspection and analysis of the docking or experimental structures becomes the sole approach in terms of the structure based approaches. In an attempt to find an alternative way of modeling the system that may have an indirect correlation between the BFE of a ligand and the assay outcome, allosteric inhibition of the Leukocyte Function associated Antigen-1 (LFA-1)/Intracellular Adhesion Molecule-1 (ICAM-1) interaction has been studied with normal mode analysis (NMA).

COMP 281 [834696]:  PRECISE: A database of predicted and consensus interaction sites in enzymes

Karl Clodfelter1, David Lancia2, Melissa R. Landon1, and Sandor Vajda2. (1) Program in Bioinformatics, Boston University, 44 Cummington Street, Boston, MA 02215,, (2) Department of Biomedical Engineering, Boston University
We have developed a computational resource and database, called Predicted and Consensus Interaction Sites in Enzymes (PRECISE) to provide query and visualization tools for the comparative analyses of the interactions extracted from all relevant structures. For each enzyme, the analysis yields a consensus binding site, obtained by aligning all homologous sequences, identifying the residue positions that are important for the binding of any ligand, and assessing the roles of amino acids at these positions. The identification of consensus residues is based on: (1) relevant enzyme-ligand complex structures in the PDB, (2) computational solvent mapping, a novel binding site prediction method, and (3) interactions submitted to the data base. The resource is useful both for understanding the behavior of enzymes at the molecular level, and for rational design aimed at altering enzyme selectivity. Version 1.0 of the webpage is available at

COMP 282 [834848]:  Structural and electronic properties of the oxygen evolving complex in photosystem II: QM/MM study of the complete ligation by protein, water and chloride

Eduardo M. Sproviero, Jose A. Gascon, James P. McEvoy, Gary W. Brudvig, and Victor S. Batista, Department of Chemistry, Yale University, P. O. Box 208107, New Haven, CT 06520-8107, Fax: 203-432-6144,

QM/MM computational models of the Oxygen-Evolving Center (OEC) in photosystem II are investigated at the ONIOM (UHF_B3LYP/lacvp:AMBER) level of theory. The models are based on X-ray diffraction data [Ferreira et al., Science 303 (2004), 1831-1838] and include the complete ligation of the Mn4CaO4 cluster in the S1 state by protein residues, water and chloride. The coordination by carboxylate groups includes η2 bridging of Mn(2) and Mn(4) by D1-Glu333, bidentate coordination of CP43-Glu354 to Mn(3) and monodentate coordination of D1-Asp342 to Mn(1). The structure of the OEC is in very good agreement with EXAFS data. The analysis of possible protonation states of metal-bound water molecules and protein ligands is also presented. The influence of the protein on the OEC architecture is explored by comparing the QM/MM models to the OEC models prepared in the absence of the protein environment. Such a comparison is essential for understanding fundamental aspects of structure-function relationships.

COMP 283 [830825]:  Interactions of alcohol, anesthetic and aromatic ligands with LUSH, an odorant binding protein using molecular dynamics simulations

Satyavani Vemparala, Department of Chemistry, University of Pennsylvania, 231S, 34th Street, Philadelphia, PA 19104,, and Michael L. Klein, Department of Chemistry, Center for Molecular Modeling, University of Pennsylvania

LUSH is an odorant binding protein and plays a crucial role in the insect olfactory functions. Recent experiments have suggested specific binding sites, involving serine and threonine amino acids, for short n-chain alcohols and aromatic ligands. Simulations over 70ns have been performed to study the interactions of alcohols (ethanol, butanol, proponal), anesthetics (halothane) and aromatic ligand (dibutyl pthalate) with LUSH. The alcohols form hydrogen bonds predominantly with two amino acids SER52 and THR57. Water at the binding site effects the binding profoundly. We have also studied the interaction of inhalational anesthetic, halothane, with the LUSH protein to study possible overlap of binding sites with alcohols. Finally interactions of aromatic ligand dibutyl pthalate were studied to understand any competition with alcohols for the proposed binding site. Our simulations suggest that the binding of alcohols in LUSH is weak and water near the binding site plays an important role on binding of ligands.

COMP 284 [831304]:  Mechanism of substrate binding to HIV-1 protease

Gergely Toth1, Attila Borics2, and Sia Meshkat1. (1) Locus Pharmacuticals, 1999 South Bascom Avenue, Suite 700, Campbell, CA 95008,, (2) Creighton University

The active site of aspartic proteases is covered by one or more flaps which restrict access to the active site. In the case of HIV-1 protease (PR), X-ray crystallography reveals that in the free enzyme the two flaps are loosely packed onto each other in a ‘semi-open' conformation, while in the substrate-HIV-1 PR complex the flaps are reversed into a more compact ‘closed' conformation. This study aims to shed light on the process of substrate access to the active site of HIV-1 PR and the mechanism of flap reversal due to substrate binding. First, the structure and dynamics of the substrate free HIV-1 PR with semi-open flap conformation was investigated using molecular dynamics (MD) simulations. At 296 K the flaps stayed in the semi-open conformation, while at 306 K and 321 K the flaps separated in an unsymmetrical way through a transitional state into open conformations. The opening of the flaps is possibly due to the high sensitivity of the flap interactions in the semi-open conformation, which can be attributed to the network of weakly polar interactions between the flap tips. Next, the open flap structure of HIV-1 PR and a long peptide from a natural substrate cleavage site were used to perform MD simulations to investigate the mechanism of flap conformational change due to the binding of the substrate peptide. These simulations suggest that the substrate induces the closing of the flaps in an unsymmetrical way through a similar transition state as they opened in the substrate free enzyme. These results support the model of substrates binding to aspartic proteases, where first the substrate accesses the active site through open flaps and then the substrate induces the closing of the flaps.

COMP 285 [829927]:  Computational investigation of specificities of glycoside hydrolase family 1 members

Anthony D. Hill, Department of Chemical Engineering 2114 Sweeney Hall, Iowa State University, 2114 Sweeney Hall, Ames, IA 50011-2230, Fax: 515-294-2689,, and Peter J. Reilly, Department of Chemical Engineering, Iowa State University

Glycoside hydrolase family 1 is composed of β-glucosidases, β-galactosidases, 6-phospho- β-galactosidases, myrosinases, and other less specific enzymes having similar primary and tertiary structures yet diverse specificities. Among these enzymes, β-glucosidases hydrolyze cellobiose to glucose, and therefore they are key players in any cellulose to glucose process. All members of this family attack β-glycosidic bonds between a pyranosyl glycon and an aglycon, but they have little specificity for the aglycon or for the bond configuration. Furthermore, specificity for the glycon is not absolute. Fourteen family members, eight β-glucosidases, one β-galactosidase, one 6-phospho-β-galactosidase, one myrosinase, and three beta-glycosidases, now have known tertiary structures. We have used automated docking to computationally bind disaccharides with mannosyl, allosyl, glucosyl, galactosyl, 6-phosphogalactosyl, and 6-phosphoglucosyl glycons, all linked by β-(1,2), β-(1,3), β-(1,4), and β-(1,6)-glycosidic bonds, into these structures to investigate the structural determinants of the specificities of these enzymes.

COMP 286 [834828]:  Mechanisms of ammonia activation and ammonium ion inhibition of quinoprotein methanol dehydrogenase: A computational approach

Swarnalatha Y. Reddy, Chemistry & Biochemistry, University of California at Santa Barbara, Santa Barbara, CA 93117, Fax: 805-893-2229, and Thomas C. Bruice, Department of Chemistry & Biochemistry, University of California, Santa Barbara

The mechanism of methanol oxidation by quinoprotein methanol dehydrogenase (MDH.PQQ) in combination with methanol (MDH.PQQ.methanol) involves Glu171-CO2- general base removal of the hydroxyl proton of methanol in concert with hydride equivalent transfer to the >C5=O quinone carbon of PQQ and rearrangement to hydroquinone (PQQH2) with release of formaldehyde. Molecular dynamics (MD) studies of the structures of MDH.PQQ.methanol in the presence of activator NH3 and inhibitor NH4+ have been carried out. In the MD structure of MDH.PQQ.methanol.NH3, the hydrated NH3 resides at a distance of ~24 Ĺ away from methanol and the ortho-quinone portion of PQQ. As such, influence of NH3 on the oxidation reaction is not probable. We find that NH4+ competes with the substrate by hydrogen bonding to Glu171-CO2- such that the MDH.PQQ.methanol.NH4+ complex is not reactive. Ammonia readily forms imines with quinone. Imines are present in solution as neutral (>C5=NH) and protonated (>C5=NH2+) species. MD simulations establish that the >C5=NH2+ derivative of MDH.PQQ(NH2+).methanol structure is unreactive due to the non-productive means of methanol binding. The structure obtained by the MD simulations with the neutral >C5=NH imine of MDH.PQQ(NH).methanol structure is similar to the reactive MDH.PQQ.methanol complex. This active site geometry allows for catalysis of hydride equivalent transfer to the >C5=NH of PQQ(NH) by concerted Glu171-CO2- general-base removal of the H-OCH3 proton and Arg324-H+ general-acid proton transfer to the imine nitrogen. Enzyme bound >C5(H)NH2 derivative of PQQ [PQQ(NH)] and CH2O product are formed.

COMP 287 [832913]:  Ab initio Studies of methyl and t-butyl group internal rotation in aromatic molecular crystals

Xianlong Wang1, Frank B. Mallory1, Michelle M Francl1, and Peter A. Beckmann2. (1) Department of Chemistry, Bryn Mawr College, 101 N. Merion Ave, Bryn Mawr, PA 19010, Fax: 610-526-5086,, (2) Department of Physics, Bryn Mawr College
To gain a comprehensive understanding of the dynamics of t-butyl internal rotation in crystal packing environment and its relationship with structure, we carried out ab initio calculations on reorientation barrier of t-butyl and its constituent methyl groups in a few aromatic crystalline solids which have been studied with nuclear magnetic resonance relaxometry and the structures have been elucidated by single crystal x-ray diffraction. The computations were done for the compounds both as a single molecule in vacuum and as in the crystal-packing environment. Comparison with results from NMR relaxometry shows ab initio calculation giving trustable energy barrier. Furthermore, the calculation results differentiate contributions from intramolecular and intermolecular interactions in the crystalline solids. We also target to formulate the barriers in terms of familiar concepts in chemistry, e.g. intramolecular electronic effects, intramolecular steric effects and intermolecular steric effects.

COMP 288 [825303]:  Importance of post-CCSD(T) correlation effects for molecular properties

A. Daniel Boese1, Mihály Kállay2, Juergen Gauss2, and Jan M.L. Martin1. (1) Department of Organic Chemistry, Weizmann Institute of Science, P.O. Box 26, 76100 Rechovot, Israel, Fax: +972(8)934-4142,,, (2) Institut für Physikalische Chemie, Universität Mainz

We consider the effect of electron correlation contributions beyond the CCSD(T) level on molecular properties. Higher-order connected triple excitation (T3) effects almost universally decrease molecular binding energies; connected quadruple excitations (T4) systematically increase them. The excellent performance of infinite-basis CCSD(T) extrapolation methods (such as W2 theory [1]) for molecular binding energies thus results from error compensation. Basis set convergence for this latter effect is generally very rapid: W3 theory [2], which includes both higher-order T3 and T4 effects, is is both more accurate overall (error statistics for total atomization energies approximately cut in half) and more robust (particularly towards systems exhibiting significant nondynamical correlation) than W2 theory. The importance of connected quintuple excitations (T5) was likewise assessed: contributions reach 0.3 kcal/mol for the pathologically multireference lowest singlet state of C2 but are quite small for other systems. Time permitting, effects on other spectroscopic constants will be discussed.

[1] JML Martin and G de Oliveira, J. Chem. Phys. 111, 1843 (1999) [2] AD Boese, M Oren, O Atasoylu, JML Martin, M Kallay, and J Gauss, J. Chem. Phys. 120, 4129 (2004)

COMP 289 [853148]:  New picture of electron transfer

Marcus Lundberg and Per Siegbahn, Department of Physics, Stockholm University, SE-106 91 Stockholm, Sweden, Fax: 46-8-55 37 86 01,

Electron transfer can be of fundamental importance for chemical reactivity. Intramolecular electron transfer, e.g. in a Mn(II)-Mn(III) dimer, is analyzed by calculating the full reaction pathway, including transition states, using the DFT functional B3LYP. In metal dimers with weak ligand fields, the first step is to change from antiferromagnetic to ferromagnetic coupling, if applicable. If the spins on the two centers are not parallel, electron transfer leads to a low-spin species that is high in energy. The spin crossing between the antiferro- and the ferromagnetic spin surfaces is located and used as good approximation to the transition state of the spin flip. In the second step, the electron moves from one center to the other. The transition state for this reaction is fully optimized using a Hessian calculation. Finally, relaxation back to antiferromagnetic coupling occurs. Comparisons with Marcus theory will be provided.

COMP 290 [830738]:  Scaling the acidic properties of aluminosilicate and aluminophosphate molecular sieves: A PDFT study

Mohamed Elanany and Daniel P. Vercauteren, FUNDP, Département de Chimie, Faculté des Sciences, Rue de Bruxelles 61, B-5000, Namur, BelgiumCluster model approach and TPD technique could not give reliable and clear answers for acidity characterizations. In this study, the acidic properties of MOR, CHA, AlPO-5 and AlPO-34 are investigated using periodic DFT method.  Figure 1(a) shows the electron density distribution of NH3 on H-MOR. The calculated adsorption energies of ammonia in main channel and side pocket of H-MOR are -147 and -111 kJ/mol, respectively. CHA and AlPO-34 have the same structural topology as shown in Figure 1(b). Acidity measurements by NH3 adsorption and deprotonation energies reveal the following order: MnAlPO-34 > CoAlPO-34 > NiAlPO-34 > FeAlPO-34 > SiAlPO-34 > CrAlPO-34> Ti-AlPO34.  Lewis acid sites that may exist in dealuminated zeolites eg., AlO+ and ≡ Si+ showed very strong acidity compared to that of Na-counter ions. Results of Alkylamines adsorption showed that using primary amines is more appropriate than using other amines for scaling the acidity of a molecular sieve.


COMP 291 [813067]:  Theoretical confirmation of the experimental Raman spectra of the lower-order diamondoid molecule: Cyclohexamantane (C26H30)

Steven L Richardson1, Tunna Baruah2, Michael J Mehl2, and Mark R Pederson2. (1) NSF CREST Center for Nanomaterials Characterization Science and Process Technology, Howard University, School of Engineering, 2300 Sixth Street, N.W, Washington, DC 20059,, (2) Center for Computational Materials Science, Code 6390, Naval Research Laboratory

The lower-order diamondoid hydrocarbon molecule, cyclohexamantane (C26H30), has been recently isolated from distilled Gulf Coast petroleum. While the structure of C26H30 has been confirmed through x-ray diffraction, mass spectroscopy, and 1H/13C NMR spectroscopy, its vibrational Raman spectra has only been identified through an indirect comparison with the experimental Raman spectra for adamantane and diamond. We used density-functional theory (DFT) to calculate a Raman spectra whose frequencies and relative intensities are in excellent agreement with the observed experimental Raman spectra for cyclohexamantane, thus providing direct vibrational proof of its existence.

COMP 292 [853151]:  Theoretical studies on the ethylene forming enzyme 1-aminocyclopropane-1-carboxylic acid oxidase

Arianna Bassan1, Tomasz Borowski2, Vladimir Pelmenschikov1, Christopher Schofield3, and Per Siegbahn1. (1) Department of Physics, Stockholm University, SE- 106 91 Stockholm, Sweden,, (2) Department of Physics, Stockholm Center for Physics, Astronomy and, Stockholm University, (3) Oxford University

The reaction catalyzed by the plant enzyme 1-aminocyclopropane-1-carboxylic acid oxidase (ACCO) has been investigated using hybrid density functional theory. ACCO plays a fundamental role in the biosynthesis of ethylene, which acts as a signaling molecule in many processes connected with plant development and defense (e.g., rooting, fruit ripening, germination). This enzyme carries out the two electron oxidation of the substrate ACC (1-aminocyclopropane-1-carboxylic acid) concomitantly with the four-electron reduction of dioxygen and oxidation of ascorbate. This complex reaction, which gives ethylene, CO$_2$ and cyanide occurs in the enzyme active site hosting a mononuclear non-heme iron center. A model including the metal complex and ACC coordinated in the first coordination sphere is used to study the details of O-O bond cleavage and cyclopropane ring opening.

COMP 293 [815583]:  First principles and tight-binding quantum chemical molecular dynamics approach to vibrationally excited states dynamics of water

Ewa Broclawik1, Keiko Chiba2, Yumiko Sasaki2, Abdul Rajjak Shaikh2, Qiang Pei2, Hideyuki Tsuboi1, Michihisa Koyama2, Momoji Kubo2, Kazuyoshi Akutsu3, Masahiro Hirota3, Masayoshi Kitada3, Hajime Hirata3, and Akira Miyamoto1. (1) New Industry Creation Hatchery Center, Tohoku University, 6-6-10 Aoba, Aramaki, Aoba-ku, Sendai 980-8579, Japan, Fax: +81-22-217-7235,, (2) Department of Materials Chemistry, Graduate School of Engineering, Tohoku University, (3) Honda R&D Co., Ltd
Infrared (IR) absorption is one of the main tools for investigating dynamical properties of condensed systems, also for liquid water, where the fundamental dynamical process is the formation and breaking of hydrogen bonds. Time dependence of relaxation of the vibrational excitation in liquid water is strikingly different from that in common condensed phases and it seems that this unusual behavior could be attributed to specific properties of H-bond networking. However, classical Molecular Dynamics is not a sufficient tool to describe fine details of hydrogen bonds' network since explicit treatment of electronic polarization effects is required. Thus quantum chemical MD simulation is the best tool to investigate e.g. the fate of vibrational excitation in liquid water. In this study we present CASTEP by Accelrys and our original tight binding MD simulation of dynamical behavior of intramolecular vibrations in water and their dependence on instantaneous H-bond network.

COMP 294 [826797]:  NMR chemical shifts in a DFT QM/MM scheme

Daniel Sebastiani, Department of Spectroscopy, Max-Planck-Institut fuer Polymerforschung, Ackermannweg 10, Mainz 55116, Germany, Fax: +49-6131-379-100,
We present the combination of a pseudopotential plane-wave based density functional theory code (CPMD), its module for the calculation of spectroscopic properties and an interface to classical molecular mechanics (QM/MM). In particular, we show how to improve calculated nuclear magnetic resonance chemical shifts of atoms in the QM/MM boundary region within this scheme by means of an additional repulsive potential for the electrons. The method can applied to complex liquids, such as water, as well as to highly ordered crystalline solids.

COMP 295 [831910]:  DFT study of the effects of solvent environment on photophysical properties and electronic structure of paracyclophane chromophores

Artëm Masunov1, Sergei Tretiak1, Janice W. Hong2, and Guillermo C. Bazan3. (1) Theoretical Division, Los Alamos National Laboratory, MS B268, Los Alamos, NM 87545, Fax: 505-665-3909,, (2) Department of Chemistry, University of California, Santa Barbara, (3) Department of Chemistry and Materials, Institute for Polymers and Organic Solids, university of California, Santa Barbara
Emisson spectra of recently synthesized [2.2]paracyclophane (PCP) chromophores exhibit large (compared to their monomer analogs) wavelength and radiative lifetime shifts in water vs. toluene. We use first principles quantum chemical approaches to understand the reasons for this behavior. The molecular environment is simulated using implicit solvation models, explicit water molecules and counterions. Calculations show that neither implicit, nor explicit solvent is sufficient to reproduce the experimental data, and consideration of the complex between the chromophore and counterion is necessary. The mechanism of the lifetime increase can be described as follows. In nonpolar solvent both HOMO and LUMO are localized on the same branch of PCP chromophore. In water increased polarizability of the chromophore in the excited state attracts the nearby ion by charge/induced dipole interaction. The approaching ion localizes the hole and the particle on the different branches of PCP chromophore, decreasing the overlap between them, and increasing the lifetime.

COMP 296 [833940]:  Expanding the scope of DFT calculations: Techniques for calculating the A and C terms of magnetic circular dichroism and the excitation energies of molecules with degenerate ground states

Michael Seth1, Jochen Autschbach2, and Tom Ziegler1. (1) Department of Chemistry, University of Calgary, University Drive 2500, Calgary, AB T2N1N4, Canada,, (2) Department of Chemistry, State University of New York at Buffalo

This talk will discuss two aspects of our work to further expand the range of systems and properties that can be treated using density functional theory. The first part of the talk considers the calculation of the A and C terms arising in magnetic circular dichroism spectroscopy. This spectroscopic method measures the effect of a magnetic field on the absorption properties with respect to circularly polarized light of the substance of interest. The A and C terms are two parameters that can be extracted from such a spectrum and generally correspond to the splitting of degenerate states and modification of the populations of components of a degenerate ground state, respectively. The evaluation of the A term generally requires knowledge of the magnetic moment of excited states and transition dipole moments and the calculation of this parameter was therefore formulated within the framework of time-dependent DFT. The C term also depends on the transition dipole moments but only on the magnetic moment of the ground state and the related C/Dquantity depends only on the ground state magnetic moment making it more straightforward to evaluate. In the second part of the talk, work looking at the evaluation of excitation energies of molecules with degenerate ground states will be discussed. TD-DFT has been widely applied to the calculation of the excitation energies of closed shell molecules. The extension of this theory to open-shell systems is relatively straightforward, provided the ground state of that system is nondegenerate. Extension of the theory to cover degenerate ground states is a little more complex and our efforts in this direction will be discussed.

COMP 297 [834263]:  GridChem: A computational chemistry grid

Sudhakar Pamidighantam, NCSA, University of Illinois at Urbana Champaign, 4147 Beckman Inst, 405 N. Mathews Ave., Urbana, IL 61801, Fax: 217-244-2909,

In this presentation, we will describe a virtual organization named GridChem, a computational chemistry Grid, that provides access to high performance computing resources for computational chemistry. GridChem is a three tiered system that includes a client, a grid-middleware server and a distributed high performance computational resources. The client provides an interface that contains familiar attributes that computational chemists need including pre and post processing tools. The grid middleware server contains all the grid software components for authentication, file management and job submission. The grid middleware server hides the complexities of dealing with the the heterogeneous computational resources, their access mechanisms, job scheduling and management policies from the end user. The computational resources would include not only the hardware that a calculation would be executed but also the applications and schedulers and allied tools to efficiently manage the load as well as the job related data. Gridchem project leverages existing tools and middleware technologies to provide an intuitively simple interface to the end user chemists to be able to submit, monitor and manage their computational chemistry calculations. We will examine need for policies and issues regarding the access, authentication and management of user jobs within GridChem. As the community grows new applications will be integrated into GridChem architecture.

COMP 298 [816926]:  Molecular rearrangements via continuous diradical transition states

K. N. Houk, Department of Chemistry and Biochemistry, University of California Los Angeles, 405 Hilgard Ave, Los Angeles, CA 90095-1569, Fax: (310) 206-1843,

John Pople created the ideas and programs that extended ab initio and density functional quantum mechanics to the organic chemistry community. This lecture pays homage to the things John Pople created, with thanks for the personal influences he had on my career. The potential energy surfaces for a variety of experimentally well-studied rearrangements have been explored with DFT and CASSCF methods. A general class of reactions is identified, involving stepwise bond breaking and formation, but no long-lived intermediates. These include the vinylcyclopropane-cyclopentene, vinylcyclobutane-cyclohexene and related rearrangements. All have in common the features called a twixtyl by Roald Hoffmann, and a continuous diradical or caldera by W. v. E. Doering.

COMP 299 [804188]:  Odd-electron bonds and electron transfer in model systems

Tim Clark, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Computer-Chemie-Centrum, Naegelsbachstrasse 25, 91052 Erlangen, Germany, Fax: +49-9131-8526565,

One- and three-electrons bond strengths are controlled by factors, such as the difference in ionization potential between the partners, very different to those that govern the strengths of conventional bonds with even numbers of electrons. A general equation, first proposed on an empirical basis and later rationalized by Hiberty et al. using valence-bond theory, gives reasonable estimates of the dissociation energies of both one- and three-electron bonds. Modern high level calculations on the systems first studied in the mid 80s have been used to test this equation.

Electron transfer between metal atoms and ions and small hydrocarbons (ethylene and acetylene) is used as a model system to demonstrate the dominant effect of the Coulomb energy of the ion pair that results from electron transfer in determining the thermodynamics of electron transfer. This ion-pairing energy results, for instance, in the unexpected effect that the unipositive ions of group II metals reduce, rather than oxidize, organic substrates.

COMP 300 [816662]:  Analytical second derivatives, parameterization, and improvement of the DFTB (Density Functional Tight Binding) method

Henryk A. Witek1, Guishan Zheng1, Djamaladdin G. Musaev1, Stephan Irle1, David Quińonero1, Marcus Elstner2, and Keiji Morokuma1. (1) Cherry L. Emerson Center for Scientific Computation and Department of Chemistry, Emory University, 1515 Dickey Dr, Atlanta, GA 30322, Fax: 404-727-7412,,, (2) Universität Paderborn, Fachbereich Physik, 33095 Paderborn, Germany, Deutsches Krebsforschungszentrum, Abteilung Molekulare Biophysik, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany

The DFTB method is a semiempirical two-center approximation to the density functional method, and has been shown to provide reasonable reliability at modest cost. This method is applicable to large molecular systems, and can be a good mid-level method in a three-layer ONIOM(QM:QM:MM) method. We have recently implemented analytical geometrical second derivatives and numerical derivatives of gradient with respect to external electric field. The calculated vibrational frequencies and infrared and Raman intensities are in good agreement with experiment. Improvement in the functional fit of diatomic repulsive parameters resulted in substantially better vibrational results with little change in geometry. Only a few transition metals were parameterized previously. We have recently determined and tested parameters for many first row transition metals with HCNOPS atoms. The results are quite encouraging.

COMP 301 [830377]:  Paradigm shifting energy evaluations

Paul v. R. Schleyer, Department of Chemistry, University of Georgia, Computational Chemistry Annex, Athens, GA 30602-2525, Fax: 706-542-7514,

John Pople, along with Warren Hehre and Leo Radom, conceived highly instructive and very important strategies for characterizing and analyzing the energies of molecules. Isodesmic bond separation reactions revealed interactions of the component parts of molecules by separating bonds between non-hydrogen atoms into the simplest two heavy atom parent species. Many other, seemingly more sophisticated methods, have also been applied, e.g., to evaluate the energies associated with the very basic concepts of hyperconjugation, conjugation, the anomeric effect, aromaticity, anti-aromaticity, chain branching, etc. Our critical reexamination now suggests that widely recommended values for these energies need basic revision. Thus, we argue that the long accepted strain energy of cyclopropane is much too large, and the stabilizations due to conjugation, hyperconjugation, and aromaticity are much too small. Propane and higher straight chain alkanes are stabilized, much like their branched chain counterparts, due to the presence of 1,3 (“protobranching”) interactions.

COMP 302 [825628]:  Influence of temperature and DFT models in ab initio MD simulation of liquid water

Joost VandeVondele1, Fawzi Mohamed2, Matthias Krack2, Juerg Hutter3, Michiel Sprik1, and Michele Parrinello4. (1) Department of Chemistry, University of Cambridge, Lensfield road, CB2 1EW Cambridge, United Kingdom,, (2) Department of Chemistry, ETH Zurich, (3) Physical Chemistry Institute, University of Zurich, (4) Physical Chemistry ETH (Zurich)

The performance of density functional theory methods for the modeling of condensed aqueous systems is hard to predict, and validation by ab initio molecular simulation of liquid water is absolutely necessary. The effect of temperature on the structure and dynamics of liquid water has been characterised with 16 simulations of 20 ps in the temperature range of 280K to 380K. We find a pronounced influence of temperature on structure and dynamics including non-ergodic behaviour on the time scale of the simulation in the lower temperature range (which includes ambient temperature). These observations were taken into account in a consistent comparison of a series of density functionals (BLYP, PBE, TPSS, OLYP, HCTH120, HCTH407). All simulations were carried out using an ab initio molecular dynamics approach in which wave functions are represented using Gaussians and the density is expanded in an auxiliary basis of plane waves. Whereas the first three functionals show similar behaviour, it is found that the latter three functionals yield more diffusive dynamics and less structure.

COMP 303 [834972]:  Liquid/vapor interfaces of hydrogen bonding fluids via ab initio molecular dynamics

Christopher J. Mundy1, Ilja Siepmann2, Will. I-F. Kuo1, and Matthew J. McGrath3. (1) Chemistry and Materials Science Directorate, Lawrence Livermore National Laboratory, Livermore, CA 94550,, (2) chemsitry, University of Minnesota, (3) Department of Chemistry, University of Minnesota
Liquid-vapor interfaces engender phenomena ranging from atmospheric science to biology. In this presentation, we use ab intio molecular dynamics to study the aqueous and neat methanol liquid-vapor interface. Comparisons with classical empirical potentials will be made.

COMP 304 [821056]:  Tractable time correlation function theories of nonlinear spectroscopy

Brian Space1, Russell DeVane1, Angela Perry2, Christina Ridley1, and Christine Neipert1. (1) Chemistry Department, University of South Florida, 4202 E. Fowlwer Ave. SCA400, Dept. Chem.T, Tampa, FL 33620-5250, Fax: 8139743203,, (2) Department of Chemistry SCA400, University of South Florida
Nonlinear, multidimensional spectroscopy provides new insights into condensed phase dynamics. However, the response functions required for its interpretation pose an exceedingly difficult challenge to theorists. Recently an approach was proposed in which the Sum Frequency Generation (SFG), fifth order 2D Raman and two dimensional infrared (2DIR) quantum response functions were expressed as computationally tractable, classical time correlation functions (TCF's). As a rigorous test of the theories the 2D Raman spectrum of liquid xenon is calculated and compared to an exact numerical calculation. Remarkable agreement is obtained, suggesting that nonlinear spectroscopy can generally be described using our approach. Further, SFG spectra of the water/vapor interface show a well defined intermolecular mode at 875 wavenumbers that has a fifth the intensity of the strong free O-H stretching peak. The resonance is due to a wagging mode localized on a single water molecule and represents a well defined population of water molecules at the interface in addition to the free O-H species that was previously unknown.

COMP 305 [825765]:  Topologies of protonated water clusters: A combined study by vibrational predissociation spectra and Monte Carlo simulations

Jer-Lai Kuo, School of Physical and Mathematical Sciences, Nanyang Technological University, 1 Nanyang Walk, Block 5, Level 3, Singapore 637616, Singapore,, Huan-Cheng Chang, Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, Taiwan, and Michael L. Klein, Department of Chemistry, Center for Molecular Modeling, University of Pennsylvania

The topologies of protonated water clusters are examined by both theoretical and experimental methods. The experimental observations via vibrational predissociation spectra (VPS) at around 150K are (1) ring-structure appearing at n=7 evident by the presence of 3-coordinated dangling OH (3coord-dH), (2) mixture of multiple-ring and cage structure are mostly like for n>10 as 3coord-dH become the dominating feature, and (3) for n=21 and 28, VPS is characterized by single 3coord-dH peak indicating clathrated cage structures. More importantly, we found precise transition sizes are sensitive to experimental temperature. Extensive Monte Carlo simulations were therefore carried out to investigate the low-energy minima and to gauge the finite temperature effects. Our calculations found that at the experimental temperature, the structures of these clusters are far from their global minima counterparts.

COMP 306 [832692]:  Car-Parrinello molecular dynamics studies of aqueous HCl and HF mixture

Kari Laasonen and Julen Larrucea, Department of Chemistry, University of Oulu, POB 3000, 90014 University of Oulu, Finland, Fax: +35885531603,

We have studied HF/HCl(aq) mixture using Car-Parrinello (CPMD) molecular dynamics at ca. 350 K. These simulations have shown some interesting interactions between the F- and Cl- ions. The structure of this system is compared to our earlier simulations of aquaous HF and HCl.

COMP 307 [803409]:  Protein ensemble docking: Progress toward an accurate virtual screening protocol

Daniel L. Cheney and Luciano Mueller, Department of Macromolecular Structure, Bristol Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, Fax: 609-818-3545,

Computational capacity has increased dramatically over the last decade making possible the use of more sophisticated and computationally intensive methods in computer-assisted drug design. As capacity continues to grow and algorithms become more efficient, those in the molecular computational community are faced with the enviable challenge of how to best to utilize this new potential. In this report, we show that existing docking programs generally perform poorly in terms of binding pose prediction in real-world settings, i.e., cross-docking multiple ligands into a single rigid protein. For example success rates even for relatively easy targets such as thrombin and factor Xa were typically 50% or less. We explore a general strategy for lead docking which utilizes representative conformational ensembles of target proteins. Retained stacks of docked poses are further refined and re-scored using fixed charge or polarizable forcefields in the presence of a solvent model. We show that this protocol can lead to dramatic improvements in both sampling and scoring over conventional single rigid protein docking, regardless of the docking program or target.

COMP 308 [819265]:  Automating inhibitor discovery with multiple protein structures (MPS)

Heather A. Carlson1, Michael G. Lerner2, Kristin L. Meagher1, and Kelly L. Damm1. (1) Department of Medicinal Chemistry, University of Michigan, Ann Arbor, 428 Church Street, Ann Arbor, MI 48109,, (2) Biophysics Research Division, University of Michigan, Ann Arbor

Developing new methods in computer-aided drug design (CADD) often involves as much art as science. We present our successes in developing a CADD method that incorporates protein flexibility through the use of an ensemble of protein structure. Our initial studies relied heavily on user input and chemical intuition. To remove the subjectivity, we have created several procedures to automate the method. This makes our CADD method more accessible and easier to use by other groups. Furthermore, the procedures we've created can be incorporated into other CADD methods and structural biology studies.

COMP 309 [824490]:  Improving the quality of virtual ligand screening against homology models

Katarzyna Bernacki1, Chakrapani Kalyanaraman1, Ilya Chorny2, and Matthew P Jacobson1. (1) Department of Pharmaceutical Chemistry, University of California San Francisco, Box 2240, San Francisco, CA 94143-2240,, (2) Department of Pharmaceutical Chemistry, University of California, San Francisco

Protein homology models have been used in conjunction with virtual screening to successfully identify novel inhibitors over the past few years. However, it is widely accepted that docking to homology models is more challenging and less successful than docking to crystallographic structures. We are developing methods to improve the quality of homology models for in silico screening, especially by energy-based refinement of binding site residues. The homology modeling and refinement protocols use an all-atom force field (OPLS-AA) and a Generalized Born implicit solvent model; docking is performed with Glide. Test cases so far include DHFR, CDK2, several parasitic cysteine proteases, human lipoxygenase, and alphaVbeta6 integrin. In all cases, we demonstrate that the enrichment of known inhibitors can be improved by refinement of the binding site, and that the refined homology models (at ~50% sequence identity) perform comparably to crystal structures. In two cases so far (alphaVbeta6 integrin and human lipoxygenase), experimental collaborators have identified new inhibitors based on our docking results, with hit rates comparable to docking against crystal structures.

COMP 310 [833307]:  Mining docking space

Christian Lemmen, Marcus Gastreich, and Holger Claußen, BioSolveIT GmbH, An der Ziegelei 75, 53757 Sankt Augustin, Germany, Fax: +49 2241 2525 525

Modern experimental technology produces an ever increasing mass of data. However, with more and more cheap computer power, also virtual experiments are crried out in high throughput mode, which further adds significantly to this flood of data. One aspect in this regard is virtual docking. Typically hundreds of possible docking poses are generated for every single compound and hundred thousands of compounds are processed overnight on a cluster in a routine fashion. The mere storage of tens of millions of protein-ligand complexes is a challenge, however, analysis down to the level of interaction profiles so far impractical to say the least.

We implemented a system based on Oracle which facilitates the analysis of large volume docking data. It utilizes Flex*-Technology and is equipped with a graphical front-end which provides a spreadsheet-type view on the data. Additionally to interactive filtering, sorting, searching and visualization, this system called Docking Database (DDB) has an interface to a Machine Learning Toolbox (MLT) facilitating the generation of target tailored scoring functions. DDB was taken to the test in an application study which is discussed in this presentation. Significant docking-parameters for the particular target could be detected, filters have been optimized and a new target-specific scoring function was derived, all of which led to an improved performance of the docking method when used on novel compounds.

COMP 311 [833699]:  Integrating protein sequence and structural information: An in silico method for predicting kinase selectivity

Huifen Chen, Computer Assisted Drug Discovery, Pfizer Global Research and Development, Ann Arbor Labs, 2800 Plymouth Rd, Ann Arbor, MI 48105, Fax: 734-622-2782,, and Eric B. Fauman, Computer Assisted Drug Discovery, Pfizer Global Research & Development

Protein kinases, one of the largest gene families, are important components of signaling pathways and are responsible for regulation of a variety of physiological processes. Due to their critical roles in signal transduction and cellular regulation, protein kinases have been extensively studied and remain attractive targets for drug discovery in several disease areas. Most of the small molecule approaches target the highly homologous ATP-binding site where selectivity issues are major concerns. Thus, there is a critical need for identifying potential kinase cross-reactivity liabilities in silico to ensure proper setup of counter-screens and ways of achieving selectivity at the molecular level. Using the available sequence and structural information, a novel computational method has been developed for clustering protein kinases and predicting kinase selectivity. The methodology and its applications will be presented.

COMP 312 [825490]:  Uncovering networks within protein structures

Birgit Albrecht, Department of Chemistry, University of Oxford, Central Chemistry Laboratory, South Parks Road, Oxford OX1 3QH, United Kingdom, Fax: 0044 1865 275905,

Previous studies (1) have shown that proteins can be described as networks with small world properties due to their short characteristic path lengths and high clustering coefficients. Now we have confirmed these experimental results with computational methods. Three proteins have been identified that exhibit different amino acid sequences but identical topology. We proved that it is the long range interactions of a protein network that determine its topology. Molecular dynamics studies were carried out at different temperatures using the three different proteins mentioned above. We compared long range as well as short range contacts and a set of randomly chosen residue pairs to gain information about network stability and the influence of these contacts on protein structure. Once suitable networks for these three proteins had been established, the final test was to predict a protein structure based on its network. Previous studies1 have shown that proteins can be described as networks with small world properties due to their short characteristic path lengths and high clustering coefficients. Now we have confirmed these experimental results with computational methods. Three proteins have been identified that exhibit different amino acid sequences but identical topology. We proved that it is the long range interactions of a protein network that determine its topology. Molecular dynamics studies were carried out at different temperatures using the three different proteins mentioned above. We compared long range as well as short range contacts and a set of randomly chosen residue pairs to gain information about network stability and the influence of these contacts on protein structure. Once suitable networks for these three proteins had been established, the final test was to predict a protein structure based on its network. (1)L. Greeene, V. Higman, J. Mol. Biol, 334, 781-791, 2003

COMP 313 [834673]:  Exploration of structure-derived protein sequence alignments

Nathalie Meurice, F.N.R.S. Scientific Research Worker, Department of Pharmacology and Toxicology, University of Arizona, College of Pharmacy - 1703 E. Mabel Street, P.O. Box 210207, Tucson, AZ 85704, Fax: 520-626-2466,, Daniel P. Vercauteren, Département de Chimie, FUNDP, Laboratoire de Physico-Chimie Informatique, and Gerald M Maggiora, Department of Pharmacology and Toxicology, University of Arizona

It is well known that the 3-D structures of proteins of similar function are conserved to a far greater extent than are their sequences. In light of this, we present an exploratory study aimed at identifying the structurally conserved residues (SCRs) among proteins known to have the same function. SCRs are determined using the MIMIC program [1] by first aligning the 3-D structures of the proteins, computing their inter-residue similarities, and, from this, identifying regions of high inter-residue similarity, namely the SCRs. This information is then used to determine the consensus sequence alignments in these regions, which is used to search for sequences of proteins of similar function. An example will be presented illustrating the methodology.

[1]G.M. Maggiora, D.C. Rohrer, and J. Mestres, J. Mol. Graph. Model., 19 (2001), 168-178.

COMP 314 [803414]:  De novo design of novel and selective T-type calcium channel blockers

Daniel L. Cheney1, Jon J. Hangeland2, Todd J. Friends2, and Paul C. Levesque3. (1) Department of Macromolecular Structure, Bristol Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, Fax: 609-818-3545,, (2) Cardiovascular Discovery Chemistry, Bristol-Myers Squibb, (3) Cardiovascular Diseases, Bristol-Myers Squibb Pharmaceutical Research Institute

Hypertension and angina pectoris afflict an estimated 200 million people in North America and Europe. Current therapies are limited to L-type calcium channel blockers which produce undesirable, mechanism-based side effects, such as edema and organ damage. An increasing body of evidence suggests that selective T-type calcium channel blockers may be clinically efficacious with significantly fewer side-effects. In this study, we describe the de novo design of novel, selective, and synthetically accessible T-type calcium channel blockers. Initial “idea structures” are generated by the program Sprout using a pharmacophore model derived from ComFA, small molecule crystal data, and high quality quantum mechanical conformational energy surfaces. Raw output structures were iteratively evolved into plausible, drug-like chemotypes, representatives of which were synthesized and found to exhibit moderate to high potency in in-vitro assays.

COMP 315 [832852]:  The application of workflow technology to the creative, computationally intensive and technically challenging area of library design

Ashley George, Cheminformatics, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow CM19 5AW, United Kingdom, Fax: +44 (0)1279 622904,, and Jonathan Sheldon, Cheminformatics, InforSense Limited, 48 Princes Gardens, London SW7 2PE, United Kingdom, Fax: +44 (0)20 7594 6836,

The pharmaceutical industry is still challenged in enabling collaborative access to various and disparate information sources from multiple locations. The lack of appropriate tools to exploit this heterogeneous environment hinders internal collaboration, the capture and dissemination of best practices, and the overall efficiency company wide. In addition, such tools need to serve the requirements of a varied user community of computational and bench chemists. We will describe the application of workflow technology to library design and how using this approach we were able to overcome the above limitations. Particular attention will be given to the flexible manner by which data and applications were integrated into the system via the web service methodology and how this can be accessed by the varied user base. Also, we will describe the concept of a process warehouse to capture these workflows and thus provide a mechanism by which knowledge can be centralised within an organisation.

COMP 316 [803968]:  Automatic discovery and annotation of organic chemical names in patents

James W Cooper1, Stephen Boyer2, Alex Nevidomsky3, and Anni R Coden1. (1) Text Analytics, IBM T J Watson Research Center, PO Box 704, Yorktown Heights, NY 10598,, (2) Life Sciences, IBM Corporation, (3) Languageware, IBM Ireland
We have designed a series of algorithms to recognize and annotate organic chemical names in technical documents, and have applied this system to 1 year of US patents. The system uses only two small dictionaries and is primarily rule-based. Once we have extracted these names, we can use one of several commercial products to convert these names to SMILES strings, which can then be loaded into a database. We can then use this database to allow searches of the patents by chemical substructure rather than by chemical name, thus providing a much more thorough search of the compounds mentioned in the patents. We will present evaluation data and demonstrate the search system in action.

COMP 317 [821172]:  Computational design of mutation-resistant HIV-1 protease inhibitor libraries

Sripriya Chellappan and Michael K. Gilson, Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, MD 20850,

The emergence of HIV strains that are resistant to current protease inhibitors has challenged the effectiveness of these inhibitors in the treatment of AIDS. There is thus a need for new protease inhibitors that effectively inhibit both the wild type and its mutant forms. We aim to accelerate the discovery of such compounds by designing targeted combinatorial libraries, using computational docking and the substrate envelope concept as criteria for affinity and broad specificity. The design protocol is optimized through systematic studies of factorization of the combinatorics, and through the use of a genetic algorithm for automated ligand discovery. The applicability of the method to other drug targets is also considered.

COMP 318 [809942]:  Modeling of GSK-3’s allosteric pocket and validation by fragment-based grand canonical Monte Carlo simulations and docking

Suo-Bao Rong, Frank Guarnieri, Jeffery S. Wiseman, and Frank P. Hollinger, Locus Pharmaceuticals, Inc, 215 Township Line Road, Four Valley Square, Blue Bell, PA 19422, Fax: 215-358-2020,

Glycogen synthase kinase-3 (GSK-3) is one of the most attractive therapeutic targets for development of selective inhibitors as new promising drugs for a number of disease such as neurodegenerative disease, type II diabetes, bipolar disorders, stroke, cancer, and chronic inflammatory disease. The majority of GSK-3 inhibitors currently being developed might have wide-spectrum effects due to non-specifically binding to the ATP sites of kinases. Recently, an allosteric binding site has been discovered for Abl and P38 kinases. The allosteric site is opened through the flip of the DFG activation loop, triggered by binding of an allosteric inhibitor. A physicochemical profile of the kinase family reveals a higher diversity in the allosteric binding site than the ATP site, thus opening a path to design selective GSK-3 inhibitors. In order to use this strategy, the GSK-3's allosteric site has been modeled from the apo-GSK-3 using homology modeling. Because both sequence profile and structural comparison of apo-structures indicate that the GSK-3 might have similar allosteric conformational change with P38, a series of known allosteric P38 inhibitors were employed to validate the model of the GSK-3's allosteric site. Known allosteric P38 inhibitors were separated into their component fragments to run fragment-based grand canonical Monte Carlo (GCMC) simulations. The objective being to confirm is the identification of important pharmacophore elements characterized by allosteric inhibitors of the kinases. Attempts were also made to dock these compounds into the allosteric site of GSK-3 model. Both the GCMC simulations and the docking experiments establish similar functionality maps, which not only show fundamental hydrogen bonding interactions contributed by the residues Glu97 and Asp200, but display the diversity of interactions in the regions surrounding these two residues. Accordingly, the structural model of GSK-3's allosteric site has potential to be used as the structural starting point for designing selective GSK-3 inhibitors.

COMP 319 [833673]:  Predicted CCR1 structure and binding modes of CCR1 antagonists

Sabine K. Schlyer1, Monica Kochanny1, Gary Phillips1, Sunil Koovakkat1, Rene Trabanino2, Richard Horuk3, Wely B. Floriano2, Spencer E. Hall2, N. Vaidehi2, and William A. Goddard III2. (1) Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, Fax: 510-262-7844,, (2) Materials and Process Simulation Center, California Institute of Technology, (3) Department of Immunology, Berlex Biosciences

GPCRs comprise an important family of drug targets, but there is only one crystal structure available, from which homology models can be derived. However, low sequence homology to bovine rhodopsin, may introduce large uncertainties into structural models, and thus may adversely affect our understanding of ligand-receptor interactions. In order to address issues of species selectivity and cross reactivity, more accurate models of GPCRs are needed, which can guide us in the design of more specific and potent ligands. We present a method to model GPCRs from first principles. The transmembrane domains and their relative translation are determined only from the protein sequence, and the helix packing, i. e. the rotations of the helices within the membrane is solely based on physical and energetic criteria. No assumptions are made about the location and size of the ligand binding site. The binding site is determined by an automated procedure, which has the advantage of possibly identifying multiple binding sites or alternative binding sites different from the retinol binding site in rhodopsin. The structure building and docking methods have been validated using the bovine rhodopsin crystal structure and experimental binding and mutation data for a number of other GPCRs. In this work, we present a structural model of the interaction of a non peptide antagonist of CCR1 that was constructed using the above described methods. We have validated this model using known in-house affinity data and are currently completing virtual screening efforts. Mutation studies are also underway. These approaches are useful since the CCR1 antagonist is currently being evaluated in phase II clinical trials. The receptor model will provide us with a detailed understanding of the receptor-ligand interactions. This can be the basis for guiding future studies aimed at identifying second generation CCR1 antagonists.

COMP 320 [797813]:  BMK: A novel general purpose DFT exchange-correlation functional especially suitable for kinetics and reaction mechanisms

A. Daniel Boese and Jan M.L. Martin, Department of Organic Chemistry, Weizmann Institute of Science, P.O. Box 26, 76100 Rechovot, Israel, Fax: +972(8)934-4142,,
Virtually all commonly used DFT (density functional theory) exchange-correlation functionals share a weakness for reaction barrier heights: as a rule, they are seriously underestimated if DFT finds a transition state at all. Hybrid GGAs with very high percentages (40-50%) of HF exchange improve predicted barrier heights, at the expense of seriously degraded performance for equilibrium properties. We have constructed a “penalty function” consisting of a large number of molecular dissociation energies, gradients at equilibrium geometries, and other equilibrium properties, and another from a moderately large number of accurately known reaction barrier heights. We then considered the dependence of these penalty functions on the percentage of Hartree-Fock exchange for highly parametrized GGA and meta-GGA functionals of the Becke/HCTH type, with all other parameters optimized self-consistently. For large basis sets, we found minima around 42% for barrier heights and around 18% for equilibrium properties. However, upon including the kinetic energy density, we find that performance for equilibrium properties is much more weakly dependent on the percentage of HF exchange than for ordinary GGAs. We have therefore optimized a new functional for a combined penalty function (involving about 500 systems) in which barrier heights were assigned large weights. This functional, denoted BMK (Boese-Martin for kinetics, J. Chem. Phys. 2004, 121, 3405), combines excellent performance for barrier heights with performance rivalling the best available hybrid functionals (such as B97-1) for thermochemistry, and at least B3LYP-quality performance for other properties. BMK represents a new and very powerful tool for the exploration of potential energy surfaces and reaction mechanisms.

COMP 321 [825330]:  Duocarmycins binding to DNA explored by molecular simulation

Katrin Spiegel, International School for Advanced Studies (SISSA/ISAS) and INFM-Democritos center, Trieste 34100, Italy, Fax: +390403787528,, Ursula Rothlisberger, Institute of Molecular and Biological Chemistry, Federal Institute of Technology EPFL Institute of Molecular and Biological Chemistry, and Paolo Carloni, Sector of statistical and biological physics and INFM-Democritos Center, International School for Advanced Studies, SISSA/ISAS, 34100 Trieste, Italy
Duocarmycins are a potent class of antitumor agents. Their activity arises by their covalent binding to adenine nucleobases of DNA. We use classical molecular dynamics and hybrid (QM/MM) Car-Parrinello molecular dynamics simulations to study non-covalent and covalent binding of three duocarmycins with different reactivities, namely DSA, DSI and NBOC-DSA. Reactions in water are explored for NBOC-DSA with adenine and simple model reactants. Our calculations suggest that: (i) Non-covalent drug binding does not significantly perturb the DNA structure. (ii) The experimentally observed DNA catalytic power might be due, at least in part, to a polarization of the biomolecular scaffold over the drugs. Instead, our calculations do not support the “shape induced activation” mechanism, in which the conformational properties of the drug play a pivotal role for catalysis (5). (iii) The chemical nature of the drug influences the structure of the drug-DNA adduct, thus affecting the reactivity of the initial complex. (iv) The functional groups of the drugs affect the intrinsic reactivity of the compound.

COMP 322 [831765]:  A new approximate quantum mechanical method to study biopolymers

Xihua Chen1, Yingkai Zhang2, and John Z. H. Zhang2. (1) Department of Chemistry, Department of Chemistry, New York University, 100 Washington Square East, Main Building, Room 1002, New York, NY 10003,, (2) Department of Chemistry, New York University
A new approximation approach, namely, MFCC-Assembled Density Matrix (MFCC-ADM), is proposed for the quantum mechanical study of large biomolecular systems such as proteins and nuclear acids. The system is firstly decomposed systematically by the Molecular Fractionation with Conjugated Caps(MFCC) scheme into fragments and concaps which are then computed by conventional ab initio methods to obtain density matrices. These subsystem density matrices are subsequently assembled to construct the total system density matrix which is finally used to calculte the system's energy. The features of MFCC-ADM include: biopolymers are segmented in a systematical and chemically consistent manner; no empirical partition function or parameter is needed to assemble the full density matrix; the SCF procedure is circumvented and linear scaling efficiency is achieved; accuracy can be systematically enhanced by improving the MFCC scheme to take into account the structural complexity of the biomolecular system; this approach is adaptable to use most of the available semiempirical, ab initio and DFT methods/basis sets. Tests on small protein molecules show that MFCC-ADM results are in good agreement with those of conventional ab initio full system computation.

COMP 323 [834461]:  Group III atomic wires on Si(100)-(2x1) reconstructed surfaces

Deborah D. Zorn, Chemistry Department and Ames Laboratory USDOE, Iowa State University, 201 Spedding Hall, Ames, IA 50011,, and M. S. Gordon, Department of Chemistry, Iowa State University
When group III metals are deposited onto the Si(100)-(2x1) reconstructed surface they self assemble into chains of atoms that are one atom high by one atom wide. These chains have applications as atomic wires. In order to better understand the 1D island growth of these systems, Ab Initio calculations of Al atoms on silicon clusters have been performed. Natural orbital occupation numbers show that Si(100) reconstructed surfaces display diradical character, so a multi reference method is needed. A multi-configuration self consistent field (MCSCF) calculation with a 6-31G(d) basis set and effective core potentials was used to optimize geometries. A potential energy surface for diffusion of Al adatoms on the surface was identified. Hessians were calculated to characterize stationary points and improved treatment of dynamic electron correlation was obtained using multi-reference second order perturbation theory (MRMP2) single point energy calculations.

COMP 324 [831346]:  A joint theoretical and experimental study of phenylene-acetylene molecular wires

Rudolph J. Magyar, Theoretical Chemistry and Molecular Physics, Los Alamos National Lab, Group T-12 Mail Stop B268, Los Alamos National Laboratory, Los Alamos, NM 87545, Fax: (505) 665-3909,, and Sergei Tretiak, Theoretical Division, Los Alamos National Laboratory

The excited state electronic structure of pi conjugated phenylene-acetylene oligemers is calculated using time-dependent density functional theory (TD-DFT) approaches. The theoretical fluorescence spectra are analyzed in terms of Frank-Condon active nuclear normal modes and shown to compare well with experiment. Theoretical and experimental results for the optical absorption and emission spectra of these molecules indicate that the conjugation length can be significantly reduced by conformational rotations about the triple-bonded carbon links. This has serious implications on the electronic functionalities of polyphenylene-acetylene based molecular wires and their possible use as charge/energy conduits in nano-assemblies.

COMP 325 [829910]:  Ab initio calculations of new polynuclear aromatic subphthalocyanine macrocycles

C. M. McCallum and Ronald Nohr, Department of Chemistry, University of the Pacific, 3601 Pacific Ave., Stockton, CA 95211, Fax: 209-946-2607,

br>Subphthalocyanines are cone-shaped, aromatic macrocycles composed of three diiminoisoindoline units N-fused around a boron atom. Their π-electron core and their peculiar geometry have made this class of compounds of special interest in the fields of dyes, optical recordings, supramolecular chemistry and nonlinear optics. We report a new sub-class of subphthalocyanines in which the aromatic system is polynuclear. These anthracene- and naphthalene-containing molecules have been studied at the Hartree-Fock (HF) and Density Functional (DFT) levels. Geometry optimizations along with normal mode analyses were made. Conjugation patterns as well as dipole moments will be reported as well as patterns of molecular orbital occupation. In addition, vibrational analysis at the different levels of theory will be presented in order to help explain the contribution that electronic correlation plays in the structure of these macrocycles.

COMP 326 [818605]:  Ab initio studies of aromatic side-chains in solution and in proteins

Jonathan D. Hirst, School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom, Fax: +44-115-951-3562,
Electronic transitions in aromatic side chains are responsible for the characteristics of proteins in the near UV. Using the polarisable continuum model in the framework of a complete active space self-consistent reaction field, we have calculated the vertical transition properties for the valence electronic excited pi-pi* singlet states of the chromophores benzene, phenol and indole in bulk solvent. The predicted solvatochromic shifts generally agree with previous experimental and computational results. From the ab initio calculations for benzene, phenol, and indole, we derive new parameter sets that describe the valence electronic transitions in the side chains of amino acids phenylalanine, tyrosine, and tryptophan. Circular dichroism (CD) spectra were calculated, using the matrix method with the new side-chain parameters, for 30 proteins whose CD spectra and crystal structures have been made publicly available. The mean absolute errors for computed wild-type spectra in the near UV are reduced by a factor of two.

COMP 327 [826274]:  Accurately solving the electronic Schrödinger equation of small atoms and molecules using the explicitly correlated (r12-) multi-reference averaged coupled-pair functional (MR-ACPF)

Robert J. Gdanitz, Department of Physics, North Carolina A&T State University, Marteena Hall, Greensboro, NC 27411,

The recently proposed r12-MR-CI method, which includes terms that are linear in the interelectronic distances (r12) in the ansatz for the wavefunction—in combination with MR-ACPF—allows for systematically solving the electronic Schrödinger equation to accuracies that cannot be obtained with present day (traditional) CI methods and computers, without the aid of extrapolations.

To demonstrate the high efficiency of this method, it has been applied to the computation of: i) the potential energy curve of N2; ii) the ground-state energies of first-row atomic ions; iii) their electron affinities; and iv) the dispersion interaction within dimers of He, Be, and Ne [for a recent review, see: Recent Res. Devel. Quantum Chem., 3, (2002) 245–276].

In my talk, I will give an outline of the method, demonstrate the outstanding accuracy that can be obtained, and present some new results.

COMP 328 [832759]:  Calculation of the electronic spectra of molecules in solution and on surfaces

Nicholas A. Besley and Jonathan D. Hirst, School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom, Fax: +44-951-3562,

An approach to calculate the electronic spectra of molecules in solution or adsorbed on surfaces is presented. Through limiting the single excitation space to include only excitations localized on the solute or adsorbant, large computational savings are achieved with only a small additional error. This approach has been implemented within time-dependent density functional theory. Calculations of the electronic spectrum of formamide in water and carbon monoxide on the Pt(111) surface will illustrate the method.

COMP 329 [828285]:  Effect of basis set superposition error on the convergence of intermolecular interaction energies for hydrogen-bonded complexes

Masao Masamura, Graduate School of Medicine and Dentistry, Okayama University, Shikata-cho 2-5-1, Okayama 700-8525, Japan, Fax: 81-86-235-6714,

The intermolecular interaction energies of 21 deprotonated hydrogen-bonded complexes, 23 protonated hydrogen-bonded complexes and 21 neutral hydrogen-bonded complexes were calculated with correlation consistent basis sets at the MP2, MP4, QCISD(T) and CCSD(T) levels. For the deprotonated hydrogen-bonded complexes [1] and protonated hydrogen-bonded complexes [2], when the basis set is smaller, the counterpoise-uncorrected intermolecular interaction energies are closer to the complete basis set limit than the counterpoise-corrected intermolecular interaction energies. The counterpoise-uncorrected intermolecular interaction energies obtained at the MP2/aug-cc-pVDZ level are close to the interaction energies obtained at the extrapolated complete basis set limit in the most complexes. For the neutral hydrogen-bonded complexes [3], we analyze the data.

[1] M. Masamura, J. Comput. Chem. 25 (2004)1771. [2] M. Masamura, Preparation for submission. [3] M. Masamura, Preparation for submission.

COMP 330 [819561]:  High precision evaluation of the thermochemistry of some radicals challenged by structural flexibility, strong anharmonic effects, and spin-vibronic coupling

Aleksandr V. Marenich and James E. Boggs, Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712,

Thermochemical properties of some important intermediates (HCO, CH2OH, and CH3O) in atmospheric and combustion chemistry were evaluated beyond the rigid rotor – harmonic oscillator approximation by means of a variational solution of the nuclear Hamiltonian with the inclusion of cubic and higher order anharmonic terms. The strong structural flexibility due to the out-of-plane motions in CH2OH (Cs) and the pronounced Jahn-Teller effect and spin-orbit coupling in the X2E ground electronic state of CH3O (C3v) were included. The electron problem solution for the selected radicals was performed with the coupled cluster electron correlation technique and augmented basis sets of triple- and quadruple-ζ quality. The partition functions were calculated by the explicit summation of energy levels. Expectation values of the structural parameters were computed. Heats of formation were evaluated with the geometry and energy parameters extrapolated to the complete basis set limit.

COMP 331 [832867]:  Structural aspects of the enzyme attack of phospholipid bilayers

Robert K Thomas1, Hanna P Vacklin1, and Carmen Domene2. (1) Physical and Theoretical Chemistry, University of Oxford, South Parks Road, OX1 3QZ Oxford, United Kingdom, Fax: 0044-1865-275410,, (2) Physical and Theoretical Chemistry Laboratory, Department of Chemistry, University of Oxford

Interfacial enzymes are soluble enzymes that execute their chemistry at interfaces. Phospholipases are a special class that change the structure of individual phospholipid molecules within a membrane. A key part of their control, which is not understood, is the cooperative interaction between enzyme and bilayer. We present direct observation of the structural changes that occur when a phospholipase enzyme interacts and destroys a range of different phospholipid bilayers. The results based on neutron reflection supported by computer simulation give stong clues as to how the cooperativity of the system could act as a biological control mechanism.

COMP 332 [833322]:  Development and applications of an arylamide force field for molecular simulations

Vojislava Pophristic1, Satyavani Vemparala2, Ivaylo Ivanov2, Michael L. Klein2, and William F DeGrado3. (1) Department of Chemistry and Biochemistry, University of the Sciences in Philadelphia, 600 S. 43rd Street, Philadelphia, PA 19104,, (2) Department of Chemistry, University of Pennsylvania, (3) Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine

Arylamide oligomers are increasingly becoming a focus of many organic synthesis efforts, due to versatile biomedical roles they are designed to have. Their composition can be tailored to achieve the desired functions which typically involve binding to specific biological targets, and depend on their overall physicochemical properties, mainly conformation and amphiphilicity. Molecular simulations can provide the needed insight into their properties, thus aiding synthetic designs. Highly accurate forcefields are essential for such simulations. Taking into account the limitations of currently available forcefields regarding torsional parameters, we have undertaken a series of high-level ab initio calculations (B3LYP/6-311G(d,p)) on arylamide model compounds to determine torsional potentials. Obtained torsional parameters differ significantly from the general amber force field (gaff) parameters, routinely used for organic molecules. Based on these parameters, we have developed a complete forcefield for this class of compounds, and applied it to study the arylamide interaction with heparin and lipid bilayers.

COMP 333 [830704]:  Binding of organoruthenium anticancer drugs to DNA

Ursula Rothlisberger, Institute of Chemical Sciences and Engineering, Federal Institute of Technology EPFL, 1015 Lausanne, Switzerland, Fax: 0041-1-21-693-0320,, Christian Gossens, Institute of Chemical Sciences and Engineering, Federal Institute of Technology Lausanne, and Ivano Tavernelli, Institute of Chemical Sciences and Engineering, Federal Institute of Technology

Abstract Organoruthenium compounds have emerged as promising novel anticancer agents but very little is known about their molecular mechanism of action. Here, we present classical and mixed QM/MM first-principles MD simulations of two ruthenium(II) compounds and their binding to DNA.

COMP 334 [831976]:  Hydration water dynamics of biological systems and connections to anomalous dynamics of supercooled liquids and glasses

Daniela Russo1, Rajesk K. Murarka1, Greg L.B. Hura2, Joseph D. Batchelor2, and Teresa Head-Gordon1. (1) Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, Fax: 510-486-6488,,, (2) Biophysics Graduate Group, University of Califonia at Berkeley
We present QENS experiments and MD simulation analysis for the hydration water dynamics of N-acetyl-leucine-methylamide (NALMA) solutions as a function of concentration and temperature. The experiments show non-Arrhenius translational dynamics over the temperature range of -3C to +37C at all concentrations, and fits to the experimental intermediate scattering function show non-exponential relaxation dynamics. The hydration dynamics of the most concentrated solution exhibits very good correspondence with the same signatures of non-Arrhenius behavior and non-exponential dynamics as that observed for supercooled water well below -20C. The corresponding MD simulation analysis of the high concentration data using the SPC water model, a common companion water model used in protein simulations, is severely limited in application to the dynamics of this system due to the very low temperature of maximum density. However the use of the TIP4P-EW water model, with its superior simulation of bulk water transport properties, shows quantitative agreement with experiment for the hydration dynamics of the solutions examined here. By contrasting the hydration dynamics of NALMA with NAGMA (glycine) using QENS and MD, we find that NALMA shows more pronounced anomalous diffusion signatures than that found for NAGMA. The more normal diffusion exhibited in the hydration dynamics near the hydrophilic backbone model provides experimental support for the origin of the anomalous diffusion behavior for NALMA as arising from frustrated interactions between water molecules when a chemical interface is formed upon addition of the hydrophobic side chain, which induces spatial heterogeneity in the hydration dynamics in the two regions of the NALMA peptide. We provide discussion in regards to the mutually beneficial connection between supercooled liquids and glasses and its biological importance for protein-water systems.

COMP 335 [829711]:  Correlation between the dynamics of amino acid residues and water molecules in aqueous protein solutions

Sanjoy Bandyopadhyay, Department of Chemistry, Indian Institute of Technology, Molecular Modeling Laboratory, Kharagpur 721302, India, Fax: 91-3222-255303,
A molecular level understanding of the biological activity of a protein molecule is an important problem. To perform its activity a protein must undergo certain critical dynamical motions around the active site residues. The time scales of these motions may determine the reaction pathways and also the rate. As most of the proteins are known to function in aqueous medium, it is natural to expect that the water molecules around the protein also to participate in various dynamical events that lead to activity. Recently, we have attempted atomistic simulations of aqueous solutions of two proteins, HP-36 and lysozyme. HP-36 is a small globular protein containing 36 residues and is the thermostable subdomain present at the extreme C-terminus of chicken villin protein. It contains three short α-helices and the activity of the protein is believed to be centered around helix-3. We have studied the local dynamics of different secondary structures of the protein as well as that of the water around them. We will also highlight a few preliminary results obtained from our study on hen egg-white lysozyme containing 129 amino acid residues.

COMP 336 [803547]:  Crystal structure prediction of diastereomeric salts: A step toward rationalization of racemate resolution

Frank J.J. Leusen, Institute of Pharmaceutical Innovation, University of Bradford, Bradford, United Kingdom, and Cikui Liang, Accelrys Inc, 9685 Scranton Road, San Diego, CA 92121
When a chiral compound cannot be obtained in an optically pure form, its racemate can be separated into enantiomers by co-crystallization with a resolving agent, resulting in two diastereomeric salts with different structures and physical properties such as solubility. Resolution efficiency of a resolving agent is estimated by the lattice energy difference between the salts.

Polymorph Predictor was used to explore the solid-state packing alternatives of the diastereomeric salts of two ephedrine enantiomers and a resolving agent, chlorine-substituted cyclic phosphoric acid (cyclophos). Three experimentally observed diasteromeric salts (two polymorphic forms for n-salt and one p-salt) were predicted correctly. The resolution efficiency for cyclophos was predicted to be 0.61, comparable with the experimental value.

The study indicates that simulations could help reduce a list of potential resolving agents to the most promising candidates. Such computational approach potentially leads to a predictive model for racemate resolution by preferential crystallization of diastereomeric salts.

COMP 337 [830259]:  Consensus feature selection for multi-objective SVM modeling of protein ion-exchange displacement chromatography

Dechuan Zhuang1, Curt M Breneman1, Kristin P. Bennett2, and Steve M. Cramer3. (1) Department of Chemistry, Rensselaer Polytechnic Institute, Cogswell Laboratory, 110 8th Street, Troy, NY 12180-3590, Fax: 518 276-4887,, (2) Department of Mathematics, Rensselaer Polytechnic Institute, (3) Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute
A new method has been proposed and implemented for consensus descriptor selection under multiple objectives based on linear support vector regression. All objectives are considered simultaneously during the process by minimizing the individual model risk altogether and the upper bounds of each component of the weight vectors. Applied to quantitative structure retention-time relationship (QSRR) modeling in protein chromatography separation processes, this new method has proven able to find a common set of descriptors that are important to all objectives, corresponding to different combinations of experimental conditions. The underlying protein separation mechanism is discussed in terms of the nature of the common set of descriptors and their weights in consensus models. The resulting models gave predictions of comparable accuracy with respect to those provided by individual models with independent feature selection. Some potential applications of this new method are also discussed.

COMP 338 [834749]:  Developing models for activity using conformation mining

Santosh Putta, Gregory A. Landrum, and Julie E. Penzotti, Rational Discovery LLC, 555 Bryant St. #467, Palo Alto, CA 94301,

Given the large conformational space accessible to most drug-like molecules, it is often difficult to predict the key ligand-protein interactions responsible for binding without structural data. We have developed an algorithm for mining hundreds of low energy conformations of multiple active compounds in order to discover a handful of biologically relevant conformations. This technique also provides multi-molecule alignments between these conformations that mimic the binding orientations. These multi-molecule alignments and their consensus chemical feature maps can be used to filter new data by removing irrelevant conformations. Here we present the application of conformation mining to developing predictive models for activity. We will present a set of novel descriptors derived from conformation-mining results that can be used as inputs to machine learning algorithms. Details of these descriptors and results of their application to multiple drug-discovery data sets (e.g. CDK-2, Cox2, and HIV) will be presented.

COMP 339 [818792]:  Mechanism of action of tirapazamine and its analogs: A computational study

Jin Liu, Christopher M. Hadad, and Matthew S. Platz, Department of Chemistry, The Ohio State University, 100 W 18th Avenue, Columbus, OH 43210, Fax: 614-292-5151,
The two possible mechanisms of action of the anti-cancer drug tirapazamine have been investigated using density functional theory (DFT). Tirapazamine is a novel anti-cancer drug which is inactive in oxygen-rich, healthy cells but is active in oxygen-poor, cancerous cells for DNA strand scission. We calculate that the mechanism via a series of electron-transfer/proton-transfer/fragmentation steps to eventually produce hydroxyl radical is energetically favored. The generated hydroxyl radical may then react with the sugar residues of the DNA backbone moiety to produce a sugar-centered radical. However, a direct mechanism involving hydrogen-atom abstraction from the sugar residues by a tirapazamine-centered radical is not energetically feasible. The calculations predict that tirapazamine, acting as a surrogate for molecular oxygen, can then react with the sugar radical exothermically to oxygenate the radical center and thereby cause the DNA strand break. Related reactions of the tirapazamine analogs were studied, and promising new drug candidates will be discussed.

COMP 340 [828534]:  Quantitative analysis of pH effect on the molecular interaction

Toshihiko Hanai, Health Research Foundation, Kyoto 606-8225, Japan, Fax: 045-547-4874,
A fast analytical method is required to measure HSA-drug binding affinity in drug discovery research. The pH effect on molecular interaction can be examined using liquid chromatography experimentally without proteins. The quantitative analysis of retention in liquid chromatography is easy, because a homogeneous model phase can be used instead of a complicated protein model for studying docking mechanisms. The direct interaction between a model-phase and a drug was calculated as energy values using the molecular mechanics (MM2) calculation. Several model phases were constructed and a suitable model phase was screened to demonstrate the importance of ion-ion interaction. The retention factor in a given pH eluent in liquid chromatography can be predicted from a following equation: k = (km + ki([H+]/[K])/(1 + ([H+]/[K]). The km and ki values were linearly related with Denergy values of molecular and ionized form analyte with high correlation coefficients. The precision of k depended on that of K.

COMP 341 [834054]:  Active learning for compound screening

Megon Walker and Simon Kasif, Bioinformatics Program, Boston University, 44 Cummington Street, Boston, MA 02215,

At the intersection of drug discovery and experimental design, active learning algorithms guide selection of successive compound batches for biological assays when screening chemical libraries in order to identify many target binding compounds with minimal screening iterations. The active learning paradigm refers to the ability of the learner to modify the sampling strategy of data chosen for training based on previously seen data. During each round of screening, the algorithm selects a batch of unlabeled compounds to be tested for target binding. Once their activity is known, the model of activity is recomputed on all compounds labeled so far, and another set of chemicals is selected for screening. The compound screening method proposed here combines committee-based active learning, bagging and boosting techniques, and several sample selection options to analyze the pharmacophore fingerprints of two pharmaceutical datasets, retrieving up to 87% of the actives after screening 30% of the compounds.

COMP 342 [819896]:  Novel computational quantum chemistry approach in drug screening

Rishi R. Gupta, Ioana Stanescu, and Luke E. K. Achenie, Department of Chemical Engineering, University of Connecticut Storrs, 191 Auditorium Road, UNIT 3222, UTEB, Storrs, CT 06269, Fax: 860-486-2959,

In this work we investigated the molecular recognition of the interacting molecules with the chemical structure of active sites as a rational approach towards pharmaceutical drug design. The structure of target protein is known apriori. Considering the biological activity, the information gained from this study can be used as a method for virtual screening of drugs in the final stages of pre-clinical development and for design of new or improved drugs. We have employed a computational quantum chemistry approach using Gaussian 98, and the Jaguar software packages. Primary considerations during this investigation are geometrical characteristics, and energy considerations at various points of the reaction pathway of the drug under study. As a case study we considered aspirin and studied its therapeutic effect on serine. Serine is a protein, which is significant in the formation of prostaglandin H2 synthase (PGHS), one of the factors associated with pain and inflammation. Aspirin binds to the serine molecule and prevents serine from producing PGHS. This reaction pathway was studied critically to find various transition states and energy calculations were performed using ab-initio and density functional methods (B3LYP) at every critical state in the reaction pathway. The binding ability between the target and the drug was calculated using the energy values. The computational results were compared with established experimental results to benchmark our study. The study was further extended to new drugs and candidate drugs were screened using physico-chemical properties of various drugs. Further more, to make the study more realistic, water molecules were included explicitly to study the solvation effects on drugs.

COMP 343 [823326]:  Structure and binding of glycopeptide antibiotics to bacterial cell wall analogs: Theoretical study

Jung-Goo Lee, Celeste Sagui, and Christopher Roland, Center for High Performance Simulation and Department of Physics, North Carolina State University, Box 8202, 110 Cox Hall, Raleigh, NC 27695, Fax: 919-513-4804
The recent rise of VRSA (Vancomycin-Resistant Staphylococcus Aureus) has given new impetus to the study of the binding between bacterial cell wall termini and glycopeptide antibiotics. Here, we report on an extensive ab initio Quantum Mechanical (HF and DFT) investigation of the binding of vancomycin, teicoplanin, ristocetin and avoparcin with Ac-D-Ala-D-Lac and Ac-D-Ala-D-Ser (characteristic of VRE and VRSA), Ac-D-Ala-D-Ala (characteristic of some MRSA) and Ac-D-Ala-Gly. The ordering of the average binding, from strongest to weakest, is: Ac-D-Ala-Gly ~ Ac-D-Ala-D-Ala, Ac-D-Ala-D-Ser, and Ac-D-Ala-D-Lac. Especially, the binding of all the antibiotics to Ac-D-Ala-D-Ala over Ac-D-Ala-D-Lac was found to be stronger by about 3-5 kcal/mol. These results are in good agreement with experimental findings.

COMP 344 [829292]:  Virtual exploration of the small molecule chemical universe below 160 daltons

Tobias Fink1, Heinz Bruggesser2, and Jean-Louis Reymond1. (1) Department of Chemistry and Biochemistry, University of Berne, Freiestrasse 3, Berne 3012, Switzerland, Fax: 41-31-6318057,, (2) Department of Mathematics, University of Berne
The development of modern medicine largely depends on the continuous discovery of new drug molecules for treating diseases. One striking feature of these drugs is their relatively small molecular weight (MW), which averages only 340 daltons. Recently drug discovery has focused on even smaller building blocks with MW of 160 daltons or less, to be used as lead structures that can be optimized for biological activity by adding substituents. At that size it becomes legitimate to ask how many such very small molecules would be possible in total within the boundaries of synthetic organic chemistry. To address this question we have generated a database (GDB) containing all possible organic structures with up to 11 main atoms under constraints defining chemical stability and synthetic feasibility. The database contains 13.9 million molecules with an average MW of 153 daltons, corresponding to approximately 44 millions stereoisomers. A reference database (Rdb) of known compounds of similar size contains 36'227 compounds. Virtual screening returns over 30'000 high-scoring compounds for GPCR ligands, ion-channel modulators and kinase inhibitors. The database construction strategy chosen also ensures that the majority of GDB, although presently unknown, should be synthetically accessible.

COMP 345 [826891]:  PEST vs. CoMFA: A comparative study of two 3D-QSAR technologies

C. Matthew L. Sundling and Curt M Breneman, Department of Chemistry, Rensselaer Polytechnic Institute, Cogswell Lab 319A, 110 8th St, Troy, NY 12180, Fax: 518-276-4045,

Property Encoded Surface Translator (PEST) is an algorithm for the generation of whole molecule shape descriptors from encoded molecular surfaces. It combines the information content of electron density-derived TAE surface property descriptors with shape information from ray tracing technology. The PEST algorithm surface analysis procedure captures conformationally-dependent geometric information about the shape of a surface, without the excessive variation in properties observed in Gasteiger-style surface autocorrelation analysis. The PEST descriptors are characteristic of molecular reactivity patterns in addition to shape specificity and have enabled us to capture essential molecular shape and property information in an unsupervised and robust manner.

PEST offers an alignment-independent alternative to current 3D-QSAR methods such as CoMFA (Comparative Molecular Field Analysis), a method successful for several reasons that include (1) effective PLS model building and (2) isolation of regional chemical information. The regional information provided by CoMFA allows for intuitive model interpretation. Namely, CoMFA isocontours geometrically resolve the structure-activity relationship into a quickly digestible form. On the other hand, these results come at the significant cost of accurate and appropriate molecular alignment, in addition to the selection of appropriate CoMFA algorithm parameter settings.

We compared PEST results with established 3D-QSAR CoMFA methods on three main factors: model building, model interpretation, and method overhead. Method overhead is slightly less precise than the other two, because it includes semi-qualitative user interaction times like data preparation and supervision. Three ‘CoMFA' datasets selected from the literature ensured the data was successfully used in a prior CoMFA study, and allowed us to avoid obvious bias that would favor the PEST method.

COMP 346 [806652]:  The use of exclusion volume in feature based alignment pharmacophore models: Catalyst HipHopRefine

Allister J. Maynard1, Samuel Toba2, Jon Sutter1, Marvin Waldman1, Jiabo Li3, and Roman Kuchkuda1. (1) Accelrys, 9685 Scranton Rd., San Diego, CA 92121, Fax: 858 799 5100, (2) Rational Drug Discovery, Accelrys, (3) Accelrys Inc
This presentation provides an overview of the Catalyst HipHop and HipHopRefine pharmacophore generation and refinement algorithms. HipHop performs feature-based alignment of a collection of compounds and generates pharmacophore models. HipHop is used to match features, such as surface-accessible hydrophobes, surface-accessible hydrogen bond donors/acceptors, and charged/ionizable groups, against a set of active candidate molecules. HipHop does not incorporate any penalty for incompatible sterics, and the HipHopRefine algorithm has been designed as a post processing technique, suited to HipHop pharmacophores, which targets the addition of excluded volumes as just such a penalty. Details of the detection, ranking and selection of locations for excluded volume addition to pharmacophores based on a set of active and inactive molecules is given, along with details of improved enrichments and elimination of false positives in database searches compared with the original pharmacophores.

COMP 347 [833691]:  Using pharmacophore models to gain insight into structural binding: An application study

Samuel Toba, Rational Drug Discovery, Accelrys, 9685 Scranton Road, San Diego, CA 92121, Fax: 858-799-5100,, and Jayashree Srinivasan, Client Services Group, Consultant - Accelrys Inc
We report here pharmacophore hypotheses derived from a set of compounds experimentally determined as actives to a kinase target. We will compare the results in terms of the how the pharmacophore models provide insight to the ligand target binding. To facilitate this comparison, we use results obtained from internal docking studies of the same set of ligands to the receptor

COMP 348 [834987]:  Prediction of absorbtion and emission UV-VIS band shapes using semiempirical methods

John M. McKelvey, McKelvey Computational Chemistry, 861 Bennett Rd., Carmel, IN 46032,, and Sergei Tretiak, Theoretical Division, Los Alamos National Laboratory
For small and medium sized organic chromophores solution and gas phase UV-VIS absorbtion and emission band shapes and Lmax have been studied using semiempirical methods including ZINDO, MNDO, AM1, and NDDOG. All excited state properties were computed via the CEO all-singles CIS and all-singles CIS/RPA methods in conjunction with the listed Hamiltonians. For the NDDO base methods the excited state geometries and vibrational frequencies were determined using analytical gradients for the CEO method.

COMP 349 [834476]:  Quantum dynamics of [1,7] hydrogen shift in 1,3,5-heptatrienes

John D. Thoburn and Ryan T. Smith, Department of Chemistry, Randolph Macon College, Ashland, VA 23005, Fax: 804-752-4724,

Variational transition state theory with multidimensional tunneling is used to calculate rates, kinetic isotope effects, and Swain-Schaad exponents for the [1,7] antarafacial hydrogen shift in 1,3,5-heptatriene (1) and 7-methyl-1,3,5-octatriene (2). Rates were calculated at the B3LYP/6-31G* level using GAUSSRATE-POLYRATE. Tunneling corrections were incorporated into the transmission coefficients using a one-dimensional tunneling model (ZCT) as well as a multi-dimensional tunneling model (SCT) that allowed for “corner-cutting”. The effect of tunneling on the KIE was found to be moderate, in line with experimental results. Interestingly, “inverse” secondary KIEs become positive when tunneling is included. Inclusion of tunneling actually deflates the Swain-Schaad exponent in some cases, in contrast to the popular idea that tunneling should inflate the exponent. An analysis that rationalizes both deflation and inflation is presented. The origin of the misconceptions regarding the relation between tunneling and the Swain Schaad exponents will be discussed.

COMP 350 [820177]:  Tight-binding quantum chemical molecular dynamics approach to the formation dynamics of hydrogen by the chemical reactions of vibrationally excited water on Si surfaces

Momoji Kubo1, Yumiko Sasaki2, Keiko Chiba2, Pei Qiang2, Abdul Rajjak2, Hideyuki Tsuboi3, Michihisa Koyama2, Ewa Broclawik3, Kazuyoshi Akutsu4, Masahiro Hirota4, Masayoshi Kitada4, Hajime Hirata4, and Akira Miyamoto5. (1) Department of Applied Chemistry, Graduate School of Engineering, Tohoku University and PRESTO-JST, 6-6-07 Aoba, Aramaki, Aoba-ku, Sendai 980-8579, Japan, Fax: +81-22-217-7235,, (2) Department of Applied Chemistry, Graduate School of Engineering, Tohoku University, (3) New Industry Creation Hatchery Center, Tohoku University, (4) Honda R&D Co., Ltd, (5) New Industry Creation Hatchery Center and Department of Applied Chemistry, Graduate School of Engineering, Tohoku University
Recently, we have succeeded in generating hydrogen from water on the Si materials under 373.15 K. However, the formation mechanism of hydrogen molecules from water on the Si materials on electronic and atomic level has not been clarified, yet. On the other hand, recently we have succeeded in the development of accelerated quantum chemical molecular dynamics program "Colors" based on our original tight-binding theory. It realizes over 5,000 times acceleration compared to the conventional first-principles molecular dynamics method, which enables us to simulate more than 1,000 atoms system. Therefore, in the present study we applied our new accelerated quantum chemical molecular dynamics program to the formation dynamics of hydrogen molecules from water on the Si materials, and then we succeeded in clarifying that vibrationally excited water leads to the formation of hydrogen on the Si materials.

COMP 351 [834264]:  Structure and energetics of thiazolo[5,4-d]thiazole and derivatives: Promising materials for organic electronics

A. T. Yeates1, Douglas S. Dudis1, Albert V. Fratini2, Troy E. Reynolds1, and Kenneth A. Loescher1. (1) Materials and Manufacturing Directorate, Air Force Research Laboratory, Polymer Branch - AFRL/MLBP, 2941 Hobson Way, Wright-Patterson AFB, OH 45433-7750, Fax: 937-255-9157,, (2) Chemistry, University of Dayton
Neutral and protonated thiazolo[5,4-d]thiazole and some of its derivatives have been examined quantum chemically to determine molecular structures, ionization energies, electron affinities, triplet state energies and UV/vis transition energies. These molecules show promise as n-dopable conducting polymers, electron transporting organic semiconductors, photovoltaic, FET and nonlinear optical materials. SCF, MP2, Multiconfiguration SCF and CC as well as B3LYP methods were employed in the present study. Semiempirical methods proved surprisingly unacceptable even for geometry optimizations. Comparison of the results to experimental data will be discussed.

COMP 352 [827017]:  Stuctures and energetics of small third-row molecules determined with correlation consistent basis sets

Scott Yockel, Benjamin Mintz, and Angela K. Wilson, Department of Chemistry, University of North Texas, P.O. Box 305070, Denton, TX 76203-5070, Fax: 940-565-4318,

Both advanced ab initio [coupled cluster theory through quasiperturbative triple excitations CCSD(T)] and density functional [B3LYP] computational chemistry methods were used in combination with the standard and augmented correlation consistent polarized valence basis sets [cc-pVnZ and aug-cc-pVnZ, where n=D(2), T(3), Q(4), and 5] to investigate the energetic and structural properties of small molecules containing third-row (Ga–Kr) atoms. These molecules were taken from the Gaussian-2 (G2) extended test set for third-row atoms. Several different schemes were used to extrapolate the calculated energies to the complete basis set (CBS) limit for CCSD(T) and the Kohn–Sham (KS) limit for B3LYP. Relativistic effects were determined using spin-orbit (SO) corrections and two scalar relativistic (SR) approaches: (a) the Douglas-Kroll (DK) relativistic correction in combination with the newly recontracted standard correlation consistent sets (cc-pVnZ-DK); and (b) a relativistic effective core potential (RECP) comprised of a small core ECP with the new pseudopotential correlation consistent sets (cc-pVnZ-PP and aug-cc-pVnZ-PP).

COMP 353 [832980]:  Studies of self-directed growth of ordered organic nanostructures on silicon surfaces

Gino A. DiLabio and Robert A. Wolkow, National Institute for Nanotechnology, National Research Council of Canada, W6-010 ECERF, 9107-116 Street, Edmonton, AB T6G 2V4, Canada, Fax: 780-482-8632,
It is anticipated that hybrid organic-silicon nanostructures will underpin a new generation of devices that go beyond the traditional scope of semiconductor devices to include functions such as molecular sensors. Control over the formation of ordered structures on silicon surfaces requires that we develop a set of techniques that allow the control of the extent and direction of growth and the composition of the nanostructures. To this end, our group has demonstrated the remarkable ability of different molecules to undergo a chain reaction on an H-terminated Si(100) surface. In these processes, we take a step beyond atom-by-atom crafting methods by combining elements of self-assembly and substrate templated growth. These methods achieve the ultimate resolution of one surface atom on Si(100). In this presentation, I discuss the how computational modeling is guiding experimental efforts to develop techniques to build ordered organic nanostructures on silicon surfaces.

COMP 354 [821598]:  Theoretical study of solvent effects on Kolbe-Schmitt reaction using ab initio calculations and computer aided molecular design

Ioana Stanescu, Department of Chemical Engineering, University of Connecticut, 191 Auditorium Road, Unit 3222, Storrs, CT 06269-3222, Fax: 860-486-2959,, and Luke E. K. Achenie, Department of Chemical Engineering, University of Connecticut Storrs
Solvent effects on the Kolbe-Schmitt reaction kinetics were investigated theoretically using ab initio calculations and conventional transition state theory (CTST). The use of solvent for this gas-solid reaction is desirable in order to facilitate a homogeneous reaction mixture, to enable the reaction to be carried out under milder conditions, and potentially to improve the reaction rate. The distribution and yield of reaction products may vary widely depending on the solvent or suspension media used. New / alternative solvents were designed by means of a Computer Aided Molecular Design (CAMD) technique. Quantum mechanical calculations coupled with CTST were employed to analyze the kinetics of the Kolbe-Schmitt reaction in the presence of solvent as well as without solvent. Various solvents reported in the literature were also tested using the same methodology. The research demonstrates the usefulness of coupling ab initio calculations, CAMD and reaction rate theories in studying solvent effects on reactions.

COMP 355 [834462]:  Transverse polarizability of carbon nanotubes

Edward N. Brothers1, Konstantin N. Kudin2, Gustavo E. Scuseria1, and Charles Bauschlicher3. (1) Department of Chemistry, Rice University, Mail Stop 60, Rice University, Houston, TX 77005-1892,, (2) Princeton Institute for Science and Technology of Materials (PRISM), Princeton University, (3) NASA Ames Research Center

The transverse polarizabilities of carbon nanotubes are computed using Hartree-Fock (HF) and Density Functional Theory (DFT). The results of these calculations have implications for nanoelectronics, specifically for the possibility of using nanotubes as shielding for nanoelectrical components, as the results do not support the proposed enhanced polarizability, and hence enhanced shielding, of metallic nanotubes. The HF and DFT calculations are shown to be in close agreement, and this agreement is discussed. We find the polarizability per unit length depends on the square of the tube radius, and is not dependent on metallicity. The current calculations are consistent with tight binding calculations using four orbitals per carbon with regard to both trend and magnitude, but differ from some recent tight binding calculations performed using one orbital per carbon. The calculations detailed in this presentation are the most accurate to date, and settle contradictory data in the literature.

COMP 356 [817128]:  Understanding metal-support interaction in bi-functional catalytic Pt/H-ZSM-5 zeolite

Piti Treesukol1, Kanokthip Srisuk2, Jumras Limtrakul2, and Thanh N. Truong1. (1) Henry Eyring Center for Theoretical Chemistry/Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, UT 84112, Fax: 801-581-4353,, (2) Department of Chemistry, Kasetsart University

The metal-support interaction of a dispersed Pt atom on H-ZSM-5 zeolite has been investigated by using the DFT calculation with the B3LYP functional. A Pt atom interacts with a Brřnsted proton and a nearby framework-oxygen. Interaction with a framework-oxygen causes electron-transfer from zeolite to the Pt atom. A Brřnsted proton stabilizes the Pt atom on the zeolite surface by withdrawing excess electron from the Pt atom. The binding energy of Pt on the Brřnsted acid is 15 kcal/mol. The frequency shift of absorbed CO calculated from an embedded cluster model is 11 cm-1 red-shift, compared to 20 cm-1 red-shift from experiment. Our results indicate that not only the electronic state of the Pt atom but also the Madelung potential of the support are responsible for the observed red shift of CO on the Pt-H-ZSM-5.

COMP 357 [833559]:  Effects of electric fields on water-mediated proton transport

Sergio A. Hassan1, Gerhard Hummer2, and Yong Sok-Lee1. (1) Center for Molecular Modeling, National Institutes of Health, DHHS, Bethesda, MD 20892,, (2) Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health

Ab initio molecular dynamics simulations are carried out to study effects of external field modulation on proton transport in carbon nanotubes. Proton translocation between an acid and a base occurs along a water chain in the nanotube interior, whose structure and dynamics is controlled by the external perturbation. Solvent effects are represented partially by including water molecules outside one of the nanotube ends; an acceptor group at the opposite end creates local charge-density gradients that facilitate proton translocation. A detailed study of the proton transfer mechanism perturbed by electric fields normal to the water chain is presented. It is found that proton transfer can be accelerated or slowed down depending on the strength of the field. The implications of these observations on proton transport in biomolecular systems and its control by electrostatic interactions are discussed.

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