COMP Programming

Fall 2004 National Meeting
Abstract Listing

COMP 1 [772417]:  Docking with water and post-docking analysis: New developments to the GOLD docking program

Jason C. Cole, Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB5 8QD, United Kingdom,

The docking program, GOLD, has been further developed in collaboration with Astex Technology to allow users to dock ligands while accounting for the presence or abscence of mediating water molecules in binding.

Preliminary validation shows a good rate of prediction of correct water-mediated binding modes. In this talk, the methodology used will be presented along with results of further validation using a larger test set.

CCDC has also developed a tool to allow users to post-process docking results to calculate customizable protein-ligand interface descriptors. The tool utilises an XML driven command language for the intersection of primary properties to form compound properties. This work will be presented.

COMP 2 [767167]:  Identification of novel p38 MAP kinase inhibitors using new Glide docking and scoring algorithms
Thomas A. Halgren1, Leah L. Frye2, Jeremy R. Greenwood1, Robert B. Murphy1, and Richard A. Friesner3.
(1) Schrodinger, Inc, 120 W 45th Street, New York, NY 10036, Fax: 646-366-9550,, (2) Schrodinger, (3) Department of Chemistry, Columbia University

Economic pressures have intensified efforts to decrease the time needed to bring a new drug to market and to reduce the cost, and computational methods are increasingly relied upon to expedite lead discovery. We have recently made fundamental advances in sampling and scoring algorithms for virtual screening that have led to greater accuracy in identifying active ligands. In particular, improved docking accuracy has enabled us to develop an advanced scoring function ("extra precision" mode, XP) for Glide (J. Med. Chem. 2004, 47, 1739-1749; 1750-1759) that effectively rejects "false positives" by significantly penalizing physically inappropriate interactions and that more efficiently identifies compounds likely to bind strongly by rewarding key binding motifs. The increased enrichment allows a smaller number of docked ligands to be submitted to further detailed analysis, including assessment of induced fit, ligand strain energy and visualization. Using our hierarchical protocol we docked a database of 500,000 available compounds, prefiltered for drug-like ADME properties with QikProp, to a p38 MAP kinase receptor conformation believed to favor selectivity. Of 1000 top-scoring compounds, post-processing produced a shortlist of 70 for purchase and screening as kinase inhibitors. Of 28 compounds screened to date, 8 compounds representing novel chemotypes exhibited better than 50% inhibition and may be suitable as lead candidates. Four compounds have been analyzed further and gave IC50 values ranging between 1.8 and 9.8 µM; IC50 determinations are pending for the remaining 4 hits, but we believe that one or two of these may be submicromolar. This study demonstrates that our computational algorithms and our virtual screening methodology are mature enough to present a viable alternative to High Throughput Screening at greatly reduced cost where sufficient target structural information is available.

COMP 3 [750187]:  Docking and scoring: Improvements in screening enrichment and docking accuracy
Ajay Jain, Cancer Research Institute, University of California, San Francisco, Box 0128, San Francisco, CA 94143-0128, Fax: 650-240-1781,

Docking algorithms seek to extremize the value of a scoring function by finding the optimal conformation and alignment (pose) of a ligand relative to a protein binding site. The Surflex docking method employs an empirically constructed scoring function and a search methodology that makes use of molecular similarity based pose generation. Comparative results will be presented on both docking accuracy (geometric agreement with crystallographic experiment) and screening enrichment (ability to distinguish true positives from false positives). Particular emphasis will be on screening efficiency and methods to improve scoring functions by explicit training using putative false positives. Performance of Surflex v1.21 is competitive with many popular docking methods for docking accuracy and appears to be significantly better for screening enrichment.

COMP 4 [767186]:  Modeling correlated protein main-chain and side-chain motions in ligand docking and screening
Leslie A. Kuhn1, Maria I. Zavodszky1, Sameer Arora2, Ming Lei3, and Michael F. Thorpe4. (1) Department of Biochemistry & Molecular Biology and Center for Biological Modeling, Michigan State University, 502C Biochemistry Building, East Lansing, MI 48824-1319, Fax: 517-353-9334,, (2) Departments of Biochemistry & Molecular Biology and Computer Science & Engineering, Michigan State University, (3) Department of Biochemistry, Brandeis University, (4) Physics & Astronomy Department, Arizona State University

We describe a new method for modeling protein and ligand main-chain flexibility in docking. The goal is to sample the full conformational space, including conformations not yet observed by crystallography, MD, or NMR. Flexibility analysis is performed using the graph-theoretic algorithm FIRST, which identifies coupled networks of covalent and non-covalent bonds within the protein. ROCK then explores available conformations by only sampling dihedral angles that preserve the coupled bond network in the protein. A representative set of protein conformations can then be used as targets for docking with SLIDE, which models protein and ligand side-chain flexibility. This combined approach for incorporating main-chain flexibility in docking is illustrated for cyclophilin A-cyclosporin and estrogen receptor-zearalenol complexes. Very recent results show that the maintenance of correlated motions between hydrogen-bonded and hydrophobic side chains is also a key aspect of ligand recognition across diverse protein-ligand complexes.

COMP 5 [752085]:  Docking conformationally flexible molecules with MVP
Millard H. Lambert, Computational, Analytical and Structural Sciences, Glaxo SmithKline, 5 Moore Drive, PO Box 13398, Research Triangle Park, NC 27709-3398, Fax: 919-315-0430

MVP is a molecular mechanics program with facilities for docking, conformational search, library enumeration and homology modelling (Lambert, "Docking Conformationally Flexible Molecules into Protein Binding Sites," in Practical Application of Computer Aided Drug Design, Charifson, ed, (1997)). MVP was originally developed for protein structure prediction (Lambert and Scheraga, JCC 10 770-797, 798-816, 817-831, (1989)), and implements a generalized version of Harold Scheraga's build-up procedure. MVP can dock flexible organic molecules into a protein by running this build-up, or "grow" calculation within the binding site. This build-up process requires that the compound have an "anchor group" with approximately known position and orientation in the binding site. The anchor group is subjected to limited rotations and translations, but the procedure cannot usually predict large shifts in anchor position or orientation. These MVP docking calculations have been used in the structure based design of numerous compounds at Glaxo SmithKline, including eight clinical candidates, two of which are now in Phase II clinical trials. We will illustrate how the MVP build-up process works, and describe recent improvements, including methodology that makes it possible to dock compounds without any anchor group.

COMP 6 [773957]:  Scoring functions: What works and what doesn't
Mark McGann, Principal Developer, Docking Software, OpenEye Scientific Software, Cambridge, MA 02138

Scoring is the limiting factor in well designed scoring programs. Several several scoring functions are evaluated using the FRED docking program. Functions are evaluated again two criterion. First, their ability to pick out a correctly docked structure from many alternate poses. Second, their ability to select ligands with high binding affinity from a set of decoys. Functions examined include Zap Bind (a PBSA based scoring function), Chemgauss (a smooth chemically aware gaussian based scoring function) and the well know Chemscore and PLP scoring functions. Several other functions will likely be added by the time of this presentations.

COMP 7 [766657]:  Biased torsional mutations and their role in conformational GA
Alexander Strizhev, Discovery Software, Tripos Inc, 1699 South Hanley Road, St. Louis, MO 63144, Fax: 314-647-9241,, Robert D. Clark, Software Research, Tripos Inc, Edmond Abrahamian, Research and Development, Tripos, Inc, and Philippa R.N. Wolohan, Research, Tripos, Inc

This presentation discusses conformational Genetic Algorithms. The conventional Gray Coding of torsional angles of molecules in pharmacophore elucidation tool GASP was substituted with a Biased Gray Coding (BGC). BGC explores torsional angles of molecules close to certain predetermined values where one is at better odds of finding a good solution. Results of GASP with BGC are compared with conventional GASP Gray Coding results.

COMP 8 [773891]:  Application of QM-QSAR method to predict mutagenicity of dental monomer
Andrew J. Holder, Department of Chemistry, University of Missouri - Kansas City, UMKC, Flarsheim Hall, Rm 410h, 5110 Rockhill Road, Kansas City, MO 64110, Fax: 816-235-6543,, Lin Ye, Department of Chemistry, University of Missouri-Kansas City, 5100 Rockhill Rd, Kansas City, MO 64110,, Elisabet Kostoryze, Department of Pharmacology/School of Pharmacy, University of Missouri - Kansas City, Cecil Chappelow, Midwest Research Institute, and J. D. Eick, Department of Oral Biology/School of Dentistry, University of Missouri - Kansas City

Monomers used as dental restorative have the potential to leach out of the resulting polymer matrices due to incomplete polymerization, and may thus enter the human blood stream. Such materials must be evaluated very carefully for various toxicity effects. This study will focus on the prediction of mutagenicity (as defined by mutation of the standard Ames TA100 strain of bacteria) of several potential dental materials through quantum mechanically-based quantitative structure activity relationships (QM-QSARs). The SAM1 semiempirical method is used in this study allowing extension and refinement of our previous work to include new silicon-containing dental monomers. Also, a new mathematical interpretation of the TA100 data was used to generate QSARs based on different property values than those employed previously. Comparison of the new and previously developed QSAR models will be reported.

COMP 9 [774224]:  On the role of fluorine in intermolecular interactions
Sandro Mecozzi, School of Pharmacy and Department of Chemistry, University of Wisconsin, 777 Highland Ave, Madison, WI 53705, Fax: 608-262-5345,

We wish to report on the nature and strength of fluorine-mediated intermolecular forces. Binding energies between representative fluorinated molecules and cations / hydrogen bond donors have been calculated through high level ab initio calculations extrapolated at the complete basis set limit. NBO analysis is then used to provide an explanation for the origin of these interactions. The role of the degree of substitution on the carbon atom bearing a fluorine functionality has also been analyzed. We will provide evidence of the change in the ability of carbon-bound fluorine to engage in intermolecular interactions based upon the nature of the groups attached to the fluorine-bound carbon atom. Quantitative differences in binding abilities of mono-, di-, and trifluoromethyl functionalities will also be discussed along with corresponding applications in drug design and discovery.

COMP 10 [766001]:  Possible regions of fullerene self-assembly in laser-produced plasma
Petar M. Mitrasinovic, Department of Chemistry, Dalhousie University, Halifax, NS B3H 4J3, Canada,

To produce low cost fullerenes by high-energy lasers, structure, stability, and nucleation of fullerene clusters are considered and related to the optimal control formulation at the molecular scale. Based upon indications that the behavior of the plasma/He interaction volume for laser ablation experiments essentially follows that for cathodic arc discharge experiments, the possible zones of formation of the large carbon molecules and the feasibility of a more efficient fullerene synthesis by lasers are discussed. We propose a computational algorithm linking fullerene yield and production rate to laser characteristics. The optimized plasma zones providing a C60 yield of 70% and a production rate of 5.14 g/min (PHe = 240 Torr; power density = 7×109 W cm-2, T = 2700 K) from a graphite target are identified and displayed as time response. Cathodic arc systems are suggested to be valuable tools in the determination of local conditions for fullerene formation.

COMP 11 [773065]:  Halide ions in a "methyl pocket": Competition between hydrogen bonding and ion-dipole interactions
Qadir K. Timerghazin, Centre for Research in Molecular Modeling and Department of Chemistry & Biochemistry, Concordia University, Richard J. Renaud Science Complex, 7141 Sherbrooke St.West, Montreal, QC H4B 1R6, Canada, Fax: 514-848-2868, Qadir.Timerghazin@CERMM.Concordia.CA, Tao Nhan Nguyen, Centre for Research in Molecular Modeling, and Department of Chemistry and Biochemistry, Concordia University, and Gilles Peslherbe, Centre for Research in Molecular Modeling and Department of Chemistry & Biochemistry, Concordia University

The ability of C-H bonds to participate in hydrogen bonding has been an issue of long-standing interest. In the literature, the proposed nature of the interaction between substituted methanes RCH3 and halide ions ranges from purely electrostatic, ion-dipole attraction to regular or improper, blue-shifting hydrogen bonding. The situation is especially unclear in the case of halide-acetonitrile complexes and clusters, since several reported theoretical and experimental studies disagree on the prevalent role of either ion-dipole interactions or hydrogen bonding. In this contribution, we will present a detailed systematic computational study of the structures, binding energies and potential energy surfaces for the series of small halide-acetonitrile clusters X(CH3CN). The applicability of various quantum-chemistry methods to the systems of interest will be discussed and the nature of the bonding interactions in the X(CH3CN) complexes will be analyzed using the Atoms-In-Molecues and Natural Bond Orbitals approaches and various energy decomposition schemes. In light of this computational study, possible explanations for recent cluster and bulk solution experimental results and existing theoretical models will be critically discussed.

COMP 12 [773173]:  From philosophy of computational quantum chemistry to philosophy of computational biology
Buyong Ma, Laboratory of Experimental and Computational Biology, Basic Research Program, SAIC, NCI-FCRDC, Frederick, MD 21702, Fax: 301-846-5598,

Computational chemistry has expanded from computation of hydrogen molecule to computation of living cell. Applying theories from ab initio quantum mechanics to various simplified models, the virtual worlds explored by computations provide different replicas of real world phenomena. What kind of mapping relationships should we expected from our studies? How do we interact with experimental information? The computational biology is in the world with complex organization, for which a unified theory is yet to be proposed. A computational biological model, even with clear physical or chemical meanings, may not be necessarily reduced to physics or chemistry. One common theme from computational quantum chemistry to computational biology is that the virtual worlds can affect our perception of real world. To make the perception to be truth, we have to increase mutual interaction of computation and experiment.

COMP 13 [770897]:  Integrated web-based grid-computing environment for research and collaboration in computational science and engineering
Thanh N. Truong, Department of Chemistry, Univ. of Utah, 315 S, 1400 E, Room 2020, Salt Lake City, UT 84112,

We present our development of an integrated extendable Web-based Grid-computing environment for computational science and engineering called Computational Science and Engineering Online (CSEO). CSEO allows computational scientists to perform research using state-of-the-art tools, to query data from personal or public databases, to document results in an electronic notebook, to discuss results with colleagues, and to access grid-computing resources from a web browser regardless of geophysical location or time zone. Currently, CSEO provides an integrated environment for multi-scale modeling of complex reacting systems and biological systems. A unique feature of CSEO is in its framework that allows data to flow from one application to another in a transparent manner. Advantages, disadvantages, and future prospects of CSEO are then discussed. CSEO can be accessed at

COMP 14 [773346]:  Theoretical study of atmospherically important complexes of Criegee intermediate with water clusters and its reactions
Andrew Ryzhkov and Parisa Ariya, Department of Atmospheric and Oceanic Sciences, and Chemistry, McGill University, 805 Sherbrooke Street West, Montreal, QC H3A 2K6, Canada, Fax: 514-398-6115, Andrei.Ryjkov@Mail.McGill.Ca,

Gas-phase reactions with ozone are significant removal process for volatile unsaturated hydrocarbons in troposphere, which also produce atmospherically important species: HO, HO2, organic and inorganic peroxides. The primary product of the ozonolysis of alkenes is the Criegee intermediate (CI), the most important reaction of which is interaction with water. In present work ab initio and density functional methods were applied to evaluate importance of formation of CI complexes with water clusters for atmospheric reactions. Various structures CI…(H2O)n with n=1..4 were calculated and minimal configurations are found. In addition, the reactions of these complexes were investigated; energy barriers and rate constants were estimated. The rate constant of overall process was calculated, and its dependence on temperature and relative humidity was determined. Reaction rates for all pathways were estimated based on found rate constants and typical concentrations of the reactants in atmosphere. The further reactions of products and its impact on the chemistry of atmosphere are discussed.

COMP 15 [773568]:  Family 18 chitolectins: Comparison of MGP40 and GP39
Pranav Dalal1, Jeffry D. Madura1, and Nathan N. Aronson Jr.2. (1) Department of Chemistry and Biochemistry, Center for Computational Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15226, Fax: 412-396-5683,, (2) Department of Biochemistry and Molecular Biology, Univ. of South Alabamda

Glycosidases and lectins both bind sugars, but only the glycosidases are catalytic. The glycosidases occur among 90 evolved protein families. Family 18 is one of the two familes of chitinases (EC 3,2.1.14). Interestingly, lectins are also in this evolutionary group of Family 18 glycosidase proteins. Proteins belonging to the enzymatically inactive class ("chitolectins") have a highly similar binding site to the catalytic Family 18 enzymes. One major exception is a glutamic acid which acts as the essential acid/base residue for chitin cleavage is replaced with leucine or glutamine. We present our comparison of the recently obtained structures of two Family 18 chitolectins, MGP40 (Mohanty, Singh et al., 2003) and GP39 (Fusetti, Pijning et al., 2003; Houston, Anneliese et al., 2003).

COMP 16 [774057]:  Chiral recognition by silver: A Q2MM study
Elsa Kieken1, Olaf Wiest1, Paul Helquist1, and Per Ola Norrby2. (1) Department of Chemistry and Biochemistry, University of Notre Dame, Nieuwland Science Hall, Notre Dame, IN 46556,, (2) Department of Chemistry, Organic Chemistry, Technical University of Denmark.

Chiral diamine-silver I complexes have shown chiral recognition abilities toward chiral alkenes [1]. We are investigating chiral dinitrogen ligands (diamine, 1,10-phenanthroline)-silver I complexes and their binding to alkenes and alkynes using both quantum and molecular mechanics. Ab initio calculations were used to develop additional parameters for the MM3 force field for the accurate description of the geometry and relative energies of the transition metal containing complexes (Q2MM method [2]). The application of this force field to the prediction of the best ligand for a high enantiomeric excess in the resolution of racemic alkenes or alkynes will be discussed.

[1] Organometallics 2004, 23, 15-17 [2] J. Mol. Struc. (Theochem) 2000, 506, 9-16

COMP 17 [774178]:  Nanoscale manipulation of hydrogen storage in NaAlH4: Exploring catalytic surfaces using density functional theory
Santanu Chaudhuri, Nanocatalysis Group, Department of Chemistry & Center for Functional Nanomaterials, Brookhaven National Laboratory, Building 555, Upton, NY 11973,, Ping Liu, Dept. Chemistry, Brookhaven National Laboratory, and James T. Muckerman, Chemistry Department, Brookhaven National Laboratory

NaAlH4 doped with ~2% titanium is a promising hydrogen storage material. Density Functional Theory using the RPBE functional can predict the role of Ti during the multi-step hydrogen absorption-desorption cycle. Two of the most probable mechanisms of Ti assisted hydrogen storage e.g. the replacement of Na by Ti on the surfaces and formation of a Ti-Al alloy, have been probed in this work. The energetics of the hydrogen absorption process indicates that the intermediate perovskite phase, Na3AlH6, is less reactive compared to the end product of the hydrogen desorption cycle, NaH and Al. The NaH surface doped with Ti (figure 1) has been found to promote exothermic dissociative absorption of molecular hydrogen. This explains why nanometric NaH doped with Ti is reported to be a good hydrogenation catalyst. The use of DFT in unraveling the myriad correlations between electronic structure, oxidation state, defects and hydrogen storage efficiency will be discussed.

COMP 18 [773389]: DFT study of the interactions of antiwear additives with iron and iron oxide
Hongmei Wen
, Susanne M. Opalka, and Clark V. Cooper, Physical Sciences Department, United Technologies Research Center, 411 Silver Lane, East Hartford, CT 06108,

The fatigue life and wear of a mechanical component critically depends on the functions of lubricant, especially antiwear additives, under adverse operating conditions. The atomistic mechanisms for antiwear additives to protect mechanical component surfaces are still unknown. The first step to elucidate the mechanisms is to characterize the interactions of antiwear additives with the surfaces. Density Functional Theory (DFT) has been used to study the interactions. Tricresyl phosphate (O4C21H21) (TCP), a popular antiwear additive, was chosen to study. The value of the binding energy for TCP on Fe (100) was predicted to be 0.25 eV/TCP molecule, indicating a weak physical interaction. The binding energy of TCP on alpha-Fe2O3(0001), will be reported in order to explore the effects of a passive layer on the functions of TCP. For comparison, the results of polyester, base oil in gas turbine engine oil, will also be presented.

COMP 19 [747784]:  Methods of consensus scoring for in silico screening
Kim M Branson, Joint Protein Structure Laboratory, The Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Royal Parade, Parkville, Melbourne, Australia, Fax: +613 9341 3192,, and Brian J Smith, Structural Biology, The Walter and Eliza Hall Institute for Medical Research

Consensus methods[1-4] combine various scoring functions for in silico screening of large chemical databases against protein targets. They have been demonstrated to provide improved accuracy in the docking procedure, both the prediction of binding conformations and relative binding energies. We address here the issue of determining which scoring functions should be combined to obtain optimal results from the docking procedure. We illustrate this with examples where including too many scoring functions leads to a reduced hit-rate than when a select set of functions are used, and present a method of determining the best combination of functions to apply without the use of previously known ligands. The scoring functions used in the current analysis include DOCK, AutoDock, PMF, ChemScore, Score, SmoG. and X-cscore functions.

1. Bissantz C, Folkers G, Rognan D. Protein-based virtual screening of chemical databases. 1. Evaluation of different docking/scoring combinations. J Med Chem 2000 Dec 14;43(25):4759-67 2. Wang R, Wang S. How does consensus scoring work for virtual library screening? An idealized computer experiment. J Chem Inf Comput Sci 2001 Sep-Oct;41(5):1422-6 3. Wang R, Lai L, Wang S. Further development and validation of empirical scoring functions for structure-based binding affinity prediction. J Comput Aided Mol Des 2002 Jan;16(1):11-26 4. Clark RD, Strizhev A, Leonard JM, Blake JF, Matthew JB. Consensus scoring for ligand/protein interactions. J Mol Graph Model 2002 Jan;20(4):281-95

COMP 20 [744578]:  Can we learn from active ligands to improve the efficiency of virtual screening? The BHB scoring function
Miklos Feher, Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, Fax: 858-658-7601,, Eugen Deretey, MDS Proteomics, and Samir Roy, Department of Chemistry, University of Calgary

Scoring functions for virtual screening are usually optimized to work for diverse sets of compounds. The question we wanted to answer is whether it is possible to improve the performance of the scoring function once a few active ligands have been identified. In receptor docking, the scoring function has two utilities: ligand placement in the pocket and ranking docked solutions. In our work we separated the two tasks: the former was left to the docking program, while we developed a novel function for the latter role. This function is based on the buriedness of the ligand in the receptor pocket, possible hydrogen bonding interactions and calculated binding energy. Receptor buriedness is a measure of how well molecules occupy the binding pocket in comparison to known high-affinity ligands. The possibility of hydrogen bond formation is checked for selected residues that are recognized as being important in the binding of known ligands. The approximate binding energy is calculated from the thermodynamic cycle. The information necessary for the scoring function can ideally be gleaned from the 3D structure of the receptor-ligand complex or the 3D structure of the receptor and known active ligands that bind to the given site. We show that the new scoring functions provide up to 12 times improvement in enrichment compared to the popular commercial docking program GOLD.

COMP 21 [771988]:  Native atom types for knowledge-based potentials: Application to binding energy prediction
Brian N. Dominy and Eugene Shakhnovich, Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street - Box 79, Cambridge, MA 02138,,

Knowledge-based potentials have been found useful in a variety of biophysical studies of macromolecules. Recently, it has also been shown in self-consistent studies that it is possible to extract quantities consistent with pair potentials from model structural databases. In this study, we attempt to extend the results obtained from these self-consistent studies toward the extraction of realistic pair potentials from the PDB. The method utilizes a clustering approach to define particle types within the PDB consistent with the optimal effective pairwise potential. The method has been integrated into the SMoG drug design package, resulting in an improved approach for the rapid and accurate estimation of binding affinities from structural information. Using this approach, it is possible to generate simple knowledge-based potentials that correlate strongly (R=0.61) with experimental binding affinities in a database of 118 diverse complexes. Further, predictions performed on a random 1/3 of the database consistently show an average unsigned error of 2.5 log Ki units. It is also possible to generate specialized knowledge-based potentials, targeted to specific protein target families. This approach is capable of generating potentials that correlate very strongly with experimental binding affinities within these families (R=0.8 0.9). Predictions on 1/3 of these family databases yield an average unsigned errors ranging from 1.2 to 1.3 log Ki units. Altogether, we describe a physically motivated approach to optimizing knowledge-based potentials for binding energy prediction that can be integrated into a variety of stages within a lead-discovery protocol.

COMP 22 [775018]:  SAR-directed docking
Geoffrey Skillman, Stanislaw Wlodek, Matthew Stahl, and Anthony Nicholls, OpenEye Scientific Software Inc, Suite 1107, 3600 Cerrillos Road, Santa Fe, NM 87507

Virtual high throughput screening, and lead optimization are very different problems. General docking tools can aid in both cases, but lead compounds or series are often accompanied by structure-activity information. Using structure-activity relationships (SAR) to direct ligand-protein docking can lead to higher quality binding-mode hypotheses. We will describe pose generation and evaluation algorithms that utilize SAR to guide their behavior. These methods will be evaluated across a variety of ligand-protein systems in the context of a lead-optimization docking tool with an MMFF-PB/SA binding potential.

COMP 23 [749024]:  Modeling the active site of β-secretase: Application to drug discovery
Ramkumar Rajamani, Computer-Aided Drug Discovery, Johnson and Johnson PRD LLC, PO BOX 776, Welsh and McKean Rd, Spring House, PA 19477,, and Charles H. Reynolds, Computer-Aided Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development L.L.C

The cleavage of β-amyloid precursor protein (APP) by β-Secretase (BACE) is a crucial step in the production of the β-amyloid peptide that has been implicated as a probable cause of Alzheimer’s disease (AD). This has made BACE an attractive therapeutic target for treatment of AD. There are two aspartic acid residues (Asp 32 and Asp 228) in the catalytic region of BACE that can adopt multiple protonation states and tautomers. The protonation state and precise location of the protons for these two residues, particularly in the presence of an inhibitor, have a direct bearing on efforts to model this system properly. In the present study, we have carried out full quantum mechanical calculations using a linear scaling quantum mechanical method to identify the preferred protonation states and proton locations for Asp 32 and Asp 228 in the presence of inhibitors. Additionally, a binding affinity model based on the LIE approach has been developed that is capable of rank ordering inhibitors of BACE.

COMP 24 [771328]:  Evaluating scoring functions for docking and designing β-secretase inhibitors
M. Katharine Holloway1, J. Christopher Culberson1, Joseph Shpungin1, Sanjeev Munshi2, Craig A. Coburn3, Shawn J. Stachel3, Kristen G. Jones3, Elizabeth Loutzenhiser3, Alison R. Gregro3, Ming Tain Lai4, Ming Chih Crouthamel4, and Beth L. Pietrak4. (1) Molecular Systems, Merck Research Laboratories, West Point, PA 19446, (2) Structural Biology, Merck Research Laboratories, (3) Medicinal Chemistry, Merck Research Laboratories, (4) Biological Chemistry, Merck Research Laboratories

β-Secretase (also known as β-APP Cleaving Enzyme or BACE-1) is one of two proteases responsible for processing the membrane-bound Amyloid Precursor Protein (APP) to the 40/42 residue β-amyloid peptide (Aβ), the primary constituent of the amyloid plaques observed in the brains of Alzheimer’s patients. Since BACE-1 cleavage of APP appears to be the rate-limiting step in the production of Aβ and BACE-1 knockout mice show complete absence of Aβ with no reported side effects, BACE-1 appears to be an attractive therapeutic target in the treatment of Alzheimer’s disease. BACE-1 has been characterized as the first known example of a pepsin-like aspartyl protease that is membrane-tethered. However, a crystal structure of the soluble domain reveals a high degree of similarity to the tertiary structures of other mammalian and fungal aspartyl proteases, e.g. renin, cathepsin D, and endothiapepsin. Given the availability of 3D coordinates for BACE-1, it appeared likely that an appropriate docking/scoring protocol could be identified which would aid in the design of BACE-1 inhibitors. Several scoring functions were evaluated based on the structures and observed activities for a small series of hydroxyethylamine inhibitors. To test the predictivity of the scoring, a virtual ‘reagent scan’ was performed to evaluate the predicted binding energy of approximately 700 amine reagents in the S1’ site. Several high-scoring amine reagents were selected for incorporation and led to potent BACE-1 inhibitors. This study demonstrates the utility of a virtual approach to selecting reagents. In addition, it supports previous qualitative conclusions about the character of the S1’ site in BACE-1 relative to other aspartyl proteases.

COMP 25 [772139]:  Improving docking enrichments by picking "the right pose"
Hans E. Purkey, Erik Evensen, Kenneth E. Lind, and Erin K. Bradley, Computational Sciences, Sunesis Pharmaceuticals Inc, 341 Oyster Point Blvd., South San Francisco, CA 94080, Fax: 650-266-3501,

Docking methods often generate small molecule poses that are close to crystallographically determined binding positions. Even though much effort has gone into improving scoring functions, existing scoring functions typically do not rank order candidate poses correctly. We present a complementary approach in which experimental results are used to generate models for activity that are then used to select among docking poses. We investigate whether ligand positions that lie at this intersection of two manifolds (the docking conformational space and experimentally-informed pharmacophore and shape spaces) improve compound selection by available scoring functions or by their application alone. We will present examples of this method applied to both public soluble ligand datasets and internal datasets obtained from several protein targets using TetheringSM.

COMP 26 [763287]:  Scalable second-order Moller-Plesset linear R12 method with non-exact HF orbitals
Edward F. Valeev, School of Chemistry and Biochemistry, Georgia Tech, Atlanta, GA 30332-0400, Fax: 404-894-7452,, and Curtis L. Janssen, Scientific Computing Department, Sandia National Laboratory, Livermore

Linear R12 methods of Kutzelnigg and coworkers make accuracies of better than 1 kcal/mol computationally feasible and routine. Initial applications of these methods were expensive due to the use of large MO bases to approximate or eliminate some many-electron matrix elements. The ABS MP2-R12 method, first studied by Klopper and Samson, uses a separate basis set for the approximate resolution of the identity. Since standard approximation of many-electron matrix elements assumes exactness of some MOs in Hartree-Fock sense, the question still remains: how complete the orbital basis set has to be? Here we investigate basis set convergence of some relative energies with respect to the orbital basis using the new scalable implementation of the MP2-R12 method in the publicly-available MPQC package. Preliminary results indicate that the MP2-R12 method in present form cannot be used safely when small basis sets (such as aug-cc-pVDZ and aug-cc-pVTZ) are utilized in the orbital expansion.

COMP 27 [769150]:  Self-consistent relativistic density functional calculations including scalar and spin-orbit effects
Juan E. Peralta and Gustavo E. Scuseria, Department of Chemistry, Rice University, Houston, TX 77005,

We have implemented a Gaussian basis-set two-component self-consistent field method based on the fourth order Douglas-Kroll-Hess approximation. This variational two-component approach takes the spin-orbit interaction into account by employing a generalized Kohn-Sham scheme and allows one to deal with hybrid density functionals and open-shell systems. We present benchmark results in diatomics for equilibrium bond lengths, harmonic vibrational frequencies, and dissociation energies using local spin-density, generalized gradient, and hybrid density functionals. We also present results for the bond dissociation energies of uranium fluorides.

COMP 28 [765961]:  Systematic improvement of approximate density functionals
Viktor N. Staroverov1, Gustavo E. Scuseria1, John P. Perdew2, Jianmin Tao2, and Ernest R. Davidson3. (1) Department of Chemistry, Rice University, Houston, TX 77005-1892,, (2) Department of Physics and Quantum Theory Group, Tulane University, (3) Department of Chemistry, University of Washington

Density functional theory (DFT) is often criticized for lacking a mechanical prescription for systematic convergence to the right answer. Nonetheless, performance of DFT can be gradually improved by imposing known analytic properties of the exact exchange-correlation functional on semi- and nonempirical approximations. We show how this approach is applied to constructing novel density functionals and illustrate its success with examples from atomic, molecular, and solid-state chemistry.

COMP 29 [773979]:  Transition metal chemistry: A step toward high accuracy description of structural and energetic properties
Angela K. Wilson, Pankaj Sinha, Mohammad A. Omary, and Paul S. Bagus, Department of Chemistry, University of North Texas, Box 305070, Denton, TX 76203-5070, Fax: 940-565-4318,

The correlation consistent basis sets have played a pivotal role in enabling a hierarchy of high accuracy ab initio approaches to be well established. Though the sets have been widely used for main group species, their utility in transition metal studies has not yet been established, due to the very recent development of the sets. We have used the new sets to examine the impact of method, pseudopotential, and basis set choice upon the bonding description, and energetic and spectroscopic properties of a range of ground and excited-state transition metal species.

COMP 30 [748426]:  Nth-order derivatives of nuclear attraction integrals (NAIs) and electron repulsion integrals (ERIs)
Fredy W. Aquino and Jorge H. Rodriguez, Department of Physics, Purdue University, West Lafayette, IN 47907

We present a general scheme for evaluating one- and two-electron integrals using Fourier transformed expressions of Nuclear Attraction Integrals (NAIs) and Electron Repulsion Integrals (ERIs). First-order and second order derivatives of NAIs have been used to evaluate integrals associated with first-principle computation of electric fields and electric field gradients of molecular systems. In addition, first order and second order derivatives of ERIs are used in the evaluation of integrals associated with the calculation of zero-field splitting (ZFS) parameters. Higher order derivatives of NAIs and ERIs are not commonly used, however, our expressions could be used to arbitrary order should these have some practical application. Tables of formulas have been created to speed-up electronic structure calculations for the case of first and second order derivatives of NAIs and ERIs. Our work has direct application to the ab-initio calculation and interpretation of spectroscopic parameters generated by Mössbauer, EPR and magnetic susceptibility experiments.

Research supported by NSF grant CHE-0349189 (JHR).

COMP 31 [768548]:  On emerging fields of quantum chemistry at finite temperature
Liqiang Wei, Institute of Theoretical Atomic, Molecular and Optical Physics, Harvard University, 60 Garden Street, Cambridge, MA 02138, Fax: (617)496-7668,

Abstract text not available.

COMP 32 [773305]:  Hybrid density functional studies of bulk actinide oxides
Ionut D. Prodan, Physics Department and Rice Quantum Institute, Rice University, MS-61, 6100 Main Street, Houston, TX 77005, Konstantin N. Kudin, Princeton Materials Institute, Princeton University, Richard L Martin, Theoretical Division, Los Alamos National Laboratory, and Gustavo E. Scuseria, Department of Chemistry, Rice University

We study the electronic structure and bulk properties of UO2 and PuO2. Hybrid density functionals, Gaussian-type orbitals and relativistic effective-core potentials are used in a periodic boundary condition code. Such calculations for f-element solids were first reported in our paper on UO2 [K. N. Kudin, G. E. Scuseria and R. L. Martin, Phys. Rev. Lett. 26, 266402 (2002)], where the established Perdew-Burke-Ernzerhof (PBE0) hybrid density functional was used. In the present work we perform similar calculations on PuO2. Traditional density functionals have also been employed in both studies and they are found to compare worse with experiment, most likely due to the inadequate description of the localized f orbitals in actinide ions. The magnetic behavior was explored and PBE0 predicts the antiferromagnetic state to be the lowest in energy at T = 0 K, but nearly degenerate with the ferromagnetic state. The calculated lattice constant (5.39 Å) agrees very well with the experimental value of 5.40 Å, and PuO2 is correctly predicted to be a small-band gap insulator. Inclusion of an interstitial oxygen atom in the PuO2 lattice improves the agreement with the experimental density of states. We also compare the PBE0 results for both UO2 and PuO2 with data obtained with a newly developed hybrid density functional [J. Heyd, G. E. Scuseria and M. Ernzerhof, J. Chem. Phys. 118, 8207 (2003)].

COMP 33 [772669]:  Computational study of the C-H bond dissociation enthalpies and radical reactions with substituted ethylenes and benzenes
John K. Merle, Chemistry, The Ohio State University, 100 W. 18th Ave #33, Columbus, OH 43210, Fax: 614-292-1685,, and Christopher M. Hadad, Department of Chemistry, Ohio State University

C-H bond cleavage is an important aspect in the combustion of organic fuels, such as coal. The homolytic C-H bond dissociation enthalpies, ΔH(298 K), of a series of substituted benzenes (substituents = -F, -Cl, -CN, -NO2, -OH, -CH3, -CF3, -OCH3, -SCH3, -SH, -COH, -NH2) were determined using hybrid density functional theory methods. Results showed a small substituent effect on the BDE of the C-H adjacent to the substituent and very little effect on the other C-H bonds in the ring. These values were also compared to those calculated in the corresponding substituted vinyl systems. Spin densities and the changes in electronic distribution were also evaluated using Bader’s theory of atoms-in-molecules. Furthermore, the reactivity under both atmospheric and combustion chemistry conditions of the substituted ethylenes with OH radical and H atom will be presented. Reaction barriers and energies were determined using hybrid density functional theory and composite ab initio methods.

COMP 34 [774443]:  Correlation energy extrapolation by intrinsic scaling
Laimutis Bytautas and Klaus Ruedenberg, Ames Laboratory USDOE and Department of Chemistry, Iowa State University, Ames, IA 50011, Fax: 515 294 0266,

Remarkably accurate scaling relations are shown to exist between the correlation energy contributions from various excitation levels of the configuration interaction (CI) wavefunction, considered as functions of the size of the correlationg orbital space. These relationships are used to develop a new method for extrapolating a sequence of smaller CI calculations to the full CI energy. As a result the method also offers a systematic way for constructing compact and accurate CI wavefunctions. The method called correlation extrapolation by intrinsic scaling (CEIS) has been applied to neon atom and H2O, C2, N2, O2 and F2 molecules yielding the correlation energies of the benchmark quality.

COMP 35 [773230]:  Computational estimates of the gas-phase basicities and proton affinities of the six isomers of dihydroxybenzoic acid
Faten H. Yassin, Department of chemistry and biochemistry, University of Texas at Arlington, Box 19065, Arlington, TX 76013,, and Dennis S. Marynick, Department of Chemistry and Biochemistry, University of Texas at Arlington

The gas-phase basicities (GBs) and the proton affinities (PAs) of all six isomers of dihydroxybenzoic acid (x,y-DHB), which are well known matrices used in matrix-assisted laser desorption/ionization mass spectroscopy, have been calculated using density functional theory (DFT) and Moller-Plesset perturbation theory. Respectively, the GBs vary from 803.9 kJ/mol for the least basic species (3,4-DHB) to 830.0 kJ/mol for the most basic one (2,4-DHB). The reported GBs and PAs are in good agreement with previous experimental measurements. The results indicate that protonation, in all six isomers, takes place on the carbonyl oxygens.

COMP 36 [775034]:  Activation of the alpha carbon of an alpha,beta-unsaturated carbonyl compound toward nucleophilic attack: An experimental and theoretical study
David C. Chatfield1, Elzbieta Lewandowska2, Ashish Gairola1, Cassian D'Cunha1, and Carlos Alvarez1. (1) Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, Fax: 305-348-3772,, (2) Department of Chemistry, Academy of Agriculture

We and others have recently demonstrated that nucleophilic addition to alpha,beta-unsaturated carbonyl compounds can be directed toward the alpha carbon rather than toward the beta carbon (Michael or conjugate addition) or the carbonyl carbon. This can be accomplished by attaching a pi-deficient ring or a phenyl ring multiply substituted with strong electron withdrawing groups at carbon beta. Such addition is also implicated in the nucleophilic addition to alkynoates catalyzed by trialkylphosphorus compounds. Such reactions have potential use for the synthesis of non-natural amino acids. We present a theoretical and experimental study of such reactions, identifying the barriers to reaction and the reaction routes with density functional and ab initio methods. We identify common features of these types of reaction.

COMP 37 [772713]:  Ab initio studies of methyl and t-butyl group motions in aromatic molecular solids
Xianlong Wang1, Peter A. Beckmann2, Frank B. Mallory1, and Michelle M Francl1. (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

Combining theoretical and experimental approaches to determining rotational barriers for methyl and t-butyl groups in molecular solids leads to a more comprehensive understanding of the intermolecular interactions among molecules packed in a crystal environment. We present here results of ab initio calculations at the HF/6-311+G(d,p)//HF/6-31G(d) for the reorientation barrier for methyl and t-butyl group in four aromatic compounds, for which the crystal structures have been determined and the dynamics of methyl and t-butyl group motions have been measured by low frequency NMR relaxometry: 1,4-di-t-butylbenzene, 2,6-di-t-butylnaphthalene, 2,6-di-t-butyl-4-methylphenol and 3-t-butylchrysene. Single molecule calculations were compared with models for the molecular solids. Barriers were analyzed by decomposition into contributions from non-bonding interactions, delocalization, and relaxation of the molecular backbone.

COMP 38 [741579]:  Near-neighbor net MD: A perturbation method for non-additive Hamiltonians
Leslie V Woodcock, Department of Chemistry, University of Manchester Institute of Science and Technology, Faraday Building, Manchester M60 1QD, United Kingdom,

State-of-the-art molecular simulation technology remains largely restricted to pair-wise additive site-site Hamiltonians. Commercial stste-of-the-art programs with effective site-site pair potentials can deliver “animation”, but are of limited value as a predictive research tool. Water cannot be accurately represented by a pair-wise Hamiltonian. The same applies to the energy surfaces in macromolecules, polymers and network solids. Carbon is non-additive up to at least order 4. If many-body potentials of order n>2 or 3 are included in conventional MD, simulation of N-sites becomes N to power n times slower! To overcome this, we have developed a new approach. The method uses multidimensional arrays, for saving each site force (or potential in the case of MC) in a memory bank, as a function of its neighbourhood, rather like a neural net. Once “trained”, the many-dimensional array is state-independent and useful for wider N,V,T space. An algorithm has been developed for polarizable ions. The generating function for determining the “net” needn’t be the full Hamiltonian of the system. It needs only to get the n-body spatial distributions accurate up to the highest many-body term in the full Hamiltonian. For pair-wise systems, only the 2-body distribution is required. A rigorous perturbation expansion can then obtain the requisite properties from the configurations. The full Hamiltonian divides into a reference plus the perturbation. The generating function may be the whole reference part, but it will be shownthat it can be further truncated to include only the essential near-neighbor forces that determine the structural distributions. The advantage here is in the speed of simulation; it is independent of the complexity of the Hamiltonian or the degree of non-additivity. This method will be illustrated with ionic liquids, but extends to all non-additive molecular simulations of condensed materials.

COMP 39 [749940]:  Calculation of the binding affinities for Stromelysin-1 (MMP-3) inhibitors using a linear scaling semi-empirical quantum chemistry method
Jian Li, Computer-Aided Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development LLC, Welsh and McKean Roads, P.O.Box 776, Spring House, PA 19447,, and Charles H. Reynolds, Computer-Aided Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development L.L.C

Zinc-containing matrix metalloproteinases (MMPs) are important drug targets in many inflammatory, malignant and degenerative diseases. Force field based methods such as the LIE approach and MM/PB/SA have been employed to calculate binding affinities of MMPs inhibitors. In such calculations, a bonded or nonbonded model has been adopted for the zinc ion, and the results are strongly affected by this ad hoc assumption. In addition, the calculations can't take into account the charge transfer and proton transfer in the formation of complexes.We now report a calculation of binding affinities for a series of stromelysin-1 (MMP-3) inhibitors using the linear scaling semi-empirical quantum chemistry method MOZYME. The inhibitors contain different zinc binding groups like carboxylic acid and hydroxamate. In this calculation, the whole protein and protein-ligand complexes were treated by a PM5 Hamitonian and the bonding characteristics of the zinc center and the charge / protonation states are automatically determined by the quantum mechanical wavefunction. Our results demonstrate that a combination of this QM method with the COSMO calculated solvation energy is a promising approach for calculating binding affinities in zinc-containing enzymes.

COMP 40 [764125]:  A new hybrid explicit/implicit solvent method for biomolecular simulations
Michael S. Lee and Mark Olson, Department of Cell Biology and Biochemistry, USAMRIID, 1425 Porter St., Frederick, MD 21702, Fax: 301-619-2348

Implicit solvent models, such as Generalized Born (GB) theory, have become popular alternatives to explicit solvation due to their improved computational efficiencies. However, implicit solvent models may not be sufficiently accurate for certain applications, such as free energy calculations. We present a novel method which combines explicit and implicit solvent models to obtain a balance between accuracy and computational efficiency. This method involves encapsulating a solute with a layer of water molecules and using GB theory to properly account for the reaction field around the irregular boundary of the system. Furthermore, we incorporate a multigrid algorithm to significantly speed up the electrostatic and GB pairwise interactions. Thanks to multigrid enhancements and the reduction of the number of explicit water molecules, our procedure is considerably faster than the conventional particle mesh Ewald method for the systems we have looked at so far. In an initial application, we used our method to assess the accuracy of different types of Poisson implicit solvation models. Specifically, we calculated the electrostatic charging free energies of various fixed conformations of two proteins. In our assessment of Poisson solvation models, we evaluated the relative merits of modifying van der Waals radii, varying the probe radius, and using various dielectric boundary definitions.

COMP 41 [769256]:  ALL-QSAR: A novel automated lazy aearning QSAR Approach and its application to experimental datasets
Shuxing Zhang, Alexander Golbraikh, and Alexander Tropsha, School of Pharmacy, Laboratory of Molecular Modeling, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599,

A novel automated quantitative structure-activity relationship (QSAR) method has been developed based on the local linear regression approach. Activities of test set compounds are predicted as the weighted averaged activity of their nearest neighbors in the training set. The neighbors and their weights are defined by the Gaussian function, and its smoothing parameter is optimized during model building. ALL-QSAR method was applied to three datasets, including 48 dopamine D1-receptor antagonists and 48 anticonvulsants with known IC50 values, and 250 phenolic compounds with known toxicities IGC50. Models with R2=0.8¨C0.9 were built. Y-randomization tests showed no overfitting. These models were significantly better than those built for the same datasets using kNN, SVM, and PLS approaches. ALL-QSAR is a fast and reliable method to develop statistically robust and predictive models. They can be applied to screen chemical databases and virtual libraries to discover novel biologically active compounds.

COMP 42 [772529]:  Automated Bayesian neural network modeling for chemists: Creating local models
Nathan R. McElroy and Pierre Bruneau, Centre de Recherche, AstraZeneca, Parc Industriel Pompelle, BP 1050, Reims, France, Fax: +33 326-616-842,

We present an automated software application that creates Bayesian neural network models as an aid to predict ADME/Tox properties. In-house models exist for several properties using company-wide or global data. In addition to these tools, it is interesting for researchers to make predictive models for data in smaller, more focused (local) datasets using similar modelling methodologies. A user submits a dataset of compounds for modelling and chooses several modelling parameters. Data pre-processing determines the feasibility of modelling the dataset. If data is adequate, then molecular descriptors are calculated and filtered, and data is passed to the modelling routines. Models are created using Flexible Bayesian Modelling (FBM) programs with an automatic relevance determination (ARD) factor. After a stable model is produced, irrelevant descriptors are removed from consideration in the next round of model training, and training continues until stopping criteria are met. The final list of models is searched for the highest quality factor (QF), and the best model is chosen for final training and subsequent validation. Confidence in validation set predictions can be assessed by distance-to-model measurements as well as analysis of the distribution of network errors in the training set.

COMP 43 [773554]:  Discovering cause-and-effect models in small formulation data sets using neurofuzzy logic
Elizabeth A Colbourn1, Stephen J Roskilly1, and Raymond C Rowe2. (1) Intelligensys Ltd, Belasis Business Centre, Belasis Hall Technology Park, Billingham TS23 4EA, United Kingdom, Fax: 011-44-1642-714305,, (2) PROFITS Group, University of Bradford

Formulation datasets typically contain relatively small amounts of data, but nonetheless artificial intelligence methods like neurofuzzy logic can be used to develop useful models that highlight the most important cause-and-effect interactions affecting end-use properties. In this paper we discuss some of the issues regarding model complexity as a function of the amount of data that is available, balancing the risk of overtraining with the desire to extract the maximum amount of information available. In particular, it is crucial that the correct statistical model selection criterion be used. Two examples, of pharmaceutical formulations, are used to illustrate our findings.

COMP 44 [771010]:  FlexX-Docking: Past, present and planned technological advancements
Christian Lemmen, Sally Ann Hindle, Marcus Gastreich, Ingo Dramburg, and Holger Claußen, BioSolveIT GmbH, An der Ziegelei 75, 53757 Sankt Augustin, Germany

FlexX has been among the first commercially available docking programs and established it's position as a leading software for structure-based design. Over the years a multitude of novel technology was added to the base code for incremental growth of a ligand within the active site of the protein. There is the rapid processing of combinatorial libraries, the consideration of water molecules, the ability to simultaneously handle ensembles of active site conformations and the guided search with user-defined pharmacophoric constraints to mention just a few. The latest developments on the technical end of things, besides a substantial speed-up due to code optimization, are the incorporation of smarts-based substructure recognition, facilitating rapid filters, the consideration of multiple protonation states and the exchange of bioisosteric groups. Python has been added as an interface to a generic multi-purpose programming language, allowing now also the FlexX-batch-processing. We will summarize the current status of the FlexX-docking software and the latest developments from currently running projects.

COMP 45 [766170]:  Importance of accurate docking for potency prediction
Colin McMartin, Thistlesoft, 603 Colebrook Road, Colebrook, CT 06021,

Special Equipment Needs: LCD projector for laptop

Potency prediction of docked ligands depends not only on scoring but also on reliable docked geometries. Two different algorithms for thorough docking will be described. The first (MCDOCK) uses mutiple cycles of fast grid-box screened Monte Carlo searching. The search starts broadly and becomes progressively focused. The second method (ZIPDOCK) is near systematic. It uses a conformer compression algorithm to allow millions of docking poses to be screened in less than a minute. Both methods output multiple poses optimized in the binding site (full cartesian). An important feature is that selected parts of the site can move. Multiple docking poses were used to derive a new scoring function (CONTACT). Choice of docking method and number of rotatable bonds are found to have critical effects on the scores. Combining both docking methods significantly improves scores for flexible ligands.

COMP 46 [749648]:  Recent advances in AutoDock: Search, representation and scoring
Garrett M. Morris1, Ruth Huey1, William Lindstrom1, Chenglong Li1, Yong Zhao1, William E. Hart2, Richard Belew3, Michel F. Sanner1, David S. Goodsell1, and Arthur J. Olson1. (1) Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., Mail Drop MB-5, La Jolla, CA 92037-1000, Fax: 858-784-2860,, (2) Computational Sciences, Computer Sciences, and Mathematics Center, Sandia National Laboratories, (3) Cognitive Computer Science Research Group, University of California, San Diego

Docking is often described as consisting of two major components: a scoring function and a search method. Implicit in this is the representation of the molecules being docked, and how new candidate dockings are generated. Recent developments in AutoDock in each of these areas will be presented, including the development of a new empirical free energy scoring function, new search and optimisation methods, and a novel representation of molecular flexibility able to incorporate motion of both domains and side-chains in proteins.

Thanks to on-going advances in computer hardware, AutoDock is able to benefit from a bold, new way to interact with computational chemistry code, by using an extensible, object-oriented interpreter.

Progress in ease-of-use of AutoDock, and applications in protein-protein docking, covalent docking, and in silico high-throughput screening (HTS), will also be presented.

COMP 47 [743490]:  Model systems for docking
Brian Shoichet, Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, CA 94143-2240, Fax: 415-502-1411,

Molecular docking is widely used to screen large compound collections for novel lead molecules that complement a receptor of known structure. Docking energy functions are approximate and many degrees of freedom are under-sampled. To understand where algorithms can be improved, we have turned to model systems where predictions can be tested in detail. We are using both highly simplified, cavity sites in T4 lysozyme, slightly more complicted cavity-like sites that are also open to solvent at one end, and full "drug-like" binding sites, the latter in b-lactamase. Predicted ligands are being tested for binding, geometry, and protein motion using x-ray crystallography. We hope to use this cycle of theory development and testing in a range of simple and more complicated sites to understand some of the weaknesses in our current docking algorithms, and to improve them.

COMP 48 [768465]:  Enhanced ligand docking and scoring with LigandFit
C. M. Venkatachalam, Jeff Jiang, André Krammer, and Marvin Waldman, Accelrys, 9685 Scranton Road, San Diego, CA 92121,

We present recent improvements to the LIGANDFIT program including algorithmic enhancements to improve positional and orientational sampling of the ligand and better selection of poses retained for scoring. Improved sampling is achieved by employing “site partitioning” where the binding site is further partitioned into smaller sites of various sizes and the ligand aligned to various partitioned sites by shape comparison. This procedure has been recently further refined by considering sites obtained by fusing various adjoining sites. In cases where the defined binding site is much larger than the size of the candidate ligand, the site partitioning technique significantly improves the quality of the docking. Results obtained with various Protein-Ligand complexes using this improved sampling will be presented. A technique for retaining poses that improves the overall diversity of the pose list will be discussed. Finally, ongoing work in the area of scoring function development will also be presented.

COMP 49 [761665]:  Ehits: Exhaustive flexible ligand docking with customizable scoring function tailored to protein families
Zsolt Zsoldos, Research and Development, SimBioSys Inc, 135 Queen's Plate Dr, Unit 355, Toronto, ON M9W 6V1, Canada, Fax: 416-741-5083,

Experimental proof is provided that sampling of low energy conformers is insufficient to reproduce protein-ligand binding geometries. eHiTS explores the conformational search space exhaustively, producing accurate docking poses at competitive speed. The customizable scoring function of eHiTS combines novel terms with traditional empirical and statistical approaches. Automatic training tools can adjust the scoring system to any set of experimental data. The program recognizes if the input receptor matches one of the protein families from its knowledge base and uses the appropriate scoring scheme that was trained for that specific family. Validation results of eHiTS are presented on a set of 50 PDB structures representing various DHFR-ligand complexes to demonstrate the ability of the program to accurately reproduce known binding poses. Cross docking results and enrichment results from a diverse library of 5000 ligands will also be presented to evaluate the selectivity of the scoring function. More information:

COMP 50 [748698]:  Bonding ideas out of calculations
Roald Hoffmann, Department of Chemistry and Chemical Biology, Cornell University, Cornell University, Baker Laboratory, Ithaca, NY 14853-1301, Fax: 607-255-5707,

Bonding ideas, good and bad, emerge out of looking at calculations. Some which come from years of following Fritz Schaefer's work, will be described. More generally, we are approaching a time when ideas of bonding may emerge as much from mining theoretical data as experimental findings. With some interesting attendant tactical problems.

COMP 51 [784696]:  MO crossings in cycloaromatization reactions
Igor V. Alabugin, Department of Chemistry and Biochemistry, Florida State University, Dittmer Chemistry Building, Tallahassee, FL 32306-4390, Fax: 850-644-8281,

Cycloaromatization reactions transform closed shell molecules into reactive diradical species – the process which has been used by nature to develop lethal chemical warfare of astounding power. Photochemical triggering of such processes may provide the temporal and spatial control needed to harness the record-breaking DNA-damaging power of these processes in the design of tumor-selective anticancer agents.

In this talk, I will give an example of how fundamental concepts of physical organic chemistry can be combined with computational and experimental studies to provide a better insight into the nature of factors controlling the efficiency of cycloaromatization reactions and lead to the discovery of new reactions with increased DNA-cleaving potential. In particular, I will discuss how the large effects of benzannelation and remote substituents on radical-anionic cyclizations originate from crossing of out-of-plane and in-plane MOs in the vicinity of transition states. This crossing leads to restoration of the aromaticity lost upon one-electron reduction of benzannelated enediynes. The trade-off between reduction potentials and cyclization efficiency as well as the possibilities of switching of enediyne cyclization modes (exo- or C1-C5 vs. endo- or C1-C6)) under kinetic or thermodynamic control conditions will also be outlined.

COMP 52 [772178]:  In pursuit of subchemical accuracy in computational thermochemistry
Wesley D. Allen1, Michael Schuurman1, Steven Wheeler1, Joseph P. Kenny2, and Henry F Schaefer III1. (1) Center for Computational Chemistry, University of Georgia, Athens, GA 30602,, (2) High Performance Computing and Networking Department, Sandia National Laboratories

Several research projects are highlighted involving our continuing pursuit of purely ab initio methods for thermochemical accuracy to the level of 0.1 kcal/mol. Molecular principal and partial wave expansions of problematic systems have been computed for both conventional and R12 correlation methods, with one-particle basis sets extending to k spherical harmonics, thus probing fundamental accuracy limits and demonstrating the superior convergence behavior of explicitly correlated methods. New cusp-satisfying ansätze for pair correlation functions are investigated by means of analytic work on atomic models. The problem of accurately computing connected quadruple excitation effects on bond dissociation energies is elucidated by benchmark full CCSDTQ studies. Improved formulas are derived for computing anharmonic zero-point vibrational energies from quartic force fields, with application to species as large as the amino acid proline. Finally, chemical applications are reported ranging from soot formation intermediates to proton affinity scales for biomolecules.

COMP 53 [772614]:  Two-component approach to molecular parity violation
Robert Berger and Christoph van Wüllen, Chemistry Department, Technical University of Berlin, Str. d. 17. Juni 135, Berlin 10623, Germany, Fax: 0049-30-314-21102,

One of the most intriguing effects the fundamental weak interaction may have in chemistry is the parity violating energy difference (ΔEpv) between two mirror-image molecules. While a successful measurement of ΔEpv is still lacking, considerable progress has been made in the past few years in the theoretical prediction of molecular parity violating effects. The methods developed for this purpose include correlated one-component linear response approaches (MCLR) and four-component Dirac-Hartree-Fock (DHF) schemes.

Here we present a two-component approach to molecular parity violation which employs the zeroth order regular approximation (ZORA) and allows to combine the strengths of previous one-component and four-component schemes since spin-orbit coupling is treated self-consistently. For benchmark systems of the type H2X2 (X=chalcogen) we compare results obtained with the ZORA approach with those of former MCLR and DHF treatments and we present studies on systems of significance for a spectroscopic proof of molecular parity violation.

COMP 54 [772585]:  Investigations of the properties of functionalized single-walled carbon nanotubes
Holger F Bettinger, Lehrstuhl fuer Organische Chemie 2, Ruhr-University Bochum, Universitaetsstr. 150, Bochum 44780, Germany, Fax: +49 234 321 4353,

We report computational and experimental investigations aimed at gaining an understanding of the energetic and structural properties of chemically functionalized single-walled carbon nanotubes. The main focus is on fluorinated single-walled carbon nanotubes, for which we report a detailed investigation of the fluorine loss and an assessment of their propensity to form CF-HO hydrogen bonds. More generally, detailed density functional computations on finite carbon nanotube clusters of increasing size and periodic systems with increasingly larger unit cells enable an evaluation of finite lengths effects and ultimately the determination of the binding energies of addends (fluorine and carbenes) to the nanotube sidewalls depending on chirality and diameter. This approach also allows comparing the reactivity to sidewalls with defects.

COMP 55 [767110]:  Interallylic bonding in the transition structures for degenerate Cope rearrangements: Modification by substituents and by strain, and the effects of changes in interallylic bonding on the calculated barrier heights
Weston T. Borden, Department of Chemistry, University of Washington, Box 351700, Seattle, WA 98195-1700,

Substituent and strain effects that weaken interallylic bonding are predicted to be capable of transforming the boat transition structure for the Cope rearrangement of semibullvalene into the global energy minimum. B3LYP and ab initio calculations have been used to compute the strengths of the interallylic bonds in semibullvalenes that are predicted to have delocalized equilibrium geometries. The insights that these calculations provide into the question of whether such semibullvalenes are "bishomoaromatic" will be discussed.

COMP 56 [770377]:  Limitations of interactive drug design: Can de novo programs fill the gap?
Regine S. Bohacek, Boston De Novo Design, 50 Commonwealth Ave. #702, Boston, MA 02116,

When designing new molecules to fit a target binding site, it is easy to see where hydrophobic or hydrogen bonding ligand atoms should lie. However, it is often very difficult to find a chemical fragment that will place all these atoms into optimal positions. To be successful, a de novo program should have a rich repertoire of diverse motifs generated rapidly and with accurate geometry. The de novo program, AlleGrow (1), has achieved these goals and has been shown to generate ligands with geometries similar to those found in x-ray structures. Because AlleGrow lacked the ability to create the large number of polycyclic structures found in many drugs, a library of ~5000 heterocycles has been added. AlleGrow explorations of the binding sites of thermolysin, Src SH2 and CDK2 will be reported.

(1) AlleGrow is a second generation program based on GrowMol (R.S. Bohacek, C. McMartin, JACS (1994) 116, 556—5571).

COMP 57 [766030]:  Interactive rapid ligand prototyping: The MindRocket
Chris M.W. Ho,, Drug Design Methodologies, LLC, 4355 Maryland #105, St. Louis, MO 63108

Numerous products are available to discover viable drug leads through virtual screening. However, drug refinement entails a collaborative effort between computational and synthetic chemists. Ideal design tools should empower chemists to utilize their knowledge of the active site and exploit their synthetic intuition. The MindRocket is a ligand development system that allows chemists to rapidly generate, dock, visualize, and iteratively amend novel chemical structures on the fly. Optimal poses are quickly determined with full ligand-receptor flexibility using scoring functions derived from user structure activity data. Immediate feedback is provided for refinement. Series of structures can be enumerated using scaffolds via Markush-like descriptors. A key aspect of this software is novel technology incorporating user constraints and ADMET properties to govern synthetic feasibility and rapidly eliminate undesired chemical constructs. This presentation will discuss the MindRocket’s unique capabilities along with specific applications that demonstrate its value in ligand optimization.

COMP 58 [771123]:  Improved methods for the de novo design of synthetically accessible ligands
A. Peter Johnson, Krisztina Boda, Tamas Lengyel, and Shane Weaver, Department of Chemistry, University of Leeds, Leeds LS2 9JT, United Kingdom,

De novo ligand design systems have undergone substantial development over the past decade, to the extent that several of the currently available systems are capable of suggesting large numbers of ligands with high estimated affinity for the target protein. This has led to increased emphasis on the development of methods for the automated selection of specific ligands for synthesis. Clearly estimation of synthetic accessibility must be a key component of any ligand scoring system. In the SPROUT system, this problem has been addressed in three ways: a) the stand alone CAESA program for estimation of synthetic accessibility; b) the SynSPROUT program in which the ligand construction process mimics reactions taken from a knowledge base; c) a new feature in SPROUT which assesses synthetic complexity by a multilevel comparison of generated structures with structures from databases of previously synthesised potential drugs and also from supplier catalogs.

COMP 59 [769083]:  Automated de novo design with LUDI, minimizer, QSAR, and scoring functions: Development and validation of AutoLudi
Marguerita Lim-Wilby1, Jayashree Srinivasan2, Jurgen Koska1, André Krammer1, C. M. Venkatachalam1, and Marvin Waldman1. (1) Accelrys Inc, 9685 Scranton Rd, San Diego, CA 92121, Fax: (928) 752-8479,, (2) Consultant

Fundamental issues with de novo modifications of lead compounds include the presentation of results to chemists, incorporation of chemical sensibility, ADME-like properties, and other preferred properties, as well as the all-important prediction of affinity. We have integrated the de novo design engine, LUDI (Böhm, JCAMD 6:61 1992; Böhm, JCAMD 6:593 1992), with C2.Minimizer, C2.QSAR+, and C2.Descriptor+ to produce, in an automated fashion, either (1) novel inhibitors that are selected as survivors from improving generations of inhibitors, or (2) combinatorial enumeration of all derivatives of a given scaffold that satisfy user-selected rules. Both modes will be presented with validations and correlations to published experimental data.

COMP 60 [765720]:  Combinatorial computational ligand optimization
Bruce Tidor, Biological Engineering Division & Department of Electrical Engineering and Computer Science, MIT, 77 Massachusetts Avenue, Room 32-212, Cambridge, MA 02139

Recent progress will be presented in the use of optimization approaches to study and design binding partners for proteins. The focus will be on methods for simultaneously satisfying packing and electrostatic constraints in a computationally efficient manner. Illustrative examples involving lead optimization as well as lead discovery will be presented, as well as cases of improving affinity and strategies for altering specificity of binding interactions.

COMP 61 [745225]:  Insights from momentum space
E. R. Davidson, Department of Chemistry, University of Washington, Seattle, WA 98195-1700,

Compton scattering, (e,2e) spectra, and PES all give some information about the momentum dependence of orbitals. In this lecture we will compare some results using large CI wave functions and DFT. Even though DFT does not give a momentum density, use of Kohn-Sham orbitals as though they formed a wave function does yield reasonable results in momentum space. The average kinetic energy, however, is the Kohn-Sham kinetic energy so clearly this momentum distribution is not exact.

COMP 62 [770766]:  Aromaticity beyond the organic chemistry domain
Zhongfang Chen, Department of Chemistry and Center for Computational Quantum Chemistry, University of Georgia, Athens, GA 30602,

"Aromaticity" also is applicable to inorganic compounds and clusters, although its detailed understanding is even more complicated. Thus, both the degree of bond length equalization and simple electron-counting rules often fail to characterize aromaticity satisfactorily. (1) The recently claimed 4p antiaromatic Al4Li3- cluster with alternating bond lengths is actually aromatic since the s-aromaticity dominates its p-antiaromaticity. (2) Isoelectronic molecules may behave quite differently; highly symmetrical (Td, Oh, Ih etc.) clusters with equal bond lengths may either be aromatic or antiaromatic, depending on the elements and the substituents involved. Aromatic stabilization energies strongly depend on the reference molecules, and are difficult to evaluate. In contrast, NICS (Nucleus-Independent Chemical Shift), a magnetic measure of aromaticity, not only is simple and effective, but also provides useful prediction of stable species, and deep insights into the seemingly erratic behavior of inorganic compounds and clusters.

COMP 63 [764322]:  Diverting diradicals: From methylene to metal-dioxygen complexes
Christopher J Cramer, Department of Chemistry and Supercomputing Institute, University of Minnesota, 207 Pleasant St. SE, Minneapolis, MN 55455-0431, Fax: 612-626-2006,

The diversity of structure and reactivity associated with carbenes, nitrenes, arynes, nitrenium ions, and related reactive intermediates has long been a source of fascination for organic chemists, and of consternation for computational chemists. Accurate predictions of both singlet- and triplet-state electronic structures can be particularly challenging owing to the typically multiconfigurational nature of at least one of the relevant wave functions. The quantitative and qualitative lessons learned from organic systems may be applied to inorganic systems with similar frontier orbital characteristics. This can become an issue when single-determinantal density functional theory, usually well suited to the description of many properties of 1:1 metal:dioxygen complexes, fails to accurately compute state-energy splittings because of limitations associated with diradical character. A key example of this latter situation will be discussed within the context of the copper-dioxygen species of Tolman and co-workers; general historical and algorithmic discussion will sample from the organic diradicals too.

COMP 64 [755162]:  Coupled cluster calculations of optical rotation
T. Daniel Crawford, Department of Chemistry, Virginia Tech, 107 Davidson Hall, Blacksburg, VA 24061, Fax: 540-231-3255,

The reliable prediction of specific rotation in chiral molecules is a long-standing goal of chemistry. Although empirical models such as the quadrant and octant rules have been used for decades, they provide only qualitative results, at best. We have recently developed a new series of programs for the computation of frequency-dependent optical rotation using coupled cluster linear-response theory. In this work, we consider the importance of basis set size and character as well as high-level electron correlation effects on coupled cluster optical rotation angles for rigid species such as S-methyloxirane. We find that although both basis-set and electron-correlation contributions are significant, the former are paramount: qualitatively incorrect results can be obtained even for relatively large basis sets. Furthermore, we find an unexpected frequency dependence: errors relative to experiment are sometimes larger for shorter wavelengths than for the sodium D-line.

COMP 65 [769844]:  Modeling mechanisms of hydron transfer in the condensed phase
Neil A. Burton, Raman Sharma, Sara Nunez, Gary Tresadern, and Ian H. Hillier, Department of Chemistry, Manchester University, Oxford Road, Manchester, United Kingdom,

Hydron transfers, particularly of protons, are perhaps the most common reactions in nature and their mechanisms are of fundamental importance in chemistry. This paper will discuss recent hybrid and quantum mechanical computational studies which have been employed to understand the novel catalytic tunnelling mechanisms now evident in enzymes and to model experimental intramolecular mimics in the aqueous phase.

COMP 66 [767495]:  Insights into mesoscale and electronic events during keV particle bombardment of solids
Barbara J. Garrison, Department of Chemistry, Penn State University, 152 Davey Laboratory, University Park, PA 16802, Fax: 814-863-5319

KeV particle bombardment of solids induces a cascade of events that ultimately leads to the emission of neutral and ionic particles.  Recently experimental interest has focused on using C60 ion beams that appear to allow for molecular depth profiling of materials such as biological cells.  The molecular dynamics (MD) simulations of the process clearly delineate that the underlying physics giving rise to the ejection of material is mesoscopic in nature as shown in the figure and the simulations explain the possibilities for depth profiling.  Concomitant studies are underway to examine the emission of ionic species from water ice in order to make a complete description of the ejection events.

COMP 67 [769761]:  High-accuracy first-principles rovibrational spectroscopy
Attila G. Császár, Department of Theoretical Chemistry, Eötvös University, Pázmány sétány 1/A, H-1117 Budapest, Hungary, Fax: 36-1-2090602,

Electronic structure calculations have become capable of predicting a large number of rovibrational band origins and other spectroscopic properties to within a wavenumber or better. Such state-of-the-art ab initio electronic structure computations, resulting in a highly accurate potential energy (PES) and dipole moment (DMS) surface for the prototypical triatomic molecule H2O, are reviewed highlighting the hierarchy of the physical effects to be considered. The use of high-order force fields for the representation of the PES is also discussed. Different variational strategies for solving the nuclear motion problem are discussed next. Emphasis is put either on the simplicity of the approach, provided by the discrete variable representation (DVR) of the Hamiltonian, or on the utility of the solution strategy in handling singularities in the Hamiltonian. Generalization of the DVR approach and its accuracy is addressed. Representative numerical results are presented for triatomic systems.

COMP 69 [774410]:  Linking chemical and biological data using ChemCart and SRS Gateway for Oracle
Manish Sud1, Andrea Schafferhans2, Darryl León1, and Yvonne Shimshock3. (1) LION bioscience Inc, 6125 Nancy Ridge Drive, Suite 118, San Diego, CA 92121, Fax: 858-450-5083,, (2) LION bioscience AG, (3) DeltaSoft Inc

Over the last few years, the amount of chemical and biological data generated during the drug discovery process has continued to grow rapidly. This data is quite heterogeneous and resides in a variety of formats - from local flat files to relational databases. Consequently, for bench scientists, it is often difficult - or even impossible - to search and retrieve relevant chemical and biological data for compounds and protein targets of interest. This poster presents a unique solution to this dilemma. DeltaSoft’s ChemCart and LION’s SRS Gateway for Oracle products have been integrated to provide scientists with an easy-to-use, customizable tool to search and retrieve structures, primary/secondary screening results, images, gene, protein, clinical, and expression data. Using the NCI gene expression data set, we provide an example of retrieving relevant chemical and biological information into to a single cohesive view.

COMP 70 [763078]:  Mechanistic insight from computer models of tyrosine kinase mutations that cause ligand-independent activation of the receptor
Maricel Torrent1, Keith Rickert2, Bo Sheng-Pan2, and Laura Sepp-Lorenzino2. (1) Molecular Systems, Merck & Co, WP53F-301, Sumneytown Pike, West Point, PA 19486, Fax: 215-652-4625,, (2) Department of Cancer Research, Merck & Co., Inc

Molecular modeling provides a mechanistic hypothesis at the molecular level for the constitutive activation recently observed and reported for tyrosine protein kinases Flt-3 and c-Kit. Three-dimensional homology models for the active and inactive forms of these two kinases were made. Comparison of these models at the molecular level reveals that mutations of specific residues located in the activation loop (D835X and 836-deletion in Flt-3; D816V in c-Kit) as well as a 6-base pair insertion at residue 840 in Flt-3 operate in a similar way. Each mutation tends to weaken the forces that maintain the activation-loop folded inwards. None of the mutations are found to particularly stabilize the active state directly. The reason why the equilibrium is shifted towards the gate-open conformation of the protein is because the mutations, at least in these models, are found to critically destabilize the inactive conformational state of the kinase.

COMP 71 [774507]:  Computational identification of proteins for selectivity assays
Sukjoon Yoon, Informatics and modeling group, Arqule, Inc, 19 Presidential way, Woburn, MA 01801,, Andrew Smellie, ArQule Inc, David S. Hartsough, Informatics and Modeling, ArQule, Inc, and Anton Filikov, Informatics and Modeling, ArQule Inc

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 72 [774642]:  Physical basis for conformational energies in substituted ethanes
Ronald F. See, Department of Chemistry, Indiana University of Pennsylvania, Weyandt Hall, Indiana, PA 15705,

The preference for the staggered conformation in alkanes is well known, but the physical basis for this preference remains surprisingly controversial. It had long been thought that the preference for the staggered conformation was largely due to “steric” effects, but a recent publication asserted that an effect termed “hyperconjugation” is actually the key component in the observed conformational geometry. Unfortunately, neither steric effects nor hyperconjugation is rigorously defined, so assessing their relative contributions is problematic. The work to be presented averts these semantic problems by analyzing the conformational energies (LMP2/6-31G*) of XCH2-CH2X (where X includes H, F, Cl, CH3, CF3 and t-butyl) molecules in terms of attractive and repulsive forces. The results indicate that the repulsive interactions are very significant, and that the magnitude of the energetic difference between staggered and eclipsed conformations can be approximated by a simple distance-interaction function.

COMP 73 [771272]:  De novo computational method to increase ligand-receptor binding selectivity
Deliang L. Chen, Medicinal Chemistry, Virginia Commonwealth University, Box 980540, Richmond, VA 23298-0540, Fax: 804-827-3664,, and Glen E. Kellogg, Department of Medicinal Chemistry, Virginia Commonwealth University

A program designed to increase ligand-receptor binding selectivity is described. The goal is to modify the structure of a ligand that can bind two proteins with similar binding affinity such that its binding affinity to one protein is increased, while the binding affinity to the other protein is decreased. Two methods are used to modify the ligand structure to increase its selectivity: 1) Steric Complementarity; the ligand is modified to tightly match the steric requirements of one of the proteins, thus increasing its selectivity for that protein. 2) Functional Group Complementarity; acidic, basic or hydrophobic functional groups are added to the ligand to form specific favorable interactions with residues of one protein (DHINT score >0) and to form unfavorable interactions with the residues of the other protein (DHINT score <0). This program has been used to modify the structure of CB3717 to computationally build models selective with respect to two very similar proteins: L. casei thymidylate synthase and E60Q L. casei thymidylate synthase.

COMP 74 [765599]:  Analysis of changes of protein fluctuation upon ligand binding and incorporation of protein fluctuation into scoring function development for structural-based drug design
Chao Yie Yang, Department of Internal Medicine, Hematology and Oncology Division, University of Michigan, 2423 Med. Sci. I, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, Fax: 734-764-2532,, Renxiao Wang, Department of Internal Medicine, University of Michigan Medical School, and Shaomeng Wang, Departments of Internal Medicine and Medicinal Chemistry, University of Michigan

We have studied the effects of ligand binding on protein fluctuation by analyzing the changes of B-factors in proteins using 64 protein-ligand complex structures solved by X-ray crystallography. The structures chosen were based on the following criteria. (1). both unbound and ligand-bound complex structures were determined by the same research group for consistency. (2). At least one of the two structures (free and bound) has a resolution better than 2 Å. For most of protein-ligand structures we have analyzed, the B-factors for binding-site residues (i.e. within 8 Å from the ligand) have decreased upon ligand binding. Interestingly, for several protein-ligand complexes, the B-factors for binding-site residues increase upon ligand binding. Classification of the ligands based on their physical properties and the atom depth descriptor of the residues in proteins were used to gain more insights. The protein fluctuation information as determined by the B-factors from crystal structures is being incorporated into the development of new scoring functions and the results will also be presented.

COMP 75 [775048]:  Calculations of hydration force
Lifeng Tian, Department of Chemistry & Biochemistry, University of the Sciences in Philadelphia, 600 S 43rd street, Philadelphia, PA 19018, Fax: 215 5967539,, and Randy Zauhar, Department of Chemistry and Biochemistry, University of the Sciences in Philadelphia

The functions of most proteins require recognition and binding of other molecules. Further understanding of the affinity and specificity of the binding requires a detailed knowledge of the relative magnitudes of the individual atomic forces. The dielectric continuum model has been widely used to approximate the electrostatic interaction. We have been working on an improved Poisson equation solver by boundary element method (BEM), incorporating better surface triangulation and polarization charge gradient based surface subdivision. Also, a hydration force model may be parameterized based on the BEM calculation. Such a model can be parameterized by geometry parameters such as distance to surface, distance to other charges and the surrounding atoms types. Initial results of the work on the hydration force model will be reported.

COMP 76 [766732]:  Can a QSAR model reliably predict a query compound’s activity?
Linnan He, Department of Chemistry, The Pennsylvania State University, 152 Davey Laboratory, University Park, PA 16802,, and Peter C. Jurs, Department of Chemistry, Pennsylvania State University

With a given QSAR model and a query compound for prediction, can the model be reliably used for the desired prediction? To answer this question, an approach employing hierarchical clustering was developed and tested on a dataset containing 322 organic compounds with fathead minnow acute aquatic toxicity as the activity of interest. The core of the approach is to determine the relationship between the similarity of query compounds to the training set compounds of the QSAR model and the prediction accuracy given by that model. This relationship determination was achieved by comparing the results given by the two major components of the approach: objects clustering and activity prediction. A positive relationship was shown. Therefore, we concluded that a query compound could be predicted reliably if it is sufficiently similar to the compounds used to generate the QSAR model.

COMP 77 [771678]:  Characterization of the ice/water interface with TIP4P-Ew water
Thomas J. Dick, Department of Chemistry and Biochemistry, Duquesne University, 308 Mellon Hall, 600 Forbes Ave., Pittsburgh, PA 15282, Fax: 412-396-5683,, Jeffry D. Madura, Department of Chemistry & Biochemistry, Center for Computational Sciences and Duquesne University, and Pranav Dalal, Department of Chemistry and Biochemistry, Center for Computational Sciences, Duquesne University

Water exhibits unique kinetic, thermodynamic, and structural properties unlike any other solvent, which are essential in sustaining biological and geological cycles. Various models have been proposed for use in molecular simulations, but no ″perfect″ model currently exists. Typically, accurate models come at a penalty of higher computational cost; a compromise will exist between cost and reliability for a water model in molecular simulations. We have investigated the solid/ liquid interfacial region using the newly developed rigid TIP4P-Ew water model. The TIP4P-Ew model is reasonably cost effective and is parameterized to be used with Ewald summation techniques. Diffusion profiles and other order parameters are used to determine properties of the TIP4P-Ew ice/water system. Analysis of the TIP4P-Ew simulations will reveal the melting temperature as well as kinetic and thermodynamic criteria for defining the phase transitions.

COMP 78 [773921]:  Redesigning interaction specificity of short peptide oligomerization domains
Christina M. Taylor, Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 68-604D, Cambridge, MA 02142,, Mayssam H. Ali, Department of Chemistry, Massachusetts Institute of Technology, Barbara Imperiali, Department of Chemistry and Department of Biology, Massachusetts Institute of Technology, and Amy E. Keating, Department of Biology, MIT

Comments to Organizer: This poster may be more appropriate in the biological chemistry division. Please submit to whichever division has the most computational protein design posters.

Oligomerization is one of the principle methods by which nature creates greater functionality in protein. Specifically binding one protein, while not binding others, can regulate various biochemical pathways and transcription factors in cells. Designing proteins to bind specifically to a target protein is of interest to chemists in areas ranging from manipulation of biochemical pathways to design of therapeutics. To study specificity, we used a well-folded heterooligomeric mini-protein, containing a monomeric ââá motif. Using the x-ray crystal structure of the homotetrameric mini-protein as a scaffold, we used computational techniques to design a heterotetrameric miniprotein. Biophysical experiments support the model predicted from computational design. Due to its small size, the designed heterotetrameric mini-protein could be used as a novel reagent for many biochemical applications.

COMP 79 [770618]:  Trajectory and energy perturbed multiple microcanonical ensemble simulations for mapping potential energy landscapes and conformations of polypeptides
Zunnan Huang 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 multiple microcanonical ensemble simulations for finding global or local energy minima to determine the structures of polypeptides in solvent. We present tests of this new simulation method for mapping potential energy landscapes and conformations of two polypeptides: Ala13 and Trp-cage. With this method, we find that even though the energy gap between potential energy minima near 0K with large conformational differences can be very small (in a few Kcal/mol), the energy range of conformations within the same secondary structure type may be very large (up to 100 Kcal/mol). This observation may explain why proteins become trapped easily in local minima during conventional MD or MC simulations of protein folding. The simulation results are also independent of the initial coordinates indicating that the natural structures of polypeptides can be effectively predicted from the fully extended structure by this new method.

COMP 80 [758773]:  Improved workflow and results in the NMR lab: Integrated processing, prediction, searching, and data management
Victoria Rafalovsky, Bio-Rad Laboratories, Informatics Division, Sadtler Software & Databases, 3316 Spring Garden Street, Philadelphia, PA 19104,, Marie Scandone, Informatics Division, Bio-Rad Laboratories, Inc, and Deborah Kernan, Informatics Division, Bio-Rad Laboratories

Having the ability to store, organize, search and retrieve spectral and chemical information can be an important component of a company's long term plan to manage and maintain its internal knowledge base. It is often the case that a single sample or compound will be examined by a number of techniques to provide enough analytical information to characterize it properly. Because of the variety of spectral techniques and the variety of spectrometers within a given technique, managing NMR and other data is a challenge for any laboratory.

This poster will examine a number of steps that should be undertaken when developing a resource of informatics tools. This poster also introduces a system that combines tools within a fully integrated environment to include tools for processing, prediction, database building, management, search, analysis, and reporting for HNMR, CNMR, and XNMR.

COMP 81 [764490]:  Modeling outer-sphere disorder in the symmetry breaking of PPV
Limin Angela Liu and David Yaron, Department of Chemistry, Carnegie Mellon University, 4400 Fifth Ave., Pittsburgh, PA 15213

Abstract text not available.

COMP 82 [774817]:  Structure and stability of lower fullerenes C38-C50 and nitrogen-substituted heterofullerenes
Guangyu Sun, Laboratory of Medicinal Chemistry, CCR, NCI-Frederick, NIH, 376 Boyles St., Frederick, MD 21702


The recent mass spectrometry study by dos Santos and co-workers on carbon-nitride material produced by arc discharge from graphite electrodes in N2 and He suggested the existence of small heterofullerenes that are N-substituted Cn (40£n£50). We present a systematic survey using quantum mechanical calculations for the isomers of fullerenes C38, C40, C42, C44, C46, C48, C50 and an N-substituted C50 to meet the challenge raised by the mass spectrometry study. We use the B3LYP hybrid functional in the density functional theory formalism and the medium basis set 6-31G* to optimize the structures for all the fullerene isomers consisting of pentagons and hexagons. The ground-state structures of fullerenes C38-C50 are predicted based on total electronic energy and energy gap between HOMO and LUMO. Important molecular properties of the stable isomers of each fullerene, including the NMR chemical shifts, are presented. The aromaticity of the stable isomers is discussed in the context of the nucleus-independent chemical shifts (NICS) at the cage center.

COMP 83 [764631]:  BOMB for growing and scoring protein-ligand complexes
William L. Jorgensen and Julian Tirado-Rives, Department of Chemistry, Yale University, New Haven, CT 06520-8107, Fax: 203-432-6299,

BOMB, Biochemical and Organic Model Builder, is used to rapidly construct and evaluate biomolecule-ligand complexes. Ligands are grown starting from a core that is positioned in the binding site. An extensive conformational search is performed for the ligand and each conformer is optimally positioned in the binding site. The structure optimization is performed with the OPLS-AA force field, and then scoring functions are used to predict binding affinities or activities by consideration of, for example, protein-ligand Coulomb and van der Waals interactions, hydrogen-bonding, and solvation. High speed follows from the use of internal coordinates for the search and optimizations. The ligands have all principal torsion angles variable, while the host can either be rigid or have side chains with flexible dihedral angles. The BOMB libraries contain more than 100 cores and 500 substituents, which are common drug fragments; the resulting virtual library covers ca. 10 trillion molecules. QikProp is fully integrated with BOMB to filter designed molecules to be druglike. Results of validation studies and applications to multiple protein targets will be presented.

COMP 84 [743719]:  CAPRI: Assessing protein docking algorithms in the blind structure prediction of protein-protein complexes
Joel Janin, Laboratoire d'Enzymologie et Biochimie Structurales, UPR9063, CNRS, 91198-Gif-sur-Yvette, France, Fax: 33.1.69823129,

CAPRI (Critical Assessment of PRedicted Interactions) is a CASP-like experiment to assess protein-protein docking procedures. Predictors are given atomic coordinates for two proteins. They perform a blind prediction of the complex and submit models to the Web site run by K. Henrick at the EBI (Hinxton, UK). These models are then assessed by comparison with unpublished X-ray structures of the protein-protein complexes, kindly provided by their authors to the CAPRI Management Group on a confidential basis. In four rounds of CAPRI prediction involving 13 target complexes, some 25 predictor groups have submitted a total of 1629 models. The evaluation procedure was carried out by S.J. Wodak & R. Mendez (Free University of Brussels, Belgium. Models were judged of high quality if they had over 50% of the native contacts and an interface RMSD < 1 Å; good if >30% native contacts, RMSD < 2 Å; acceptable if >10% native contacts, RMSD < 4 Å. Of the nine targets of Rounds 1 to 3, five had at least one good model in the submissions, whereas three targets were not predicted at all. Overall, the CAPRI experiment reveals a growing interest in predicting protein-protein interaction. Genuine progress was evident over three years of the experiment. The results of CAPRI point out the need for faster algorithms, better scoring functions and more effective methods to handle conformational flexibility. Incorporating information from biochemical experiments and sequence analysis is another key element of success. CAPRI is a powerful drive for computational biologists who develop docking algorithms. Its continuation entirely depends on the willingness of structural biologists to provide experimental information. The CAPRI Management Group expresses thanks to those who already did, and calls upon all to support the experiment by contributing targets. Reference: Proteins Vol. 52 pp. 1-122, Special Issue July 1, 2003

COMP 85 [772887]:  Interdependence of docking performance and scoring accuracy in virtual screening
Maria Kontoyianni, Plymouth Meeting, PA 19462,, Laura McClellan, Pennsylvania State University, and Glenn Sokol, Drexel University

In an effort to uncouple scoring from docking, we first investigated the best known docking programs in their ability to provide solutions similar to the crystallographic modes, by evaluating all of the resultant poses. We then explored whether scoring algorithms can distinguish between accurate and inaccurate poses, provided the accurate poses are available, thus assessing how the docking procedure affects the performance of a virtual screening approach. To evaluate docking, we carried out an extensive computational study in which five docking programs (FlexX, DOCK, GOLD, LigandFit, Glide) were investigated against fourteen protein families (69 targets). Our results indicate that certain algorithms perform consistently better than others, while the active site polarity can be predictive of which program might perform the best. To investigate scoring, we used four docking engines and applied ten scoring functions to the top-ranked docking solutions of seeded databases against six target proteins. The scores of the experimental poses were placed within the total set to assess whether the scoring function required an accurate pose to provide the appropriate rank for the seeded compounds. The LigandFit/Ligscore1 docking/scoring combination provides the most consistent enrichment for all targets studied. We also show that better poses for the docked complexes lead to better scoring function performance, and thus a higher ranking of the active compounds. This means that the enrichment factors would be higher if the experimental poses were available.

COMP 86 [765371]:  Virtual ligand screening by combined use of two grid-based docking methods, FLOG and ICM
Vladimir N. Maiorov, Molecular Systems, Merck Research Laboratories, Merck & Co., Inc, 126 E. Lincoln Ave., Rahway, NJ 07065, Fax: 732-593-4224,, and Robert P. Sheridan, Molecular Systems, Merck Research Laboratories

Flexible docking is a routine part of a modern structure-based lead discovery process. There are a variety of docking methods available to a modeler in a typical industrial environment to screen large corporate databases. How should these tools be optimally used to improve the selection of candidate molecules from the viewpoint of screening speed, software cost, and quality of the results? Many commercial docking programs are available, but the cost of the multiple licenses to do docking calculations simultaneously on multiple CPUs (software cost factor) and relatively long time required to get qualitative results (speed factor) do not allow one to use them for “virtual screening”. A combination of two grid-based docking methods, ‘fast-and-approximate’ in-house FLOG and ‘slow-and-accurate’ commercial ICM is presented as an example of the solution. Several hundreds of compounds ranked best by FLOG from a whole database are further carefully docked and re-ranked by ICM calculations. Validation tests with PDB protein structures and MDDR compounds are given.

COMP 87 [768311]:  Critical assessment of docking programs and scoring functions
Gregory L. Warren1, Webb Andrews III2, Anna Maria Capelli2, Brian P. Clarke2, Judith M. LaLonde2, Millard H. Lambert2, Mika Lindvall2, Neysa Nevins2, Catherine E. Peishoff1, Simon F. Semus2, Stefan Senger2, Giovanna Tedesco2, Ian D Wall2, James M. Woolven2, and Martha S. Head1. (1) Computational, Analytical and Structural Sciences, GlaxoSmithKline Pharmaceuticals, Research and Development Division, P.O. Box 5089, UP1110, Collegeville, PA 19426-0898,, (2) Computational, Analytical and Structural Sciences, GlaxoSmithKline

With the recent dramatic increase in available structural data has come a need to evaluate the current state of the art for docking and scoring algorithms. In an effort to understand the strengths and weaknesses of such algorithms, we have undertaken an evaluation of the performance of 10 docking programs and 37 scoring functions against 8 proteins from 7 evolutionarily diverse targets for three tasks: accuracy of binding mode prediction, data enrichment during virtual screening, and the ability to rank order by affinity for lead optimization. While performance for any particular docking program varied across the targets evaluated, docking programs and scoring functions are able to reproduce crystallographically observed binding modes and identify active compounds from a pool of decoy compounds. However, current docking programs and scoring functions are unable to rank order compounds by affinity.

COMP 88 [758085]:  Improving the enrichment of high-throughput docking results using machine learning
Anthony E. Klon, Meir Glick, and John W. Davies, Lead Discovery Center, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02142,

High-throughput docking (HTD) is a commonly utilized technique in the drug discovery process. However, the ability to accurately rank compounds using a scoring function remains problematic. Here we show that by employing a simple machine learning method (naïve Bayes), it is possible to significantly improve the ranking of compounds and thereby the accuracy of HTD. Three protein targets were reviewed using three software packages; Dock, FlexX and Glide. For each target, known active compounds and the Available Chemical Database (ACD) were evaluated. In cases where HTD alone was able to produce enrichment of known actives, the application naïve Bayes was able to significantly improve upon the enrichment. The application of the naïve Bayes classifier to enrich HTD results can be carried out without any a priori knowledge of the active compounds. The methodology results in superior enrichment of known actives compared to the use of HTD and consensus scoring alone.

COMP 89 [753263]:  Computational main group thermochemistry
David A Dixon, Department of Chemistry, University of Alabama, Box 870336, Shelby Hall, Tuscaloosa, AL 35487-0336, Fax: 205-348-9104,, Wibe A. deJong, W. R. Wiley Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, and Kirk A. Peterson, Department of Chemistry, Washington State University

With the advent of new basis sets coupled with effective core potentials for main group elements and access to high performance, massively parallel computers, it is now possible to calculate reliably the heats of formation of many compounds containing heavier main group elements if one performs the calculations at the CCSD(T) level and includes core-valence and relativistic effects as well as zero point energy corrections. We will discuss the heats of formation of xenon fluorides, interhalogen compounds, the rare gas affinities of the methyl cation and the development of a fluoride affinity scale for the prediction of Lewis acidities.

COMP 90 [771775]:  Remarkable structures and interaction potentials of clusters of molecular hydrogen and acetylenes
Clifford E. Dykstra, Department of Chemistry, Indiana University-Purdue University Indianapolis, 402 N. Blackford Street, Indianapolis, IN 46202, Fax: 317-274-4701,

Ab initio and model calculations have been carried out to explore structural and energetic features of pure clusters of molecular hydrogen, pure clusters of acetylene, mixed clusters of hydrogen and acetylene, and certain clusters with extended acetylenes. All the interacting molecules are nonpolar species that exhibit an important role for local quadrupole-quadrupole interactions. Certain surprising structures are found, and there are unusual potential surface features, particularly very sizable regions of flatness. Because of these features, part of the characterization of the clusters includes analysis of zero-point vibrational effects, which has been done via quantum Monte Carlo calculations using the model potentials developed in this investigation.

COMP 91 [751659]:  Adventures in the land of triple bonds: The bonding situation in heavy-atom homologues of acetylene
Gernot Frenking, Fachbereich Chemie, Philipps University Marburg, Hans-Meerwein-Strasse, D-35039 Marburg, Germany,

It is well known from the work of Schaefer and coworkers that the equilibrium structures of the heavy-atom homologues of acetylene with the formula E2H2 where E = Si - Pb are very different from the linear triply bonded form HEEH. In my lecture I will discuss the bonding situation in the E2H2 isomers. I will also present recent results about the bonding situation in Robinson's gallium compound RGaGaR2-.

COMP 92 [781266]:  Theoretical prediction of spectra
Michael Frisch, Gaussian, Inc, 140 Washington Ave., North Haven, CT 06473, Fax: 203-239-0846

Recent developments in the prediction of vibrational, electronic, and magnetic spectra in both gas phase and solution will be presented. The accuracy of various models will be assessed, with an emphasis on recent density functionals which include the kinetic energy density and the Laplacian of the electron density.

COMP 93 [761946]:  Reactions of ozone with acetylene: Density functional theory for concerted and stepwise mechanisms
John D. Goddard, Change Weng, and Wai To Chan, Department of Chemistry, University of Guelph, Guelph, ON N1G 2W1, Canada, Fax: 519-766-1499,

Hybrid exchange functionals have been employed to study the reactions of ozone with acetylene to form 1,2,3-trioxolene. A concerted symmetry allowed [4+2] cycloaddition pathway as well as stepwise reactions involving biradical intermediates will be discussed. The efficacy of broken symmetry unrestricted density functional theory in describing the biradical transition states and intermediates will be considered. Implications of the biradical pathways for the kinetic data for this reaction will be presented.

COMP 94 [774044]:  Computational study of the mechanism and reactivity for the alkaline hydrolysis of N-phenylacetamides
Boris Galabov, Sonia Ilieva, and Diana Cheshmedzhieva, Department of Chemistry, University of Sofia, 1 James Bourchier St., 1164 Sofia, Bulgaria,

HF/6-31+G(d,p), B3LYP/6-31++G(d,p) and QCISD/6-31++G(d,p) computations were carried out to study the mechanism of alkaline hydrolysis of N-phenylamide (acetanilide). The reaction is of interest because it affects the amide grouping, the backbone element of proteins and peptides. It is found that the nucleophilic attack of the hydroxide ion at the carbonyl carbon atom and the formation of a tetrahedral intermediate is the rate-determining stage of the process. The present study describes also the reactivity of a series of thirteen para-substituted acetanilides in terms of electrostatic attraction forces between the reactants in the rate determining stage. The theoretically estimated shifts of energies for the rate-determining stage were plotted against atomic charges at the reaction center evaluated according several different methods as well as against theoretically electrostatic potentials at carbonyl carbon and oxygen atoms. A number of linear relationships were obtained and are discussed.

COMP 95 [785591]:  Animations of intrinsic reaction coordinates for pericyclic and pseudopericyclic reactions, including valley-ridge inflection points
David M. Birney, Chun Zhou, and Srirangam V. Addepalli, Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, Fax: 806-742-1289,

Ab initio and density functional theory calculations have been used in our laboratory to locate transition states for a variety of pericyclic and pseudopericyclic reactions. Animations of intrinsic reaction coordinate calculations have been used to confirm that the reactions connect to the appropriate minima or transition states, the latter via valley-ridge inflection points. The animations also highlight the differences between pericyclic and pseudopericyclic processes and are used to visualize relatively flat potential energy surfaces. Animations presented will include ketene [2+2] and [4+2] cycloadditions and deazetizations.

COMP 96 [772877]:  Conquer without dividing: Volume rendering of intact molecular charge densities effectively illustrates key concepts in bonding and reactivity
Preston J. MacDougall, Department of Chemistry, Middle Tennessee State University, 1301 E. Main St., Murfreesboro, TN 37132,, and Christopher E. Henze, Data Analysis Group, NASA Ames Research Center

Our volume rendering software enables the user to interactively explore a molecule’s electronic charge density for topological features that make manifest key concepts in bonding and reactivity, such as lone pairs and sites of nucleophilic attack. Using novel volume rendering techniques, the entire molecule can be probed without obstruction by opaque surfaces or preselection of specific orbitals or contours. Thus even core/valence division is not done artificially. Rather such sub-atomic partitioning is evident in the rendering of the Laplacian of computed or measured electron density distributions. The concept of the “charge cloud” is introduced early in the chemistry curriculum, and is one that is readily grasped. Visualizations with direct recourse to this entity, avoiding molecular orbital models, make concepts of chemical reactivity more accessible. The same methodology that is applied to small inorganic or organic molecules, is also applied to large biomolecules. Thus instead of a variety of visual textures for molecular models in the different sub-disciplines, which can disorient students, there is consistency.

COMP 97 [785968]:  Modeling, simulations and visualization in materials chemistry
Tahir Cagin, Department of Chemistry, California Institute of Technology, Materials and Process Simulation Center 139-74, 1200 East California Blvd, Pasadena, CA 91125,

Over the years, using various levels of theory, computer simulation and modeling have become an indispensable part of studying the physics and chemistry of materials such as metals, oxides, ceramics, zeolites, organics, and macromolecules (synthetic polymers and biopolymers). In my research, I have used both electronic structure and atomistic simulation methods and various platforms and programs for molecular graphics. In this particular forum, I will describe the use of commercial program environments such as Cerius2 and Materials Studio as environments for modeling of Metals, Ceramics, functional polymers such as dendrimers, carbon Nanotubes for device applications; metal-oxides, polyelectrolyte polymeric membranes for fuel cell applications; and diffusion, thermal transport and flow studies on materials systems. Some of these studies were conducted by programs developed by the presenter using the Software Developers Kit (SDK) of the Cerius2 product for both simulations and graphical display and analysis.

COMP 98 [785178]:  SymApps: A 3-D point group calculation and visualization tool
Victoria Rafalovsky, Karl Nedwed, Marie Scandone, Gregory M. Banik, and Deborah Kernan, Bio-Rad Laboratories, Informatics Division, 3316 Spring Garden Street, Philadelphia, PA 19104,

The 3D visualization of point groups and, in general, symmetry of chemical structures is a difficult and important concept in lectures on molecular symmetry. Bio-Rad’s SymApps™ application, offered free to academia, calculates the point group of any structure automatically, displays symmetry elements, and allows the student to create movies of symmetry operations with atoms and bonds being rotated, mirrored, etc. Since the real-world coordinates of an entered 3D molecule will not always exactly define a specific symmetry, or the symmetry is distorted, SymApps uses an uncertainty parameter to establish point group at various degrees of distortion. Thus it is possible to find different point groups and measure the degree of distortion of the structure. For example, in a Jahn-Teller-distorted structure (e.g. CuF6), SymApps reports both point groups D4h and Oh. Symmetry elements are displayed graphically, and by turning and resizing the structure the user can more clearly visualize the molecule.

COMP 99 [771072]:  Mol4D: Visualization and interactivity
Jan H. Borkent, C.M.B.I, Radboud University Nijmegen, Toernooiveld 1, 6525ED Nijmegen, Netherlands, Fax: ++31 24 3652977,

Special Equipment Needs: internet connection

The Mol4D (“Molecules in four dimensions”) project is an entirely web-based, Chime supported set of teaching modules in (mainly organic) chemistry, with a high level of scripting background to enhance both its functionality and the level of interactivity. The ‘fourth’ dimension in the title refers to its goal to incorporate animations of reactions and conformational changes in a meaningful way into the Chime pages, with a mechanism to control the course of the animation. The interactivity of Mol4D is extended with a molecule editor, which turns the web pages into an input and output computational interface. Also this editor supports the fourth dimension, insofar that it allows for the definition of a reaction path or conformational change by the user, and offers interactively (within one or two minutes) a web page with a clickable energy plot, a Chime based and controllable animation of the process and a text area with the pertaining numbers.

COMP 100 [785588]:  VRML in the undergraduate curriculum
Clifton P. Calloway, Department of Chemistry, Winthrop University, Oakland Avenue, Rock Hill, SC 29733, Fax: 803-323-2246,

Virtual Reality Markup Language (VRML) is an efficient and powerful tool for the transfer of information over the internet. VRML parallels the commonly used web language HTML in that, links to other VRML or HTML pages can be created, and a browser is required. Unlike HTML, which can be explored in two dimensions, VRML can be explored in three dimensions. With the widespread availability and use of the internet, VRML can be an effective tool for displaying 3 dimensional models and chemical information to undergraduate chemistry courses. Many chemical concepts, properties, and reactions are related to the geometry of a molecule. In these cases, a two dimensional presentation is only marginally adequate for understanding the properties or reactions of molecules. VRML can provide an interactive 3D world. Just over 1/3 of general and organic undergraduate students rank modeling exercises as one of the two most critical and helpful projects, while less than 8% ranked modeling as least critical and helpful.

COMP 101 [769915]:  PMF scoring revisited
Ingo A. Muegge, Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc, 900 Ridgebury Road, Ridgefield, CT 06877,

Topic Selection: Docking and Scoring: Scoring Functions

Knowledge-based scoring functions have become part of the mainstream arsenal of tools for ranking putative protein-ligand complexes obtained by structure-based virtual screening or de-novo design computer experiments. Five years after the introduction of PMF scoring a critical review will be presented. Areas of improvement will be discussed that relate to an increased knowledge base, optimized atom typing, and exploring ways to include hydrogen bond directionality.

COMP 102 [765786]:  Application of HINT interaction scores and Hydropathic Intermolecular Field Analysis (HIFA) to the prediction of ligand binding affinity
Simon F. Semus, Computational, Analytical and Structural Sciences, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406,, and Glen E. Kellogg, Department of Medicinal Chemistry, Virginia Commonwealth University

Topic Selection: Docking and Scoring: Scoring Functions

HINT calculates empirical atom-based hydropathic parameters that are believed to encode all significant intermolecular and intramolecular non-covalent interactions implicated in drug binding or protein folding. Coulombic, hydrogen-bonding, dispersion, as well as hydrophobic effects may be extracted from the hydrophobic atom constant. Also significant is that since hydrophobicity is defined in terms of solubilities, the effects of solvent are also encoded within the constants. Hydropathic Intermolecular Field Analysis (HIFA) is a structure-based QSAR method, in a similar vein to CoMFA, that employs empirically derived hydropathic fields generated by HINT. Ligand-receptor HINT interaction fields are calculated for all molecules and imported in to a Sybyl spreadsheet, where the HIFA model is generated in a manner akin to CoMFA using PLS with cross-validation. It should be emphasized that whereas CoMFA measures the interaction between test ligands and a probe atom, HIFA captures the interaction between the ligand and the receptor.

COMP 103 [761713]:  How well can we score now and where do we go from here: Comprehensive evaluation of 13 scoring functions on 800 protein-ligand complexes and development of new scoring functions
Shaomeng Wang, Renxiao Wang, Xueliang Fang, Chao Yie Yang, and Yipin Lu, Departments of Internal Medicine and Medicinal Chemistry, University of Michigan, 1500 E. Medical Center Dr, CCGC/3316, Ann Arbor, MI 48109, Fax: 734-647-9647,

We have carried out evaluation of 13 popular scoring functions against 800 diverse protein-ligand complexes with known Ki or Kd values. Four scoring functions, i.e. X-Score, DrugScore, Sybyl::ChemScore, and Cerius2::PLP, were found to provide better correlations between their scores and the experimentally determined binding constants of the 800 complexes than the other scoring functions evaluated. After removal of outliers from the correlation evaluation, these four scoring functions reproduced the binding constants of the entire test set with a standard deviation of 1.4 ~ 1.7 log units (corresponding to 1.9 ~ 2.3 kcal/mol in binding free energy at room temperature). To examine if a scoring function generally works better analyzing ligand molecules bound to the same target protein, we have also re-evaluated these thirteen scoring functions on three subsets of protein-ligand complexes extracted from our test set: HIV-1 protease complexes (82 entries), trypsin complexes (45 entries) and carbonic anhydrase II complexes (40 entries). For the HIV-1 protease complexes, the performance of almost all scoring functions was disappointing; for tryspin complexes, a good number of scoring functions gave excellent results; while for carbonic anhydrase II complexes, the performance of several scoring functions was acceptable.

We also wish to present new results from our recent efforts in the development of scoring functions. These efforts include the development of a large publicly accessible protein-ligand binding database (the PDBbind database) for protein-ligand complexes whose experimental 3D structures are available from the Protein Data Bank and whose experimental binding affinities have been published in the literature, and of new algorithms for the calculation of conformational entropy changes for both ligand molecules and proteins during the binding process.

COMP 104 [759927]:  Improving accuracy in protein-ligand affinity calculations
Michael K. Gilson1, Chia en Chang2, and Wei Chen1. (1) Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, MD 20850, Fax: 301-738-6255, (2) Department of Chemistry, University of Maryland

Although there is a need for greater accuracy in models of protein-ligand binding, it is not clear what direction to take to reach this goal. Analysis of relatively simple systems can provide valuable insight. We have studied 30 host-guest systems in aqueous and organic solvents, using a second-generation Mining Minima method. This method uses well-developed theory to provide the standard free energy of binding, along with information on conformational preferences and changes in configurational entropy. The computed affinities are accurate here to within about 1.5 kcal/mol. We observe large changes in configurational entropy that vary over multiple kcal/mole and do not correlate with simple descriptors. Some cases involve induced fit of the host to the guest. Such results suggest that computing protein-ligand binding affinities to “chemical accuracy” of ±1 kcal/mol will require moving to relatively detailed and precise models that include a careful treatment of configurational entropy.

COMP 105 [758202]:  Potential functions for virtual screening and ligand binding calculations: Some theoretical considerations
Kim A Sharp, Biochemistry and Biophysics, University of Pennsylvania, 3700 Hamilton Walk, Philadelphia, PA 19104, Fax: 215-898-4217,

Virtual screening requires identifying rare candidates with significant affinity for a known target structure. This requires identification of the 'best' ligand conformation/position/orientation (pose), ie. determination of the binding affinity of a given pose (at least relative to another pose): the 'binding problem'. Any method that successfully scores candidates/poses must emulate, however approximately, the true binding free energy. I will discuss: the statistical mechanics of binding, the requirements for a true free energy calculation, and some practical principles for evaluating and improving screening potentials. This includes determining whether a screening potential is deficient because the potential is unphysical, has an inadequate functional form, or because the parameters need to be improved. In the first two cases, no amount of parameterization with training/test sets will improve the screening potential significantly. Effort would be better spent re-tooling the potential function. Some issues specific to particular types of scoring/binding potentials will be discussed.

COMP 106 [765655]:  End-point free energy calculations: Synergy from continuum solvent and molecular dynamics methods
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, San Diego

A thorough investigation of end-point free energy calculations will be presented. 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 highlights several important areas: the association free energy, arising from one molecule's loss of translational and rotational freedom upon binding; the conformational free energy, due to both molecules' change in conformational freedom; and compatibility between implicit and explicit solvent models. Direct calculations of the association and conformational free energies from a molecular dynamics simulation will be discussed. The performance of several commonly used Poisson Boltzmann continuum parameter sets will be compared, and a new set of radii for use with AMBER partial charges will be presented. A number of insights from this investigation can be applied in more computationally efficient scoring and rescoring methods.

COMP 107 [781154]:  First principles predictions of the tertiary dtructures for membrane proteins
W. A. Goddard III, Materials and Process Simulation Center, California Institute of Technology, Mail Stop 139-74, 1200 East California Blvd, Pasadena, CA 91125,

We will summarize the progress in predicting the tertiary (3D) Structures of G Protein Coupled Receptor (GPCR) membrane proteins using the MembStruk first principles (no empirical data) methodology. GPCR’s play a critical role in cell communications (receptors for dopamine, serotonin, epinephrine) and in sensing the outside world (vision, smell, taste, and pain). Consequently, they also play a role in many important diseases, ranging from schizophrenia, to Parkinson’s, to asthma, and depression. Unfortunately, many GPCR’s recognize similar ligands (15 serotonin receptors, 9 adrenergic receptors, 5 dopamine receptors), so that most drugs to GPCRs have serious side effects. To develop sub-type specific drug therapies for GPCRs, it is essential to have the 3D structures required for structure-based design. Unfortunately, there are no experimental 3D structures available for human GPCRs despite their importance to pharma. Indeed, considering every form of life the structure for a GPCR is available for only one case: bovine rhodopsin. MembStruk was developed to solve this problem.

Since there are no crystal structures with which to compare our results, we developed the HierDock method to scan the complete protein and to locate the best binding site. This allows the validation of our predicted structures by using the structures to predict the binding site and binding energies for various agonists and antagonists. The results are in excellent agreement with available binding and mutation experiments.

We will discuss results for some of the following systems: Adrenergic receptors Dopamine receptors Histamine receptors Serotonin receptors Olfactory receptors Lipid receptors (LPA, S1P, LPC). Peptide recepors (MrgC11 Co-workers: Yashar Kalani, Peter Freddolino, N. Vaidehi, Rene Trabanino, Wely Floriano, Spencer Hall, Victor Kam, Peter Kekenes-Huskey

COMP 108 [781139]:  Time-dependent density functional theory applied to carotenoids, chlorophylls and porphyrins
Martin P. Head-Gordon, Department of Chemistry and Chemical Sciences Division, University of California, and Lawrence Berkeley National Laboratory, Berkeley, CA 94720, Fax: 510-643-1255,

Time-dependent density functional theory (TDDFT) is applied to the low-lying excited states a variety of biological molecules, first individually, and then in complexes. The results yield insight into the specific systems studied, and also reveal strengths and weaknesses of TDDFT itself, as currently implemented. This talk will discuss both of these aspects. We will discuss the reliable computation of valence versus charge-transfer excited states. We will then examine in detail the excited states associated with complexes composed of a carotenoid and a chlorophyll. These states give some insight into the possible mechanism of non-photochemical quenching (NPQ) in the photosynthetic reaction center, a process whose molecular origin remains unresolved.

COMP 109 [770398]:  Multireference spin-adapted variant of density functional theory
Mark R. Hoffmann and Yuriy G. Khait, Department of Chemistry, University of North Dakota, Grand Forks, ND 58202-9024, Fax: 701-777-2331,

A new Kohn-Sham formalism has been developed (J. Chem. Phys. 2004, 120, 5005-5016) for studying the lowest molecular electronic states of given space and spin symmetry whose densities are represented by weighted sums of several reference configurations. Unlike standard spin-density functional theory, the new formalism uses total spin conserving spin-density operators and spin-invariant density matrices so that the method is fully spin-adapted and solves the so-called spin-symmetry dilemma. The formalism permits the use of an arbitrary set of reference (non-interacting) configurations with any number of open shells. It is shown that, at any molecular geometry, the configuration, or alternatively configuration state function, weights can be determined by minimization of the energy, and, for given reference weights, the Kohn-Sham orbitals can be determined. From this viewpoint, the developed theory can be interpreted as an analog of the multiconfiguration self-consistent field approach within density functional theory.

COMP 110 [784045]:  Future prospects for Brillouin-Wigner-based quantum chemical methods
Ivan Hubac1, Stephen Wilson2, Jiri Pittner3, and Peter Carsky3. (1) Department of Chemical Physics, Comenius University, Faculty of Mathematics, Physics and Informatics, Bratislava 84248, Slovak Republic, Fax: 421-7-65425882,, (2) Rutherford Appelton Laboratory, (3) J. Heyrovsky Institute of Physical Chemistry, Academy of Sciences of the Czech Republic

In recent years, there has been a growing interest in Brillouin-Wigner-based methods for handling the molecular electronic structure problem. Such methods are seen as especially useful for situations which have multireference character. Multireference Brillouin-Wigner Coupled Cluster (MR-BWCC) theory is seen as a robust and, because of its simplicity, 'user-friendly' approach. Its extension to systems demanding the use of a model space consisting of several reference configurations is straightforward. Recent calculations have placed MR-BWCC among the most competitive of contemporary methods.

In this paper, we consider the application of the MR-BWCC method in the calculation of molecular properties. In particular, we address the problem of calculating analytical derivatives of the energy in the MR-BWCC method.

We also discuss other methods based on the Brillouin-Wigner perturbation theory. In particular, we describe the second order multireference Brillouin-Wigner perturbation theory (MR-BWPT2) method, which, as a generalization of the widely used MP2/MBPT2 approach, is seen as a computationally effective approach for routine applications requiring a multireference formalism.

COMP 111 [769561]:  Polarization consistent basis sets
Frank Jensen, Department of Chemistry, SDU, Campusvej 55, Odense DK-5230, Denmark, Fax: +45 66158780,

Polarization consistent basis sets are designed for providing a systematical way of approaching the Kohn-Sham basis set limit in density functional calculations. In analogy with the correlation consistent basis sets developed by Dunning and co-workers, the composition in terms of angular momentum functions is based on energy analysis. The basis sets are denoted as pc-n, where n indicates the level of polarization beyond the isolated atom. The largest of these, pc-4, is capable of calculating atomization energies to within 0.01 kJ/mol per atom, equilibrium distances to within 10-5 Å, and harmonic vibrational frequencies to within 0.5 cm-1. The basis sets can be augmented with diffuse functions for improving the basis set convergence of electric properties, like dipole moments and polarizabilities. The talk will give an overview of the current status of polarization consistent basis sets.

COMP 112 [771099]:  Sigma bonds prevent short pi bonds
Eluvathingal D. Jemmis1, Bishwajit Pathak1, Henry F. Schaefer III2, and R. Bruce King3. (1) School of Chemistry, University of Hyderabad, Central University PO, Hyderabad 500 046, India, Fax: -91-40-23012460,, (2) Center for Computational Quantum Chemistry, University of Georgia, (3) Department of Chemistry, University of Georgia

The inverse relationship between bond order and bond length is well established. Similarly the idea that a sigma bond is inherently stronger than a pi bond is also generally accepted. However there are several examples where these ideas do not work. We bring in examples from main group and transition metal chemistry where these general expectations are not met. It is possible that pi bonds would have been shorter than sigma bonds, had there been no sigma bonds. While it may not be easy to design molecules with two center pi bonds without an underlying sigma bond, that may be a way to design molecules with extremely short bond lengths.

Acknowledgements: We thank the Department of Science & Technology, New Delhi for financial support.

COMP 113 [773952]:  Using decompositions in electronic structure methods to obtain reduced scaling
Henrik Koch, Department of Physical Chemistry, Norwegian University of Science and Technology, Trondheim N-7491, Norway,, Thomas B. Pedersen, Department of Theoretical Chemistry, University of Lund, and Alfredo Sánchez de Merás, Institute of Molecular Science, Department of Physical Chemistry, University of Valencia

The presentation will focus on recent developments of algorithms using rank decomposition to obtain reduced scaling in electronic structure methods.

COMP 114 [768278]:  Adding the third dimension to the chemistry lecture hall
Joseph J. Grabowski, Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, Fax: 412-624-8611,

Computers and data projectors have dramatically impacted teaching practices across the disciplines and at all levels. This technology is often used to display images and animations that would otherwise be described only in words, or be schematized by hand drawn, icon-heavy, representations. The next use of this technology will be to transform flat two-dimensional representations of inherently three-dimensional entities, into three-dimensional, interactive projections. This presentation will document how our Chemistry faculty have built and are using such a system in a large lecture hall, and will describe a portable system that can readily be used by faculty across the campus. All aspects of the project will be available for discussion, from the technology needed, to experiences using the system in large to small classrooms, to the assessments so far available, to the challenges of changing software, to frustrating experiences with hardware, and even to speculation about the technology of tomorrow.

COMP 115 [771683]:  A novel mass spectrometry internet teaching tool
Mark E. Bier1, Chunguang G. Yang1, and Joseph J. Grabowski2. (1) Department of Chemistry, Carnegie Mellon University, Center for Molecular Analysis, 4400 Fifth Avenue, Pittsburgh, PA 15213-2683, Fax: 412-268-6897,, (2) Department of Chemistry, University of Pittsburgh

The Virtual Mass Spectrometry Laboratory (VMSL) is an interactive, Internet educational tool developed to teach mass spectrometry. The VMSL project addresses several hurdles facing colleges: the high cost of mass spectrometers, the difficulty in teaching “real-life” problem solving to large groups and the shortage of expert mass spectrometrists. The VMSL allows schools that can not afford mass spectrometers to add MS experiments to their curriculum. Students can solve real problems with out actually going to a MS laboratory. Each student can operate several virtual mass spectrometers and acquire data from their own computer. The VMSL server rapidly delivers GIF images to simulate the operation of a real mass spectrometer allowing hundreds of students to operate their instrument simultaneously. A student can solve several case studies such as identifying an unknown protein, determining a proper polymer additive, determining whether a hair sample contains cocaine, or identifying an anesthetic. (

COMP 116 [757866]:  VS-C: Cross-linked studies in chemistry
Gregor Fels, Department of Chemistry, University of Paderborn, Warburgerstr. 100, Paderborn D-33098, Germany, Fax: +49-5251-603245,

With respect to information and knowledge, the society of the twenty-first century will demand novel forms of teaching and learning, for which new educational materials and skills for a problem-related and explorative learning will be necessary prerequisites in the new media. Organic chemistry material from a Germany wide project in which in the end all the learning units for a Bachelor study in chemistry will be presented in a web-based, multimedia assisted, and interactive online textbook of chemistry. Particular emphasis will be laid on presenting reaction mechanisms which can be driven interactively as well as on complex biological processes.

COMP 117 [771864]:  Web term papers: Learning structural biology through the creation of website content
Warren H. Gallagher, Chemistry Department, University of Wisconsin-Eau Claire, Phillips Hall 437, Eau Claire, WI 54702, Fax: 715-836-4979,

For the past eight years students in a Biophysical Chemistry class at the University of Wisconsin-Eau Claire have gained hands-on experience with manipulating biological macromolecules by creating website content. The students are required to write a term paper on the structural aspects of some well-characterized biomolecular system and to publish these papers as websites that include interactive 3-dimensional molecular graphics images. These images are embedded into web pages using the Chime web browser plug-in. Simple button-activated scripts are also embedded to allow a visitor to the site to modify the images in context with the narrative of the term paper. The primary purpose of the assignment is not to train our students to become webmasters, but rather to have them use the activity of designing website content as a vehicle to become more intimately familiar with biomolecules at the molecular level. Other advantages of the website format is the ability to use hyperlinks to make connections to a diverse body of reference information from within the term papers and to share the fruits of the student’s efforts with a much larger audience.

COMP 118 [781813]:  Animations of bio-organic reactions
Paul B. Savage and Steven A. Fleming, Department of Chemistry and Biochemistry, Brigham Young University, C100 BNSN, Provo, UT 84602,

Many students who take organic chemistry courses continue on to careers in biological sciences. In their continuing education, they take multiple biochemistry and biology courses. The understanding of most biological processes is now at the molecular level, so it is important that students learn biochemical principles at this level. To achieve this end, students need to make correlations between organic chemistry and biochemical reactions. Because students may be tempted to memorize reaction outcomes rather than understand reaction processes, we have prepared animations of several enzymatic reactions. We use coordinates from X-ray structures and calculated reaction trajectories, allowing visualization of biochemical reactions in a simplified and informative format. These animations allow 3D manipulation of the enzyme active site. Students learn about the nature of the binding site, residues involved in reaction catalysis, and mechanisms of chemical transformations. This information allows a clear correlation between organic chemistry and biochemical reactions.

COMP 119 [788678]:  AEI: Knowledge-based potentials in drug design
Brian N. Dominy, Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street - Box 79, Cambridge, MA 02138,

Knowledge-based potentials have been found useful in a variety of biophysical studies of macromolecules. In this study, we apply liquid state theory and simulations to explore the failures and successes of knowledge-based potentials. We also apply these lessons toward the extraction of realistic pair potentials from the PDB in SMoG, a program developed for automated drug design. This novel approach is capable of generating broadly applicable knowledge-based potentials as well as potentials specialized to specific protein families. The general potential provides a reasonable level of enrichment during the initial stages of lead discovery (R=0.61, average unsigned error = 1.5 log Ki units), while the specialized potentials provide a much more detailed assessment of binding efficacy in closely related compounds (R=0.8-0.9, average unsigned error = 1.1-1.3 log Ki units). In summary, we explore the theoretical foundations of knowledge-based potentials and apply these lessons to the practical and challenging problem of binding affinity prediction.

COMP 120 [788590]:  CoLiBRI: A novel method for the prediction of complementary ligands based on receptor information and its application to database screening
Scott Oloff1, Shuxing Zhang2, and Alexander Tropsha2. (1) Division of Medicinal Chemistry and Natural Products, University of North Carolina, CB # 7360 Beard Hall, Chapel Hill, NC 27599,, (2) School of Pharmacy, Laboratory of Molecular Modeling

We have developed a novel chemometric approach to identifying Complementary Ligands Based on Receptor Information (CoLiBRI), which relates chemical similarities between active sites and their respective ligands to produce a model of ligand-receptor selectivity between ligand and active site chemistry spaces. Consequently, the knowledge of a ligand or a receptor’s active site structure affords straightforward and efficient identification of its complementary target from large virtual databases using rapid chemical similarity searches.

We have applied this approach to a diverse dataset of 260 ligand receptor complexes and identified known ligands of test receptor active sites among the World Drug Index (approx. 54,000 compounds). The results illustrate that CoLiBRI is capable of enriching known ligands within the top 1% of the database in 95% of all cases. This novel approach provides a powerful and efficient alternative to more traditional structure based docking and scoring approaches that require significantly greater computational resources.

COMP 121 [774941]:  Parallel simulations of four-atom wavepacket dynamics
Dmitry M. Medvedev, Chemistry Division, Argonne National Laboratory, 9700 S. Cass Avenue, Bldg. 200, Argonne, IL 60439, Fax: 630-252-9292,, Stephen K. Gray, Chemistry Division, Argonne National Laboratory, Argonne, IL, and Evelyn M. Goldfield, Department of Chemistry, Wayne State University

We present a parallel method for carrying out four-atom wavepacket quantum dynamics. Parallelization is achieved using a hybrid OpenMP/MPI approach and implemented on a cluster of IBM SP multiprocessors. The method is shown to scale well with the number of processors. The approach is applied to the OH + CO reaction.

COMP 122 [775047]:  Computational design of protein complex with non-biological cofactor
Wei Wang1, Frank Cochran2, Vikas Nanda2, Sophia Wu1, Michael J. Therien1, William F DeGrado2, and Jeffery G. Saven1. (1) Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104,, (2) Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine

De novo protein design provides new ways to probe the determinants of protein folding, stability and function. A computational method built upon a statistical formalism has been developed that directly identifies site-specific amino acid probabilities for a given backbone structure, which are then used to guide sequence design. This method was used for the de novo design of a four helix bundle that binds nonbiological porphyrin cofactor at the center of the bundle. The resulting complex is helical, tetrameric and binds two porphyrins specifically and stoichiometrically. This study provides an important first step in understanding and engineering novel functions into proteins using nonbiological cofactors.

COMP 123 [774347]:  Molecular dynamics simulation of E-coli dihydrofolate reductase and its circular permuted variants: Relative stabilities in experiment and simulations
Zengjian Hu1, Buyong Ma2, Ruth Nussinov3, 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) Laboratory of Experimental and Computational Biology, Basic Research Program, SAIC, NCI-FCRDC, (3) Basic Research Program - Macromolecular Structure, SAIC Frederick, Inc. NCI

Understanding the underlying mechanism(s) of how proteins fold will be a key factor in correlating structure-function relationships in proteins. Additionally, it is important to recognize that different amino acid sequence segments within proteins exhibit different folding capacities. Consequently, within proteins it may be possible to detect folding "sequences" or "elements" that drive overall protein folding. Understanding the factors which influence intra-protein folding will have a significant impact on protein structure prediction and protein design. Recently, essential folding sequences of the native Escherichia coli dihydrofolate reductase protein were detected [Iwakura M et al, 2000]. We have carried out molecular dynamics simulations of the native E coli DHFR and several of its circular permuted variants at standard temperature in order to correlate folded stabilities among these variants. Our initial results indicate significant difference in structural stability between amino acid sequences identified as folding sequences when compared to those not identified as folding sequences.(*This work is supported by grant RCMI-NIH 2G12RR03048, grant MCB030037P from Pittsburg Supercomputing Center, and by NCI Advanced Biomedical Computing Center)

COMP 124 [770466]:  Computational evaluation of stereoelectronic effects in fluorinated amines
Joseph J. Urban, Chemistry Department, U. S. Naval Academy, 572 Holloway Road, Annapolis, MD 21402, Fax: 410-293-2218,

The results of a systematic evaluation of the stereoelectronic effects that accompany fluoro and trifluoromethyl substitution in prototypical amine compounds will be presented. A variety of computational methods have been employed including molecular mechanics, semiempirical, density functional, and ab initio methods. The effect of solvent was also considered via a continuum solvation model. Specifically, the goals of this work are to characterize the energetic consequences of the stereoelectronic effects in terms of conformational preferences, and to characterize the changes in molecular geometry and charge distribution that accompany the stereoelectronic effects. Also, a comparison of results among the computational methods is carried out and a comparison to available experimental data is made.

COMP 125 [774827]:  Computational modeling studies of multi-targeted antifolates
Angela J Jackson1, Zengjian Hu2, and William M. Southerland2. (1) Laboratory of Molecular Computations, Howard University, 520 W Street NW, Washington, DC 20059, Fax: 202-806-5784,, (2) Department of Biochemistry and Molecular Biology, Howard University College of Medicine and the Howard University Drug Discovery Unit

Computational docking and molecular dynamics simulations have been utilized to perform detailed evaluation of enzyme-ligand interactions between the multitargeted antifolate, alimta (MTA), and the more specific antifolates methotrexate, raltitrexed and 10-CF3CO-DDACTHF with the target enzymes, dihydrofolate reductase, thymidylate synthase and glycinamide ribonucleotide transformylase. As a result, the fundamental requirements of multi-targeted antifolates which simultaneously target these three enzymes have been established. Differences in ligand structure that contribute to variations in binding stability with the diverse enzymes were characterized through identification of the arrangement of functional groups of the enzyme-specific ligands (methotrexate, raltitrexed, and 10-CF3CO-DDACTHF) within the given folate-binding sites. Comparison of chemical and geometrical differences of the binding mode of MTA with the three target enzymes exposed the unique characteristics of MTA that enable the inhibitor to efficiently target all three enzymes.

COMP 126 [774481]:  New algorithms for computational chemistry: Partial charges, resonance forms, symmetry, and conformational search
Michael K. Gilson1, Michael J. Potter2, Wei Chen1, Hillary S. R. Gilson2, and Jing Huang2. (1) Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, MD 20850, Fax: 301-738-6255, (2) VeraChem LLC

Atomic charges. This electronegativity equalization method, parameterized against 6-31G* electrostatic potentials, considers all low-energy resonance forms to ensure that equivalent atoms are assigned equal charges. Excellent results are obtained for a test set of varied compounds, at under 1s per compound.

Resonance forms. Bond-paths linking electron-donor and electron-acceptor atoms are detected, and all possible electron transfers are executed, yielding new resonance forms. This iterates until no new forms are detected.

Symmetry detection. Local and global topological and spatial symmetries are detected. The results are useful for removing redundant conformations, reducing the sampling ranges of torsions that rotate symmetrical moieties, and calculating symmetry numbers for thermochemistry.

2D to 3D with conformational search. Initial conformations built via rules and ring templates are relaxed by torsional Monte Carlo, and the resulting conformations are used to start global Tork searches. Each subsequent stage is optional, so CPU time and search intensity can be controlled.

COMP 127 [773250]:  Computational studies of MALDI matrices interacting with tripeptides as a model of MALDI matrix-analyte interactions
Faten H. Yassin, Department of chemistry and biochemistry, University of Texas at Arlington, Box 19065, Arlington, TX 76013,, and Dennis S. Marynick, Department of Chemistry and Biochemistry, University of Texas at Arlington

The mechanism of matrix to analyte proton transfer in matrix-assisted laser desorption/ ionization (MALDI) has been computationally investigated in the gas-phase by modeling the interaction of various MALDI matrices with various tripeptides. A combination of molecular dynamics/simulated annealing calculations followed by high-level density functional theory geometry optimizations using reasonably large basis sets has been done on each examined cluster in an attempt to study the ionization energy of the matrix in the cluster environment and the intracluster proton transfer from the matrix to the tripepetide.

COMP 128 [766059]:  Computational study of hyperthermophilic indole glycerol phosphate synthase: Structural alterations at the active site with temperature
Devleena Mazumder and Thomac C. Bruice, Department of Chemistry & Biochemistry, University of California Santa Barbara, UCSB, Santa Barbara, CA 93106,

Hyperthermophlic Indole-3-glycerol phosphate synthase catalyzes the terminal ring closure step in tryptophan biosynthesis. We compare the results from the molecular dynamics simulation of enzyme bound substrate at 298 K (E•S298) and 385 K (E•S385) solvated in TIP3P water box using CHARMM forcefield to address the question of the structural change of the Enzyme•Substrate complex with temperature. MD simulation was also performed on enzyme-bound intermediate to understand the mechanism better. The population of the reactive Enzyme•Substrate Michaelis conformers (Near Attack Conformers or NACs) increases by ~1100-fold in going from room temperature (E•S298) to high temperature (E•S385). This increased population of NAC conformers in the Michaelis complex correlates well with the experimentally determined increase in rate in going from 298 K to 385 K. The residues Lys53 and Lys110 may play a role in controlling the NAC formation.

COMP 129 [771648]:  Computational study of the structure of di-lithium Phthalocyanine/Pyrite interface
Yingchun Zhang1, Lawrence G. Scanlon2, and Perla B. Balbuena1. (1) Department of Chemical Engineering, Texas A&M University, College Station, TX 77843, (2) Energy Storage & Thermal Sciences Branch, Air Force Research Laboratory

The crystalline structure and self-assembly characteristics of di-lithium phthalocyanine (Li2Pc) as well as its properties as ion conductor in an electrochemical cell, where Li2Pc is used as a solid state electrolyte, have been recently analyzed. Since lithium ions diffuse from the electrolyte to the electrode, a good interfacial contact is essential. For pyrite cathodes, a thin film of Li2Pc is grown over the surface of pyrite. We use molecular dynamics simulations to analyze such solid-solid interface. The systems consist of a 5-layer slab of a pyrite (100) surface in contact with a monolayer, a bilayer, or multilayers of Li2Pc located in a tetragonal unit cell, which is subjected to periodic boundary conditions. By investigating the interfacial structure of the system, several structural and dynamical properties are analyzed, including the radial distribution functions, adsorption of Li2Pc on the pyrite (100) surface, and lithium-ion diffusion.

COMP 130 [773611]:  Computational study on the role of bridging water molecules in the energetics of protein-ligand binding
Micaela Fornabaio1, Pietro Cozzini2, Francesca Spyrakis2, Andrea Mozzarelli2, Donald J. Abraham1, and Glen E. Kellogg1. (1) Department of Medicinal Chemistry, Virginia Commonwealth University, Box 980540, Richmond, VA 23298-0540, Fax: 804-827-3664,, (2) Department of Biochemistry and Molecular Biology, University of Parma

Water molecules are an essential component of living systems and can be fundamental in the binding process. To correctly predict binding free energy, it is crucial to carefully model water molecules and consider their contribution to the energetics of binding. Our approach is founded on HINT, a model based on experimentally determined partition coefficients between 1-octanol and water, LogPo/w (a thermodynamic parameter representing the free energy for solute transfer between the two solvents). Thus, the HINT score is directly related to DG of binding. The HINT model can explicitly evaluate the contribution of each water molecule bridging between protein and ligand. HINT was applied to a set of 23 HIV-1 protease-inhibitor complexes to investigate the energetic contribution to binding played by each water molecule at the protease active site. As an integral part of this work, development of an algorithm for locating, de novo, bridging waters will also be presented.

COMP 131 [771894]:  Computer simulation of acetone with a polarizable potential model
Tsun Mei Chang and Tarisa Lerro, Department of Chemistry, University of Wisconsin-Parkside, 900 Wood Rd. Box 2000, Kenosha, WI 53141, Fax: 262-595-2056,

We carried out molecular dynamics simulations to examine the equilibrium properties of the liquid acetone and acetone-water mixtures at various compositions. The interactions between acetone molecules are described by an all-atom polarizble potential model developed in this study. The results of thermodynamic properties, radial and angular distribution functions, and hydrogen bonding patterns will be discussed. These results provide a molecular-level understanding of the local structures and orientations of the liquid acetone and acetone/water mixtures.

COMP 132 [774863]:  Free energy calculations from non-equilibrium pulling simulations on a single peptide molecule
Hui Xiong, Hai Ping Cheng, and Adrian Roitberg, Quantum Theory Project, University of Florida, Gainesville, FL 32605,

Free energy is an essential quantity in understanding biophysical processes. It's also among the most difficult quantities to obtain using equilibrium methods, either experimentally or computationally. The Jarzynski's identity, Δ F = - 1 / β ln < exp (-β W) >, gives an exact relation between the equilibrium free energy difference of a system's two states and the ensemble average of the non-equilibrium work done on the system to switch between the states. This equality makes it possible to accurately estimate the free energy difference from non-equilibrium experiments, which are inevitably perturbed. It also helps computational studies to find the most efficient way to calculate free energy difference, choosing between faster/more and slower/less switchings. The exponential average in Jarzynski's equality will induce a systematic error when averaging over a finite number of switchings. This error is not fully understood in applications yet. We simulate pullings of an alpha-helical Alanine-8 peptide molecule by molecular dynamics. Molecules are pulled from alpha-helix up to fully extended state under various pulling rates. Free energy profile curves along stretching length are calculated by Jarzynski's equality and cumulants expansion of the exponential average. Both are compared with the "true" free energy profile, obtained from ultra slow pullings. Issues of switching/hopping timescales and significance of fully sampling of initial equilibrium ensemble are discussed. Work is supported in part by DOE Contract DE-F602-02ER45995.

COMP 133 [771552]:  Computing the intrinsic conformational preferences of substituted cyclohexanes and tetrahydropyrans: Some surprises and new insights
Abby K. Jones and Gregory S. Tschumper, Department of Chemistry and Biochemistry, University of Mississippi, University, MS 38677-1848,

Cyclohexane and tetrahydropyran rings containing simple, electronegative substituents such as CH3, F, OH, OCH3 provide a paradigm for the anomeric effect. A series of ab initio and density functional (DFT) theory computations have been carried out with basis sets ranging in size from 6-31G(d) to cc-pV5Z in order to determine the conformational preference (axial versus equatorial) of these substituted 6-membered rings. In most cases, qualitative agreement exists between each of the theoretical methods and experiment. However, substantial discrepancies are observed for cyclohexanes with simple electronegative substituents such as OH and OCH3. For example, MP2 calculations with the 6-311G(2df,2pd) basis set suggest that axial methoxycyclohexane is electronically more stable than the equatorial conformer by nearly 0.6 kcal/mol. RHF and B3LYP computations with the same basis set, on the other hand, indicate that the equatorial orientation is favored by 0.2 - 0.4 kcal/mol. The relative energies of these cyclohexane conformers computed with high-level ab initio methods such as MP2 and CCSD(T) are surprisingly sensitive to the quality of the atomic orbital basis set. Only by progressing to extremely large basis sets does a consistent trend begin to emerge. In addition, corrections for the zero-point vibrational energy and entropy are very important and can even reverse the conformational preference of these species.

COMP 134 [768877]:  Conformational analysis of piperazine and piperidine analogs of GBR12909: Effect of force field and solvent
Deepangi Pandit1, William Roosma2, Milind Misra1, Kathleen M. Gilbert1, Dorota Matecka3, Thomas Prisinzano3, Kenner C. Rice3, 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) Laboratory of Medicinal Chemistry, NIDDK, DHHS, National Institutes of Health

GBR analogs form an important class of dopamine reuptake inhibitors that appears to be useful in the treatment of cocaine abuse. As the first step in the modeling of a pharmacophore for binding to the dopamine transporter, we carried out random search conformational analysis to locate local minima on the potential energy surface of the GBR12909 analogs, in vacuum phase and implicit solvent using the Tripos and MMFF94 force fields. The sensitivity of the conformational potential energy minima to solvent and force field was explored.

COMP 135 [760429]:  Conformational study of polypeptides implicated in Alzheimer’s disease
Timothy H. Click, Zunnan Huang, 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 tested a newly developed method for finding global energy minima to determine the structures of polypeptides implicated in Alzheimer’s disease. With the method, we found that the lowest potential energy structures of the polypeptides near 0 K may differ substantially from the NMR structures. To confirm the lowest potential energy structures, simulations were started from the fully extended structure and from different NMR structures.

COMP 136 [774491]:  Cytosine radicals and their respective anions: Molecular structure and electron affinities
David J Zhang, center for computational chemistry, Univ. of Georgia, 1004 Cedar St., The Univ. of Georgia, Athens, GA 30602,

Adiabatic electron affinities (AEAs) are predicted for fifteen different radicals produced by hydrogen atom addition to cytosine tautomers. Geometry optimizations were carried out utilizing the DFT functionals B3LYP and BLYP with double-ζ quality basis sets plus polarization and diffuse functions(DZP++). All optimized structures were confirmed to be minima via vibrational frequency analysis. Both the neutrals and the anion radicals were observed to possess Cs symmetry, conserving the parent molecule’s qualitative conformation.

COMP 137 [771803]:  Defining privileged reagents using sub-similarity comparison: A method for reagent ranking
Brett A. Tounge and Charles H. Reynolds, 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,

We have developed a new method for assigning a drug-like score to reagents. This algorithm uses Topological Torsion (TT) 2D descriptors to compute the sub-similarity of any given reagent to a substructural element of any compound in the CMC. The utility of this approach is demonstrated by scoring a test set of reagents derived from the “Comprehensive Survey of Combinatorial Library Synthesis: 2000” (J. Comb. Chem.). R-groups were extracted from the most-active compounds found in each of the reviewed libraries and the distribution of the sub-similarity scores for these monomers were compared to the ACD. This comparison showed a dramatic shift in the distribution of the JCC R-group subset toward higher sub-similarity scores in comparison to the entire ACD database. The ACD was also used to examine the relationship between molecular weight and various sub-similarity scoring algorithms. This analysis was used to derive a sub-similarity score that is less biased by molecular weight.

COMP 138 [772063]:  Designing a combinatorial library of mutation-resistant HIV protease inhibitors
Sripriya Chellappan, Miguel X Fernandes, and Michael K. Gilson, Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, MD 20850,

The protease inhibitors are potent antiretroviral agents, but their usefulness is threatened by protease mutations that reduce the affinity of the clinical inhibitors without destroying the activity of the enzyme. In order to address this problem, we have implemented a genetic algorithm that selects a sub library of compounds from a virtual combinatorial library which are likely to bind both wild-type and mutant forms of the protease. The fitness of a candidate ligand is assessed by structure-based docking and scoring, combined with indicators of resistance to potential mutants. This computationally intensive approach is made possible by parallel implementation on a Linux cluster. Designed libraries will be synthesized and tested by our collaborators. Success in this effort would have implications not only for the treatment of AIDS, but also for the development of therapies against other organisms where resistance arises due to mutation of the target protein.

COMP 139 [768697]:  Determination of cysteine pKas in a copper chaperone
Rasha R. Abd El-Rahman, Department of Chemistry and Biochemistry/ computational chemistry, Duquesne University, 600 Forbes Avenue, 308 Mellon Hall of Science, Pittsburgh, PA 15282,, Jeffry D. Madura, Department of Chemistry and Biochemistry, Center for Computational Sciences, Duquesne University, and Charles T. Dameron, Department of Chemistry and Biochemistry, Duquesne University

Cells utilize a variety of mechanisms to regulate essential, yet toxic trace elements such as copper. Recent studies have shown that cells use proteins called “metallochaperones” to route metal ions through the cell; metallochaperones protect the cell and ensure delivery of the metal to nascent enzymes. However, the mechanism of binding and release of metals by these metallochaperones is not well understood. Our metallochaperone, CopZ, has a common structure, consisting of two a-helices overlaying four b-strands. An exposed -Cys-X-X-Cys- metal binding motif is positioned in a loop near the N terminus of the protein. A similar motif is seen in the Thioredoxin family of proteins. The cysteinyl thiolates in the Thioredoxin family, with markedly altered pKa's, serve a catalytic function. We are proposing that, as in the Thioredoxins, the thiolates have perturbed pKa's and that differences are important in the binding and release of the metal ions. A new procedure has been developed to calculate the pKa values of the cysteines in the Thioredoxin proteins and metallochaperones. The free energy perturbation calculation of the AMBER7 program is used to calculate pKa. The calculated pKa values of the Thioredoxin family are consistant with the experimental values. Also, the program UHBD (University of Huston Brownian Dynamics) has been used to calculate the pKa values for a group of the Thioredoxin family proteins, and copper chaperon protein. The results from the continuum and explicit water calculations were consistent with the experimental values, and will be presented.

COMP 140 [774513]:  Determining partial atomic charges for fragments used in de novo drug design
Jennifer L. Ludington, Ted T. Fujimoto, and Frank P. Hollinger, Technology and Informatics, Computational Chemistry, Locus Pharmaceuticals, Inc, Four Valley Square, 512 Township Line Road, Blue Bell, PA 19422, Fax: 215-358-2020,

De novo drug design requires accurate energy simulations between small molecules and the targeted protein structure. One of the recognized important components in obtaining accurate energies is starting with good geometries and atomic charges for the small molecule under study. We have developed a proprietary fragment based method for accurately predicting binding free energies of the fragments to the protein. To obtain the best result we require accurate point charges. We will present a study in which a variety of approaches (molecular mechanics, HF, and DFT) are used to determine atomic charges for the small molecule fragments. These computed charges are compared with experimental solvation energies and dipole moments to identify the most practical approach which yields good comparison with experiment in a computationally efficient manner.

COMP 141 [775044]:  Development of an effective strategy for lead docking
Daniel Cheney, Department of Macromolecular Structure, Bristol Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, Fax: 609-818-3545,, Luciano Mueller, Macromolecular Structure, Bristol-Myers Squibb, and David R. Langley, Computer-Assisted Drug Design, Bristol-Myers Squibb Co

Multiple docking programs have been developed, and while considerable improvements have been reported, problems persist in computing scoring energies, adequate inclusion of solvation effects and protein flexibility. Several molecular docking programs were evaluated in “real world” cross docking scenarios but none reliably predicted, let alone sampled, correct protein-binding poses. Our study shows, that substantial improvements in sampling can be realized by docking lead compounds into conformational ensembles of proteins. Overall predictive accuracy was enhanced by minimizing and rescoring multiple docked protein/ ligand complexes using forcefield / solvent models such as OPLS-AA-2001/ SGB. Forthcoming inter-molecular interaction- and ligand strain energies proved superior to the original scores in the respective docking programs in ranking docked poses. Targeted relaxation of active site residues based on ligand-induced conformational variability during the energy minimization, further aided the scoring of docked ligand conformers.

COMP 142 [770606]:  DFT, molecular dynamics, and free energy calculations on the multi-coordinate Cu(I)-binding protein Hah1
Kenneth M. Merz Jr. and Bryan T. Op't Holt, Department of Chemistry, Pennsylvania State University, 152 Davey Lab, University Park, PA 16802, Fax: 814-863-8403,,


Human antioxidant protein, Hah1, is important in the regulation of Cu(I) in vivo. Here, we describe a multi-faceted investigation of Hah1. High level DFT calculations [GAUSSIAN03] at B3LYP/6-311++G* and a special basis set developed for Cu(I) by Ryde were performed on a model cluster of the binding site, [Cu(I)(SCH3)4]3-, to obtain geometrical and force constant parameters. The derived parameters were used to create an AMBER force field for the MD simulations. Several binding site coordination states of the solvated protein were analyzed after 5ns of MD runs. The information garnered from MD analysis describes residue displacement at different Cu(I) coordinations and residues that participate in H-bonding in the binding environment. Free energies of different coordination states were compared by performing free energy perturbation simulations with gibbs/AMBER in order to gain insight into the mechanistic pathway of Cu(I) transport.

COMP 143 [770338]:  Effects of grid sizes on the calculation of solvation free energy in a quantum continuum solvation model
Kenneth M. Merz Jr. and Ning Liao, Department of Chemistry, Pennsylvania State University, 152 Davey Lab, University Park, PA 16802, Fax: 814-863-8403,,

We present a quantum mechanical continuum solvation model using the Poisson-Boltzmann equation, related to the model proposed by Nicholls et al. In particular, the effect of grid size on the computed solvation free energy was inspected. 2000 solvation free energy calculations of an SH3 (PDB id: 1BBZ) were performed at various grid sizes. A systematic overestimation of the electrostatic contribution to the solvation free energy was observed. Placement of the protein in random positions within the grid did not average out the systematic error. Upon closer examination, we find the error was due to a bias in the evaluation of the surface charges. The coarser grids tend to over polarize the solvent by increasing the induced surface charges around the solute, but the sum of total surface charges still obeys Gauss’s Law. This overestimates the solvation free energy of SH3 by as much as 15 kcal/mol. This overestimation could be even larger when the solute size increases. A new approach will be described that eliminates this model bias.

COMP 144 [761746]:  Estimation of conformational entropy loss in protein-ligand binding process using 2-D and 3-D graph indices
Xueliang Fang, Renxiao Wang, and Shaomeng Wang, Intel Med, The University of Michigan, 1500 E. Medical Center Dr, Ann Arbor, MI 48109, Fax: 734-764-2532,

A series of graph indices that encode the topological and conformational properties of the organic compounds have been developed based upon the 2-dimensional and 3-dimensional chemical structure information. It was found that these numeric indices capture the conformational entropy changes associated with liquid-solid phase transition of 105 small organic molecules. We further applied these graph indices to estimate the conformational entropy change of the binding between small-molecule ligands and proteins. Further application of these graph indices in the development of empirical scoring functions has been also explored. Our results indicate that these graph indices can be used to provide a good estimate of the conformational entropy loss for both small-molecule ligands and for side chains of those amino acid residues around the ligand binding sites in proteins.

COMP 145 [774872]:  Evaluation of semi-empirical methods for protein minimization and decoy discrimination
Anrdrew M. Wollacott, Department of Chemistry, The Pennsylvania State University, 152 Davey Laboratory, University Park, PA 16802,, and Kenneth M. Merz Jr., Department of Chemistry, Pennsylvania State University

As computational power increases, it becomes increasingly feasible to apply higher-level quantum mechanical methods to protein systems. We have investigated the ability of semi-empirical methods to be used as effective scoring potentials for biological molecules. Using the linear-scaling program DivCon, we have carried out quantum mechanical calculations at the AM1, PM3, and PDDG-PM3 level on large sets of protein decoys. Being able to correctly discriminate native structures from a set of native-like folds is important in the field of ab initio folding, and using decoys provides an effective means of testing scoring functions. In addition, we have performed minimizations on a large set of small proteins. By analyzing the resulting minimized structures, we have identified areas in which semi-empirical methods improve or struggle in describing protein structure.

COMP 146 [758753]:  Human intestinal absorption (HIA) model using simple molecular descriptors
Michelle D'Souza, Bio-Rad Laboratories, 3316 Spring Garden Street, Philadelphia, PA 19104, michelle_d', and Gregory M. Banik, Informatics Division, Sadtler Software & Databases, Bio-Rad Laboratories

Many compounds fail to become drugs due to an undesirable oral absorption rate. As a result, a high Human Intestinal Absorption (HIA) is an important pharmaceutical candidate optimization and selection goal. The expense of drug R&D makes in silico HIA evaluation a desirable alternative. Most of the in silico models are built upon complex molecular descriptor generation and assembling, which has created difficulties for bench scientists to interpret the information and improve their synthesis processes accordingly. This paper describes an in silico HIA model using simple and obvious molecular descriptors and demonstrates how this approach works. This model predicts the percent dose of orally administered drug that reaches the hepatic portal vein. The statistical analysis includes error binning, scatter plotting, mean average error, and root mean square error.

COMP 147 [768234]:  Fuzzy clustering as a means of classifying conformations of a flexible dopamine reuptake inhibitor
Milind Misra1, Amit Banerjee2, Rajesh N. Davé2, 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 Mechanical Engineering, New Jersey Institute of Technology

A fuzzy clustering method was used to classify over 700 conformations of an analogue of GBR 12909 in order to select putative bioactive representatives as input to CoMFA studies. Due to the large number of conformations of the flexible GBR analogue, a novel feature selection process based on the structural properties of the analogue was used to reduce the associated feature space. A composite feature vector was developed and the data set was clustered using two relational clustering techniques; the classical Non-Euclidean Relational Fuzzy c-means (NERFCM) and the more recent fuzzy relational data clustering (FRC). Preliminary clustering on one side of the molecule verified the presence of natural groups on that side determined by rotational symmetry around carbon-carbon bonds. Several cluster validity measures were applied and were shown to provide reliable information about the validity of the partitions produced by the clustering techniques.

COMP 148 [774382]:  Homology modeling studies of Yersinia Kinase YpkA: Implications for structure-based drug design
Xin Hu, Gerd Prehna, and C. Erec Stebbins, Structural Microbiology, The Rockefeller University, 1230 York Ave, New York, NY 10021,

Pathogenic bacteria Yersinia spp are causative agents causing diseases ranging from gastrointestinal syndromes to Bubonic Plague. The development of novel treatments of these bacterial infections has gained high priority recently due to the emergence of antibiotic resistance and the threat of the use of these pathogens in biological attack. YpkA is an essential virulence factor of Yersinia that belong to the family of serine/threonine kinase. A three-dimensional structural model of Yersinia kinase YpkA was constructed using computer-aided homology modeling techniques. An insight into the characteristics of ATP-binding site of Yersinia YpkA provides a structural framework to guide for structure-base drug design. Aimed on the searching for potent and specific inhibitors of YpkA, we performed database screening based on the homology model. Several promising inhibitors of YpkA were selected and their inhibitions on YpkA activity as anti-plague agents were discussed.

COMP 149 [752396]:  Ligand-based design of pyridinone derivatives with potential activity against mutant strains of HIV-1 reverse transcriptase
José Luis Medina-Franco1, Sergio Rodríguez-Morales1, Alicia Hernandez1, Cecilia Jurez-Gordiano1, Jesús Jimenez-Barbero2, and Rafael Castillo1. (1) Department of Pharmacy, Universidad Nacional Autonoma de México, Avenida Universidad 3000, Mexico City 04510, Mexico, Fax: +52-5622-5329,, (2) Centro de Investigaciones Biológicas, CSIC

Potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) of the pyridinone derivative type were docked with AutoDock into the NNRTI binding pocket of HIV-1 reverse transcriptase (RT). Nine crystal structures were used to consider the binding site flexibility. Pyridinone derivatives are predicted to adopt the same binding mode that several crystal inhibitors. The docking results are in agreement with the experimental mutational data and the structure-activity relationship studies of pyridinone derivatives. Based on the predicted docking positions of pyridinones and the observed crystal conformations of MKC-442 and efavirenz, we rationalized at the molecular level the activity of recent reported hybrid pyridinone molecules with anti-HIV activity. Comparison of the docked position of pyridinone analogues with the crystal conformations of so-called second generation inhibitors led to the design of novel pyridinone derivatives with potential activity against mutant strains of RT. Further docking calculations of the novel molecules supported the design.

COMP 150 [774628]:  MD/NMR characterization of internal motions of peptide toxins
David C. Chatfield, Cassian D'Cunha, Ashish Gairola, and Alberto Augsten, Department of Chemistry and Biochemistry, Florida International University, University Park, Miami, FL 33199, Fax: 305-348-3772,,

A combination of MD and NMR is used to characterize the internal motions of small peptide toxins, alpha-conotoxin GI (GI) and microcystin-LR (LR). GI contains 13 residues and is conformationally stabilized by two disulfide bonds. LR is a 7-residue cyclic peptide containing non-standard amino acids. Characterizing the motions of small peptides is difficult due to conformational diversity, anisotropic tumbling, and the similarity in time scale for internal motions and overall tumbling. Structural 1H NMR indicates that GI has two predominant conformations in solution. MD reveals the nature of internal motions on the 100-ns time scale and predicts backbone order parameters. Simulations of the two NMR structures reveal differing patterns of mobility. For LR, 15N NMR relaxation experiments and MD simulations are compared to elucidate the peptide’s backbone mobility. This will serve as a baseline for investigations of the mobility of the peptide bound to protein phosphatase.

COMP 151 [765213]:  Computational combinatorial protein design: Sequence search and statistical design
Xi Yang, Department of Chemistry, Univ. of Pennsylvania, philadelphia, PA 19104,, and Jeffery G. Saven, Department of Chemistry, University of Pennsylvania

Given the incomplete understanding of protein stability and the approximate potential functions used to quantify the compatibility between sequence and structure, probabilistic approaches are useful to characterize the variability of sequences that fold to a common structure. A statistical computationally assisted design strategy (SCADS) has been developed to address sequence variability and to guide protein design. The SCADS method has been successfully applied to the design of a monomeric di-iron protein DFsc. Recently, we developed complementary biased Monte Carlo methods with replica exchange (BMCREM), which combine the merits of protein sequence sampling and statistical approaches. We compare these two different methods, since both characterize the sequence space compatible with given structures. The efficiency and effectiveness of these two methods are discussed.

COMP 152 [774330]:  Filling the gap between conventional and “mean-field” molecular dynamics: Implementing the EXACT approximation
Christopher Adam Hixson1, Jermont Chen1, Zunnan Huang2, and Ralph Wheeler3. (1) Department of Chemistry & Biochemistry, University of Oklahoma, 620 Parrington Oval, Room 208, Norman, OK 73019, (2) Department of Chemistry and Biochemistry, University of Oklahoma, (3) Department of Chemistry, University of Oklahoma

Molecular dynamics is a commonly used technique in studying phenomena as important as protein folding and enzyme-inhibitor binding, but its effectiveness may be limited in systems where adequate conformational sampling cannot be guaranteed. Various methods have been proposed to increase the number of sampled conformations, including simulated annealing and “mean-field” methods, which enhance the search for energy minima at the expense of calculating accurate thermodynamic properties. We have conducted a theoretical examination of “mean-field” techniques such as locally enhanced sampling (LES). Based on the insights obtained from this study we developed a new, more general "mean-field" molecular dynamics method called the Ensembles eXtracted from Atomic Coordinate Transformations (EXACT) approximation. The method implements a controlled approximation allowing researchers to scale a simulation from conventional molecular dynamics (for calculating ensemble averages) to "mean-field" molecular dynamics (for conformational searches). The systems tested include noble gas clusters and the hormone, melatonin. The results demonstrate that the EXACT approximation can be used both for accurate estimates of molecular properties and for thorough conformational searches.

COMP 153 [767744]:  Fragmentation analysis of vibrational circular dichroism of polypeptides
Jun Ho Choi and Minhaeng Cho, Department of Chemistry, Korea University, 15 KA ANAM DONG SUNGBUK KU, Seoul 136-701, South Korea, Fax: +82-2-3290-3121,

Amide I vibrational circular dichroic response of various polypeptides was theoretically investigated by using fragmentation analysis method. Molecular dynamic simulations of various polypeptides in aqueous solution were performed and analyzed. A variety of vibrational spectroscopic properties, such as local and normal mode frequencies , solvents effects, vibrational coupling constants, and dipole and rotational strength, were calculated for several representative conformations of alanine polypeptides in liquid water.

COMP 154 [772855]:  Full quantum mechanical ab initio computation of protein-ligand interaction energy and QM map for protein-ligand binding
Aiming Gao and John Z. H. Zhang, Department of Chemistry, New York University, Room 1002 100 Washington Square East, New York, NY 10003,

The full quantum mechanical ab initio energy calculation for the entire protein complex is made possible by using a recently developed MFCC (molecular fractionation with conjugate caps) approach. The method enables us to obtain an "interaction spectrum" that provides detailed quantitative information on protein-ligand binding at the amino acid levels. The detailed information on individual residues-ligand interaction gives a quantitative molecular insight into our understanding of protein-ligand binding and provides guidance to rational design of potential inhibitors of protein targets. Ab initio calculations are performed at Hartree-Forck level with a 3-21G basis set. Comparisons are made of the computed ab initio energies with those from a force field. Results for gleevec/abelson tyrosine kinase are presented.

COMP 155 [769062]:  Important roles of crystallographic water molecules in protein-ligand interaction: A comprehensive analysis of water molecules observed in the X-ray crystal structures of protein-ligand complex
Yipin Lu, Renxiao Wang, Chao yie Yang, and Shaomeng Wang, Departments of Internal Medicine and Medicinal Chemistry, University of Michigan, 1500 E. Medical Center Dr, CCGC/3316, Ann Arbor, MI 48109,

Water molecules play a crucial role in the binding of small-molecule ligands (e.g. drug molecules) to their target proteins. Toward an understanding of the important roles of crystallographic water molecules in protein-ligand interaction, we have performed a comprehensive analysis of water molecules observed in high-resolution X-ray crystal structures of ligands in complex with proteins. We developed an algorithm to classify different types of crystallographic water molecules observed in the crystal structure of protein-ligand complex and identify the water molecules that may be important for the ligand-protein binding by a detailed analysis of more than 500 high resolution crystal structures of protein-ligand complexes available at the protein data bank (PDB). Our studies indicate that crystallographic water molecules should be included in structure-based drug design, molecular docking studies and development of new scoring functions for prediction of the binding affinity of protein-ligand complexes.

COMP 156 [774536]:  In silico screening for the hERG K+ ion channel affinity
Minghu Song1, Jinbo Bi2, and Curt M Breneman1. (1) Department of Chemistry, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, Fax: 518 276-4887,, (2) Department of Mathematics, Rensselaer Polytechnic Institute

It has been recognized that the mechanism by which some drugs cause deadly heart arrhythmias is linked with the blockade of the human ether-a-go-go-related (hERG) ion channel. Therefore, it is prudent to evaluate the potential for a pharmacologically active drug to cause QT prolongation at the early drug discovery stage. In addition to traditional experimental assays, the in silico screening provides an economic and quick alternative to investigate the hERG blocking potency of active molecules. In our study, we present three different statistical models: Kernel Ridge Regression, Support Vector Machines, and Random Forest. These predictive models can be employed as a virtual screening tool for hERG activity prediction. A diverse set of compounds with hERG inhibition data was collected from available published references, from which 2D QSAR descriptors were calculated. Both regression and classification models were constructed to derive quantitative structure-activity relationships using the above three statistical approaches. Once validated, some of these models can be employed as virtual screening tools and selected important descriptors can be used to guide the combinatorial library design.

COMP 157 [771742]:  Investigation of salt bridge strength in the Generalized Born water solvation model
Raphaël Geney and Carlos L. Simmerling, Department of Chemistry, Stony Brook University, State of University of New York, Stony Brook, NY 11794-3400, Fax: 631-632-7942,

One of the greatest challenges in the application of computation techniques to biological systems is the determination of protein and RNA three-dimensional structures. The native structure of proteins is maintained at the edge of thermodynamic stability, the free energy of unfolding being in the range of a few kcal/mol. Due to its computational speed and frictionless nature, the Generalized Born (GB) implicit solvent model has become a popular choice to accelerate molecular dynamics simulations. However, this model lacks structural water detail and has been reported to yield higher fluctuations than explicit solvent simulations. More particularly, we observed that salt bridges were frequently too stable in the GB implicit water model. The energy contribution of a salt bridge itself is the net balance of the favorable Coulombic interaction between opposite charges and the costly desolvation and ordering of the interacting charges. Potential of mean force (PMF) comparisons between AMBER7 GB and TIP3P water confirmed the excessive strength of salt bridges in GB. In order to increase the desolvation penalty and reproduce explicit water PMF profiles, the GB radius of hydrogen atoms bonded to charged nitrogens was decreased. Decreasing those hydrogen GB radii is also consistent with the increased electronegativity of formally charged nitrogen atoms. A new value of 1.1Å significantly extended the stability of our test system. The effect of this modification to other systems was evaluated on the Trp-cage miniprotein construct Tc5B. Our modified GB radii set decreased the native/unfolded free energy gap by 0.5 kcal/mol, thus lowering the simulated melting temperature closer to experimental values.

COMP 158 [775099]:  Investigation of selenium-aromatic ring interaction in proteins
Izabela Hartman, Department of Chemistry and Biochemistry, University of the Sciences in Philadelphia, 600 South Forty-third Street, Philadelphia, PA 19104,, and Randy Zauhar, Department of Chemistry and Biochemistry, University of The Sciences in Philadelphia

In this research the prior study became the investigation of the importance of selenium-aromatic ring interactions in stabilizing molecular complexes and exploring the possibility that the electrostatic environment of these complexes might modulate their interaction energy. A large database of the small molecules with their geometrical analysis was created based on the Cambridge Crystallographic Database using a designed simplified model of selenium aromatic ring interaction. These studies became the template for identification of the preferred geometry of those interactions. Statistical analysis used in this research contains comparison of two hypotheses, to define proper ideal geometry model. The probability of correctness of one of these hypotheses was analyzed by non-parametrical two-sided Smirnov-Kolmogorov analysis and showed the significance of selenium-aromatic interactions.

COMP 159 [770773]:  MD simulation study of NMA-methanol system: Calculations of linear and nonlinear vibrational spectra
Kijeong Kwac and Minhaeng Cho, Department of Chemistry, Korea University, 1, 5Ka, Anam-dong, Sungbuk-ku, Seoul 136-701, South Korea, Fax: +82-2-3290-3121,

Molecular dynamics simulation method is applied to study H-bonding dynamics of an N-methylacetamide (NMA) molecule in methanol solution at several temperatures. We have recently found that the H-bond dynamics between methanol and carbonyl oxygen of the NMA molecule can be viewed as a reversible reaction between two species: NMA with one H-bonding methanol or NMA with two H-bonding methanol. In the present study we investigated the H-bonding dynamics at several different temperatures to study thermodynamics of H-bond association and dissociation and established relationships between H-bond dynamics and linear and nonlinear vibrational spectra.

COMP 160 [766403]:  Method for computing protein binding affinity
Charles F. F. Karney1, Jason E. Ferrara1, and Stephan Brunner2. (1) Biotechnology Systems, Sarnoff Corporation, 201 Washington Rd, Princeton, NJ 08543-5300, Fax: 609-734-2323,, (2) Centre de Recherche en Physique des Plasmas, Ecole Polytechnique Federale de Lausanne

A Monte Carlo method is given to compute the binding affinity of a ligand to a protein. The method involves extending configuration space by a discrete variable indicating whether the ligand is bound to the protein and a special Monte Carlo move which allows transitions between the unbound and bound states. Provided that an accurate protein structure is given, that the protein-ligand binding site is known, and that an accurate chemical force field together with a continuum solvation model is used, this method provides a quantitative estimate of the free energy of binding.

COMP 161 [764085]:  Minimizing Lennard-Jones-dipole-dipole clusters: Improvements on the basin hopping strategy for parameter space searches
Emanuele Curotto, Chemistry & Physics, Arcadia University, 450 S. Easton Rd, Glenside, PA 19038, Fax: 215 572 7595,, and Craig Oppenheimer, Chemistry, Arcadia University

The morphology of the uniform Lennard - Jones - dipole - dipole cluster with 13 centers is investigated over a relatively wide range of values of the dipole moment (0 - 1.27 D). We introduce and compare several necessary modifications of the basin - hopping algorithm for global optimization to improve its efficiency. We develop an algorithm for zero temperature Brownian dynamics in curved spaces mapped by stereographic projections, and a graph theoretical approach necessary for the elimination of dissociated states in Monte Carlo simulations at large values of the dipole moment.

COMP 162 [774650]:  Molecular dynamics simulations of the Glutamate Receptor GluR2 tetramer structure
Kirill Speranskiy and Maria Kurnikova, Department of Chemistry, Carnegie Mellon University, 4400 Fifth Ave., Pittsburgh, PA 15213

Ligand-gated Glutamate receptor (GluR) ion channels mediate synaptic signals in nervous system. The transmembrane part of the receptor changes its confirmation upon binding of the glutamate to the ligand binding domains, the channel opens and ions can be passed accross the membrane. We analyzed the interactions between the GluR2 ligand binding domains. Molecular Dynamics simulations were used to model a spatial organization of the four subunits. The tetrameric structures in open and ligand-bound states were prepared. Our analysis shows the rearrangement of intersubunit contact surfaces. In addition we used Replica Exchange algorithm to predict the geometrical configuration of the peptides connecting the transmembrane and the ligand binding domains of the receptor protein. The simulation shows the local conformational rearrangement of the ligand binding domain when connecting peptides are present.

COMP 163 [770082]:  Mutational studies of the Trp-cage mini-protein
Melinda M. Layten, Molecular and Cellular Biology Program, Stony Brook University, Life Sciences Building, Stony Brook, NY 11794,, Bentley A. Strockbine, Department of Pharmacology, Stony Brook University, Niels H. Andersen, Department of Chemistry, University of Washington, and Carlos L. Simmerling, Department of Chemistry, Stony Brook University

Earlier work in the Andersen lab created Trp-cage, a stably folding 20 residue mini protein with a well defined tertiary structure. The name arises from the prominent feature of this protein, the stacking of a tryptophan residue between 2 prolines. This cage is further stabilized by an alpha helix running from residues 2-9, a polyproline II helix from residues 17-19, a salt bridge between the Asp 9 and Arg 16, and a hydrogen bond between the Trp 6 side chain and the Arg 16 backbone. This poster will present results of our continued work using Trp-cage mutants to study folding variations produced by various point mutations. By examining stability and structural variation resulting from these mutations, factors that stabilize the Trp-cage can be elucidated and future refinements predicted.

COMP 164 [775108]:  New scoring functions for discovery of lead peptides inhibitors for thrombin
Cristina Clement and Manfred Philipp, Chemistry Department, Lehman College, City University of New York, 250 Bedford Park BLVD West, Bronx, New York City, NY 10468,

New scoring functions are proposed for quantitative analysis of peptide inhibitors interaction with target proteins from serine-protease family. A structure-based design of a library of tetrapeptides containing the sequence space dPhe/X-Pro-dArg-P1’ was employed to dicover potential inhibitors for thrombin (X= analogs of Phe, like trans/cis-cinnamic and dihydrocinnamic acids, (L)/(D)-Tic [1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid], (L)/(D)-Thi [Thienylala] and D-Naphtylalanine (DNal). The peptides were docked into active site of thrombin by taking the X-ray coordinates of thrombin template 1ABJ.pdb. The software “SCULPT” provided by MDL was used in all docking experiments and built-in molecular mechanics force-field was used to assess the free energy of interaction between the peptides and the thrombin template. Since it is already known that the salt bridge between Asp 189 (from the specificity pocket in the active site of thrombin) and the Arg in the P1 position of the inhibitors contributes to a big fraction of the energy of interaction between thrombin and different inhibitors, we hypothesized that the distances between (D/L) Arg (at P1 position) in the peptides and the Asp 189 in thrombin might be important in predicting the fitness of the peptide ligand into the active site of thrombin. Thus a new scoring function criteria for discovery of lead compounds was generated. Another scoring function was developed based on the analysis of the structural details of the docked peptides with respect to the % favorable contacts and normalized complementarity between the ligand (peptide inhibitor) and thrombin active site within 5 angstrom distance from ligand. The % favorable contacts and normalized complementarity were analyzed using the algorithm developed by Sobolev V., Wade R.C., Vriend G. and Edelman M (1996)).

COMP 165 [749960]:  Non-Hamiltonian hybrid Monte Carlo algorithms for biophysical systems
Maria Eleftheriou, Computational Biology Center, IBM Research, PO BOX 218, Yorktown Heights, NY 10598,, and Glenn Martyna, Physical Science Division, IBM Research

Hybrid Monte Carlo methods can be employed to drive complex biophysical systems to sample their conformational equilibrium on large scale parallel machines such as IBM's BlueGene/L. These methods are under utilized and little work has been done to access and improve their performance. In this poster, a novel non-Hamiltonian Hybrid Monte Carlo formalism is presented and applied to both model and realistic systems. Of particular interest are a novel set of equations motions employed in the procedure that allow very long time steps to be taken, driving sampling very efficiently without decreasing the Monte Carlo acceptance rate.

COMP 166 [764020]:  Novel conformational searching technique for low degree polymers
Ari B. Silver and Karl Sohlberg, Department of Chemistry, Drexel University, 3141 Chestnut St., Philadelphia, PA 19104,

Determination of the low energy conformations of a large molecule is a challenging computational task. The most obvious way to identify these conformers is to perform an exhaustive conformational search (testing all possible combinations of dihedral angles, each of which is sampled uniformly). We are interested in polymeric materials for molecular electronic device applications. The exhaustive searching scheme rapidly becomes computationally infeasible as the degree of polymerization increases. We therefore propose a novel conformational searching scheme for polymeric systems based on mimicking the mechanism of synthesis. The novel scheme scales much less radically with increasing degree of polymerization. Application to low molecular weight polymers of 3-phenyl-1-ureidonitrile (PUN) shows the novel method to increase in validity as the number of degrees of freedom increases.

COMP 167 [774837]:  Prediction of ligand binding modes and binding affinities of SAH/MTA nucleosidase inhibitors
Jason K. Perry, Schrodinger, 1500 SW First Ave, Suite 1180, Portland, OR 97201, Fax: 503-299-4532,, and Victoria A. Feher, Quorex Pharmaceuticals

Recently Quorex has developed several classes of potential broad-spectrum antimicrobial agents targeting S-adenosyl homocysteine/methylthioadenosine (SAH/MTA) nucleosidase, the product of the highly conserved pfs gene. In this work, we present the results of several theoretical studies employing docking, induced fit, and linear response methods to predict binding modes and binding affinities of both indazole and purine derived inhibitors. X-ray crystal structures reveal a great degree of flexibility among the active site residues, however when an appropriate structure is used for docking, accurate ligand binding modes are systematically reproduced. Similarly, among distinct chemotypes, the linear response method is able to predict binding affinities with a correlation coefficient of 0.81 for the indazoles and 0.83 for the purines.

COMP 168 [774998]:  Pyrolysis of styrene
Jonathan Rienstra-Kiracofe, Trang Pham, and Ming Chang Lin, Department of Chemistry, Emory University, Atlanta, GA 30322,

The pyrolysis of styrene to benzene and acetylene was investigated using quantum chemical methods, including B3LYP/6-31++G** and G2M(CC6). The pyrolysis of styrene may proceed by three different mechanisms: concerted decomposition to benzene and vinylidene, which has an Ea = 93.86 kcal/mol or Ea = 93.85, depending on two different orbital interactions with the transferring hydrogen; concerted decomposition to benzene and acetylene; and decomposition via the intermediate [4.1.0]-7-methylene cycloheptadiene. An intermediate similar to [4.1.0]-7-methylene cycloheptadiene has been found, suggesting that the pathway via the [4.1.0]-7-methylene cycloheptadiene may be a two-step reaction. Comparisons to previous experimental investigations are also presented.

COMP 169 [769759]:  QSAR and molecular modeling studies of small molecule inhibitors of Plasminogen Activator Inhibitor-1
Kristi Yi Fan1, Hassan Elokdah1, David L. Crandall2, Ann Aulabaugh1, and Alan H. Katz1. (1) Chemical and Screening Sciences, Wyeth Research, CN8000, Princeton, NJ 08543, Fax: 732-274-4292,, (2) Cardiovascular and Metabolic Diseases Research, Wyeth Research

Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of the serine proteases, tPA and uPA, and it is a major regulatory component of the plasminogen-plasmin system. Elevated plasma PAI-1 level is associated with decreased fibronolysis and increased risk of thrombosis and hyper-coagulation in a number of acute and chronic disorders. PAI-1 knock out mice are viable and protected from the development of atherosclerosis. Humans lacking the PAI-1 gene lead normal lives. These data suggest that modulation of PAI-1 activity offers a beneficial therapeutic for intervention in these diseases originating from fibrinolytic disorders. We present a unique approach to QSAR studies based on a data set of 90 in-house compounds. The IC50s are obtained from a kinetic assay in which the concentration of free PAI-1 is determined by monitoring the activity of tPA. A number of molecular descriptors were found to correlate with activity, and a corresponding pharmacophore model was developed using CATALYST.

COMP 170 [770795]:  Quantum mechanical and docking studies of acetylcholinesterase inhibitors of the N-arylmaleimide type
José Luis Medina-Franco1, Reyes Trejo Lino Joel2, Sergio Rodríguez-Morales1, Rafael Castillo1, Patricia Melchor-Macias3, and Jose Trujillo-Ferrara3.
(1) Department of Pharmacy, Universidad Nacional Autonoma de Mexico, Avenida Universidad 3000, Mexico City 04510, Mexico, Fax: +525-5622-5329,, (2) Department of Organic Chemistry, Universidad Nacional Autonoma de Mexico, (3) Seccion de Graduados y Departamento de Bioquimica, Escuela Superior de Medicina del Instituto Politecnico Nacional

The structural and electronic properties of some meta- and para-substituted N-arylmaleimides were studied using the Hartree–Fock and density functional theory (B3LYP) procedures and the 6-31G** basis set. The net atomic charges, frontier molecular orbitals, and molecular electrostatic potentials explain the substituent effect on the biological activity as inhibitors of bovine acetylcholinesterase in vitro of these compounds. Automated flexible docking experiments were conducted into the binding pocket of acetylcholinesterase inhibitors. The geometries of the N-arylmaleimides optimized at the B3LYP/6-31G** level were used as starting coordinates for the docking experiments. A good agreement was obtained between the observed activities and the calculated free energies of binding. A binding mode of the N-arylmaleimides into the pocket of the acetylcholinesterase inhibitors is proposed.

COMP 171 [771763]:  3D-QSAR comparative molecular field analysis on opioid receptor antagonists: Pooling data from different studies
Youyi Peng1, Susan M. Keenan2, Qiang Zhang2, Vladyslav Kholodovych2, and William J. Welsh2. (1) Department of Pharmacology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 661 Hoes Lane, Piscataway, NJ 08854, Fax: 732-235-3475,, (2) Department of Pharmacology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey

Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed using comparative molecular field analysis (CoMFA) on a series of opioid receptor antagonists. In order to obtain significant and useful CoMFA models, a large data set of naltrindole (NTI) analogs was created by pooling ligand information from independent studies. A process of "leave-one data set-out", similar to the traditional "leave-one-out" cross validation procedure employed in partial least squares (PLS) analysis, was utilized to study the feasibility of pooling data from different sources. These studies indicate that our approach is both practical and useful. Statistically significant CoMFA models were subsequently developed from the pooled data set for d,m and k antagonists. All models show excellent internal predictability and consistency with q2 =0.69/r2 =0.91 (d), q2 =0.67/r2 =0.92 (m) and q2 =0.60/r2 =0.96 (k). By comparing the steric and electrostatic contour maps for the three opioid receptors, common patterns were found in the "message" location of all ligands, and differences were observed in the "address" moiety. Furthermore, detailed structure-activity relationships (SARs) were explored for the d CoMFA model as our primary goal is to design novel d selective ligands. Together, our SAR observations shed new light on the steric and electrostatic requirements for ligand binding to the different opioid receptor subtypes and can be used to guide the rational design of novel opioid receptor active molecules.

COMP 172 [773244]:  Ab initio predictions of the heats of formation of nitroprismanes
Tracy P. Hamilton and Olaronke Olubajo, Department of Chemistry, University of Alabama at Birmingham, 901 South 14th Street, Birmingham, AL 35294-1240, Fax: 205-934-8955,

The enthalpies of formation for prismane and its nitro derivatives have been calculated using the B3LYP/6-31G* level of theory. Isodesmic reactions were used to calculate the heat of formation for the nitrated compounds. The heats of formation are predicted to be 135.7, 128.2, 125.4, 131.1, 143.2, 157.1 and 173.1 kcal/mol for zero, one, two, three, four, five and six nitro groups, respectively. The heat of formation being lowest for dinitroprismane is consistent with a similar trend seen in polynitrocubanes by Zhang, Xiao and Gong. The heats of formation reported above are only for the most stable isomers, where the nitro groups are as far apart as possible. Heats of formation computed at higher levels of theory are in progress.

COMP 173 [774580]:  Ab initio studies of the structure and bonding of sulfur and sulfoxonium ylides
Jean M. Standard, Beth A. Copack, Tami K. Johnson, David E. Przybyla, Kenneth J. McDonald, Rebecca J. Steidl, and Brian N. Ida, Department of Chemistry, Illinois State University, Normal, IL 61790-4160,

Sulfur ylides are useful synthetic intermediates that are formed from the interaction of a singlet carbene with a sulfur-containing molecule. In this work, ab initio studies of the structure and bonding of sulfur and sulfoxonium ylides were performed at the MP2 and CCSD(T) levels of theory using a variety of basis sets. Selected systems also were studied using DFT methods. The sulfur ylides investigated were formed between singlet carbenes and hydrogen sulfide or dimethylsulfide. In addition, sulfoxonium ylides formed between singlet carbenes and sulfoxides were also studied to probe the effects of the sulfoxide group on ylide stability and bonding. Double bond character in sulfur ylides frequently has been proposed as a contributor to their stability. To further characterize the ylides, Natural Population Analysis was used to determine the amount of charge transfer from the sulfur-containing species to the carbene, and Natural Bond Orbital analysis was performed to examine the extent of double bond character in the ylide bond.

COMP 174 [774565]:  Ab initio studies on the structure and stability of the anion trimers of hydrogen fluoride, water and ammonia
Xin Bai, Ping Yang, and Richard EDWIN Brown, Department of Chemistry, Michigan Technological University, 1400 Townsend Dr, Houghton, MI 49931,,

The ten electron family of polar molecules, HF, H2O and NH3, have all been reported to form stable clusters that can bind an electron. The trimers of the HF and H2O anion clusters have been observed experimentally while that for NH3 has never been observed. This work involves a comprehensive study of the stability and structure of these anion complexes as well as an analysis of their common features. A Molecular Mechanics conformational search was initially completed to identify the various local minima. This was then followed by ab initio MP2 level optimizations using the aug-cc-pvdz and aug-cc-pvtz basis sets augmented with diffuse functions. The analysis of the electron binding energies, the free energy of formation and the various stable geometric structures will be reported along with energy corrections using the single point CCSD(T) method. Comparisons with the available experimental data will be provided.

COMP 175 [774569]:  Accurate calculation of aqueous host-guest binding affinities
Wei Chen1, Chia en Chang2, and Michael K. Gilson1. (1) Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, MD 20850, Fax: 301-738-6255, (2) Department of Chemistry, University of Maryland

We computed the binding affinities of fifteen complexes of cyclodextrins with 5 compounds, including 3 anti-inflamatory drugs. The calculated free energies agree with experiment to within 0.8 kcal/mol and provide insights into the mechanisms of binding. The methodology thus appears to be suitable for use in designing of new artificial receptors.

The algorithm uses well-developed theory to provide the free energy of binding. Low energy conformations of the free and bound species are found with the TORK algorithm, which is based upon normal mode analysis. A novel symmetry detection algorithm is used to remove symmetrically redundant conformations. The potential energy of each conformation is evaluated with the CHARMM22 force field, and the solvation energy is estimated with a fast generalized Born model, corrected toward detailed finite-difference Poisson-Boltzmann/Surface area results. The free energy of each energy well is computed by configuration integration with the Harmonic Approximation/Mode Scanning technique.

COMP 176 [772514]:  Analysis of protein-oligosaccharide docking interactions using principal component analysis
Jennifer Leiss1, Pranav Dalal2, and Jeffry D. Madura2. (1) Department of Chemistry, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282,, (2) Department of Chemistry and Biochemistry, Center for Computational Sciences, Duquesne University

Protein-oligosaccharide complexes play a fundamental role in cell signaling and regulation processes. These proteins have been shown to be a signaling factor of cell survival during tissue remodeling. A molecular based understanding of protein-sugar interactions is important so that malignant neoplasm’s that use this signaling mechanism can be eliminated. Docking studies have been performed on the protein-sugar complex of inactive GP39 with N,N’-acetylchitobiose as a model system to investigate the molecular basis of the binding interactions. Our objective is to gain better understanding of the binding interactions of the protein-ligand complexes by developing a novel metric to analyze the docking results. Using structural and energetic properties from the docking studies of GP39, principle component analysis was utilized to highlight the key features that contribute to binding in the protein-sugar complex. Components that have been identified as being important in the GP39 system are hydrogen bonding, inter-atomic distances, and energy values.

COMP 177 [773139]:  Characterization of unbound conformations of gp120 core domain
Yongping Pan, Laboratory of Experimental and Computational Biology, National Cancer Institute, Building 469 Room 147, Fort Detrick, Frederick, MD 21702,, Buyong Ma, Laboratory of Experimental and Computational Biology, Basic Research Program, SAIC, NCI-FCRDC, and Ruth Nussinov, Basic Research Program - Macromolecular Structure, SAIC Frederick, Inc. NCI

Knowledge of the detailed conformational states of gp120 is crucial to intervention of HIV-1 infection, yet the unbound form is resistant to structural characterization, due to its flexibility. We performed molecular dynamics simulations on gp120 core domain for both the wild type and a mutant, S375W that are of different phenotypes. While the mutant retained a CD4 bound-like conformation, the wild type drifted to a different conformational state. The bridging sheet in wild type was very mobile and partially unfolded, and the organization among the inner and outer domains was more open than in bound form. These differences were resulted from the change in the hydrophobic core, which further explains the different thermodynamic properties between the wild type and the mutant. Taken together, our results suggest that the free form shares many of the bound structural features and simulated model appears to be a reasonable representation of the free gp120.

COMP 178 [771293]:  Clustering analysis of flexible GBR 12909 dialkyl piperazine and piperidine analogs
Kathleen M. Gilbert1, Dorota Matecka2, Thomas Prisinzano2, Kenner C. Rice2, 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) Laboratory of Medicinal Chemistry, NIDDK, DHHS, National Institutes of Health

Conformational analysis of large drug-like molecules such as the dopamine reuptake inhibitor GBR 12909 is complicated by their flexibility. Representative structures of GBR analogs were identified using hierarchical clustering for input to CoMFA. More than 700 conformers each produced by random search conformational analysis of piperazine and piperidine GBR analogs were studied. Distance matrices were created using different combinations of heavy atoms and torsional angles, as well as different superpositions. The most promising results were further analyzed to identify major clusters. Differences in minimum separation ratio were small. Results were therefore compared using distance maps and actual cluster count versus effective number of clusters. Major clusters for the piperazine and piperidine analogs were compared using representative structures. Representative structures were identified for each GBR analog, differing by shape or orientation. The piperazine and piperidine analog representative structures were compared using intermolecular atomic root mean square deviations.

COMP 179 [764161]:  Collection of binding affinities for protein-ligand complexes with known 3-D structures: The PDBbind database
Renxiao Wang, Xueliang Fang, Yipin Lu, Chao yie Yang, and Shaomeng Wang, Department of Internal Medicine, University of Michigan Medical School, 1150 W Medical Center Dr, Ann Arbor, MI 48109,

We have screened the entire Protein Data Bank (release #107, Jan 2004) to identify the complexes formed between protein molecules and small organic molecules. Out of a total of 23,790 experimental structures, 5,891 were identified as such complexes. A systematic examination of the primary references of these PDB entries (>4,200 published papers) led to a collection of binding affinity data (Kd, Ki, and IC50) for a total of nearly 1,800 complexes. The outcomes of this project have been organized into a web-accessible database called PDBbind at With the tools provided on this web site, the users can search the contents of this database conveniently using text, numerical, or structure-based queries. This database may serve as a valuable information resource for many docking/scoring studies.

COMP 180 [766806]:  Component-based integration of chemistry and optimization software
Joseph P. Kenny1, Steven J. Benson2, Yuri Alexeev3, Jason Sarich2, Curtis L. Janssen1, Lois Curfman McInnes2, Manojkumar Krishnan4, Jarek Nieplocha4, Elizabeth R. Jurrus4, Carl A. Fahlstrom3, Theresa L. Windus3, and David E. Bernholdt5. (1) High Performance Computing and Networking Department, Sandia National Laboratories, MS 9915, PO Box 969, Livermore, CA 94551-0969, Fax: 925-294-2776,,, (2) Mathematics and Computer Science Division, Argonne National Laboratory, (3) Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, 902 Battelle Boulevard, P.O. Box 999, MSIN: K8-91, Richland, WA 99352,, (4) Computational Science and Mathematics, Pacific Northwest National Laboratory, (5) Oak Ridge National Laboratory

Through the efforts of the Common Component Architecture Forum, component-based approaches to managing software complexity are being introduced to the high-performance computing community. The first milestone in the creation of a component toolkit for quantum chemistry, development of a component architecture for molecular structure optimization, has been achieved by integrating chemistry components based on the NWChem and Massively Parallel Quantum Chemistry (MPQC) packages with mathematics components based on the Toolkit for Advanced Optimization (TAO), Portable Extensible Toolkit for Scientific Computation, and Global Arrays packages. By offering a uniform interface to some of their functionality, NWChem and MPQC can be used interchangeably within the component framework. Similarly, different optimization solvers can be tested and benchmarked. A review of initial numerical results obtained using the optimization solver in the TAO package demonstrates good performance for the component software and highlights the potential areas for collaboration enabled by this platform.

COMP 181 [775069]:  Computational approach to find selective Cox-2 inhibitors
Mukesh Kumar and Randy J Zauhar, Department of Chemistry, University of the sciences in Philadelphia, 600 S, 43 St, Philadelphia, PA 19104,

The important step in the production of prostenoids is the metabolism of arachidonic acid to PGH2, which is catalyzed by cyclooxygenase(COX). The traditional COX inhibitors inhibit the cyclooxygenase(COX) and therefore inhibit prostaglandin production. The traditional COX inhibitors have been shown to be non-selective and are responsible for the various side effects like gastric ulcers in particular. The development of COX-2 inhibitors is therefore a natural focus for structure-based drug discovery. COX-1 and COX-2 are 60% structurally similar. Shape Signatures, a computational method can be applied to screen compound databases for shape and electrostatic similarity to known actives, and to suggest lead compounds for further structure-based design. The poster shows results of Shape Signature searches against the NCI database using known selective Cox-2 inhibitors as queries, along with the results of docking calculations carried out with the top ranking hit compounds.

COMP 182 [773223]:  Intramolecular proton migration in fully deprotonated myo-inositol 2-monophosphate and the formation of four-center hydrogen bonds
Ping Yang1, Xin Bai1, and Richard E. Brown2. (1) Department of Chemistry, Michigan Technological University, 1400 Townsend Dr,, (2) Department of Chemistry, Michigan Technological Unversity, 1400 Townsend Drive, Fax: 906-487-2061,

Proton migration via a hydrogen bond has been recognized as a fundamental mechanism through which many biological functions are carried out. An intramolecular hydrogen-bonding network plays a leading role in the determination of the conformation of myo-inositol 2-monophosphate (Ins(2)P1) and its anions. The intramolecular proton migration of the vicinal hydroxyl hydrogen in fully deprotonated Ins(2)P1 has been investigated by using the HF/6-31+G(d) and the density functional B3LYP/6-31+G(d) levels of theory. The hydrogen on the vicinal hydroxyl group can migrate to the phosphate group through a short strong hydrogen bond to form multiple hydrogen bonds (O−H…O-) with the oxygen atom which has lost the proton. These three hydrogen bonds have H…O- distances ranging from 1.73º to 1.84 º. These hydrogen bonds stabilized the system energy by 6.02 Kcal/mol in gas phase and 3.09Kcal/mole in aqueous phase. The solvation effect was investigated using the polarized continuum model (PCM). The effect of both the solvation and the orientation of the phosphate group, whether axial or equatorial, will be reported.

COMP 183 [769086]:  Quantum chemical approach to understand the contribution of ligand functional groups to estrogen receptor-a/b selectivity
Ray J Unwalla and Eric S Manas, Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426,

The design of Estrogen Receptor-b(ER-b) selective ligands relative to ER-a has proven to be quite challenging due to the similarity of the ligand binding domains, with only two amino acid changes occurring within the binding cavity i.e (ERbMet336 ® ERa Leu384 and ERbIle373 ® ERaMet421). In our efforts to identify ERb selective ligands, we found that certain functional groups were successful at significantly enhancing ERb selectivity when incorporated into our scaffolds. This led us to examine the fundamental chemical nature of these functional groups, which appear to be capable of making a differential interaction with sulfur containing versus aliphatic residue side chains. Using ab inito methods (LMP2/aug-cc-pVTZ), potential energy curves were calculated between various functional groups interacting with these side chains. We will describe in detail the results of these calculations. This method can potentially be also applied to evaluate chemical groups for selectivity between other closely related isoforms of nuclear receptors such as RXR, RAR etc.

COMP 184 [774223]:  Refinement of ligand structure from a comparison of experimental and calculated chemical shift perturbations
Bing Wang, Kaushik Raha, and Kenneth M. Merz Jr, Department of Chemistry, The Pennsylvania State University, 152 Davey Laboratory, University Park, PA 16802,

Recently, we havedeveloped a fast approach to calculate NMR chemical shifts using the divide and conquer (D&C) method at the semiempirical level. To demonstrate the utility of this approach for characterizing protein-ligand interactions, we used the deviation of calculated chemical shift perturbations from experiment to determine the orientation of a ligand (GPI-1046) in the binding pocket of the FK506 binding protein (FKBP12). Moreover, we were able to select the native state of the ligand from a collection of decoy poses. A key hydrogen bond between O1 and HN in Ile56 was also identified. Our results suggest that ligand-induced chemical shift perturbations can be used to refine the protein/ligand structures.

COMP 185 [748490]:  Selectivity between alkali-metal ions to 12-Crown-4 in MeOH: A Monte Carlo simulations study
Hag Sung Kim, Department of Environmental Fine Chemistry, Ulsan College, San 29 Muger-dong Nam-gu, Ulsan 680-749, South Korea, Fax: 82-52-279-3183,

We have studied the differences in stability constant (¥Älog Ks) as well as the relative free energies of binding (selectivity) of cations to 12-crown-4 i.e. the selectivity of 12-crown-4 to cations using a Monte Carlo simulation of SPT in CH3OH. The selectivity of 12-crown-4 to cations followed the sequence as Cs+ > K+ > Na+ > Rb+ > Li+ i.e., the selectivity of 12-crown-4 to Cs+ is more favorable than to other cations in CH3OH. We found 12-crown-4/cation complexes with the 12-crown-4 of almost Cs symmetry that have been never found in any crystal or ab initio structure of the cation complexes of 12-crown-4. We also found that 12-crown-4/cation complexes with the 12-crown-4 of almost Cs symmetry are more stable in CH3OH solutions than 12-crown-4 /cation complexes with the 12-crown-4 of almost C4 symmetry. ACKNOWLEDGMENT: This work was supported by Korea Research Foundation Grant (KRF-203-015-C00259).

COMP 186 [775032]:  Shape signatures and receptor based drug design
Lifeng Tian and Randy J. Zauhar, Department of Chemistry & Biochemistry, University of the Sciences in Philadelphia, 600 S 43rd street, Philadelphia, PA 19018, Fax: 215 5967539,

A unifying principle of rational drug design is the use of either shape similarity or complementarity to identify compounds expected to be active against a given target. We introduce a new technique, which we call Shape Signatures, for describing the shape of receptor site. The receptor site is enclosed in its molecular surface. A ray is initiated at a randomly chosen point on this surface, and is allowed to propagate by the rules of optical reflection. We retain the positions of the reflection points, as well as the ray tracing segments. Given a completed ray tracing, we compute probability distributions based on the geometry of the ray. Our “Shape Signatures” are just these distributions, described as histograms. The simplest signature is the distribution of segment lengths observed in the ray tracing. A match between a receptor-based query and a potential ligand indicates that they are complementary in shape.

COMP 187 [770324]:  Simulation studies of helical m-phenylene ethynylene foldamers
One Sun Lee and Jeffery G. Saven, Department of Chemistry, University of Pennsylvania, 231 S. 34 street, Philadelphia, PA 19104,

The folded states of 18-monomer oligo(m-phenylene ethynylene) foldamers solvated in water are examined using NpT molecular dynamics simulation. The turns of the helix are in close contact, but the helical folded state is found to be surprisingly flexible even though it maintains a helical structure throughout the simulation. The structure exhibits large fluctuations in both the radius of the interior cylindrical pore and the effective dihedral angle between monomers. The radius fluctuations are correlated with the number of water molecules within the helical nanopore.

COMP 188 [770135]:  The computational study of the deprotonation of cyclohexene oxide catalyzed by isopinocampheyl based chiral lithium amides
Ying Xiao, Dawoon Jung, Tamara Gund, and Sanjay V. Malhotra, Department of Chemistry and Enviromental Science, New Jersey Institute of Technology, 384 Tiernan Hall, University Heights, Newark, NJ 07102,,

Various chiral lithium amides derived from α-pinene were investigated by Gaussian 98 for the deprotonation of cyclohexene oxide. Eight different possible transition states were optimized and calculated by the ab initio HF/3-21G* and density functional B3LYP/3-21G* calculations. Also, the relative activation energies were calculated. The results of quantum calculations were compared to the experimental data. We found the theoretical calculations to be in agreement with the experimental data. A maximum enantiomeric excess of 95 % for (R)-2-scyclohexen-1-ol was achieved with (-)-N,N-diisopinocampheyl lithium amide. Our theoretical calculations help in understanding the mechanism for the deprotonation reaction.

COMP 189 [768818]:  Theoretical study of the electron density distributions in a dipeptide molecule
Kenneth M. Merz Jr. and Ning Yu, Department of Chemistry, Pennsylvania State University, 152 Davey Lab, University Park, PA 16802, Fax: 814-863-8403,,

In this poster, we utilize the semiempirical and ab initio electronic structure methods to study electron density distributions for organic and biological molecules and compare the findings with experiment. Several sets of structure factors at varying resolutions for a 30-atom dipeptide molecule whose structure was recently determined to a resolution of 0.43 Å at 110 K have been computed using the QM methods and compared to those based on the IAM model. We find that the R values of the QM structure factors at all resolutions are consistently lower than those of the IAM structure factors and the difference broadens as the resolution decreases to 1.0 Å, which is the evidence of a better description of valence density redistribution by the QM approach. Furthermore, the static and dynamical QM deformation maps are compared to the experimental deformation maps, and are shown to capture, at least qualitatively, the main features such as density accumulations in the bonds and lone pairs near oxygen atoms. Therefore QM calculations aided by linear-scaling technologies are promising methods to improve the quality of X-ray structure refinement and charge density studies of macromolecules.

COMP 190 [772935]:  Towards novel therapeutics against HIV infection and drug resistance
Ye Che, National Heart, Lung and Blood Institute, National Institutes of Health, 50 South Dr., MSC 8014, Bethesda, MD 20892, Fax: 301-402-3404,, Garland R. Marshall, Center for Computational Biology and Department of Biochemistry and Molecular Biophysics, Washington University, and Bernard R. Brooks, Laboratory of Biophysical Chemistry, National Heart, Lung and Blood Institute, National Institutes of Health

The HIV/AID pandemic continues to spread around the world at an alarming rate. The success of current therapy is limited by the rapid emergence of drug-resistant viruses, the necessity of sustained adherence to complex regimens, and the potential for toxic effects. There is, therefore, a desperate need to circumvent the drug resistance problem by focusing on novel viral and cellular targets for new compounds capable of suppressing HIV strains that are resistant to the currently available anti-HIV therapies. The development of resistance in the virus due to the appearance of specific mutations is basically inevitable under the pressure of chemical therapeutics; but, the secondary structures, instead of the primary structures, are usually invariable during the evolution. Chemical scaffolds that are capable of mimicking protein secondary structures and incorporating different amino acid side-chains, are suitable as chemical templates for modulating protein-protein interactions that are necessary for HIV infection and replication. Based on this hypothesis, we have developed a series of small molecules mimicking important protein recognition motifs, including cis-amide, α-helix, β-sheet and reverse turns, and we are trying to circumvent the drug resistance problem with a library of small molecules based on common scaffolds, instead of searching for a single or a few "magic bullets" for all different kinds of HIV variants. The development of such molecular library is undergoing for targeting several protein interactions necessary for HIV infection, including viral attachment to host coreceptors, gp41-mediated membrane fusion, subunit interactions in HIV reverse transcriptase, integrase and protease, and the maturation and assembly of HIV capsid protein.

COMP 191 [766704]:  Using similarity and classification methods to determine applicability of QSAR models to query set compounds
Rajarshi Guha and Peter C. Jurs, Department of Chemistry, Pennsylvania State University, 152 Davey Laboratory, University Park, State College, PA 16802,

We discuss methods to determine applicability of a linear QSAR model to a set of query compounds. The strategy consists of first evaluating statistical and molecular similarity measures of the training and query set molecules using non-parametric statistics, atom pairs and fingerprints. The similarity measures were correlated to indicators of model quality (regression residuals and standard errors) using a sphere density technique based on the sphere exclusion algorithm. We also considered a classification technique using random forests and support vector machines to classify residuals as good or bad. Finally we investigated a distribution based method using k-NN distances and angles. The techniques were tested with a small (n=65) and two medium sized datasets (n=179 and n=277). Results indicate that the sphere technique shows a trend between high sphere densities and low standard error. The classification technique is seen to exhibit prediction accuracies ranging from 76% to 83%.

COMP 192 [773204]:  Using walkers to find transition states from reactant and product minima
Hrant P. Hratchian and H. Bernhard Schlegel, Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202,

Locating transition states on potential energy surfaces is one of the most difficult and costly steps in the computational study of a chemical reaction. A novel approach is to head toward the reaction barrier simultaneously from both ends of the pathway (i.e., reactant and product minima). We present a method based on this principle by extending ideas from our recent developments in reaction path following. To find a transition state, two walkers are sent uphill from the starting points until they converge on the quadratic region of the transition state, at which point a standard optimization scheme is used to complete the search. Throughout the process, the two walkers communicate with each other to ensure that they both head toward the same saddle point. Using techniques from our work with reaction path following, we are able to keep to the walkers near the reaction path; in this way, the procedure yields a transition state that lies on a minimum energy path that connects the reactant and product.

COMP 193 [772593]:  "Reverse-docking" as a computational tool for the study of asymmetric organocatalysis
David J. Harriman and Ghislain Deslongchamps, Department of Chemistry, University of New Brunswick, Fredericton, NB E3B 6E2, Canada,

Peptide-based organocatalysts have emerged in the last decade as a viable approach to catalysis and are in line with the concept of “green chemistry”. Flexible peptides developed by Scott Miller (Boston College) have been shown to catalyze a variety of different asymmetric reactions. However, little is known of their exact mechanism of action. We have developed a “reverse-docking” approach in which a flexible receptor is docked around a rigid ligand. This reverse-docking procedure was used to derive a transition-state model for the peptide-catalyzed asymmetric addition of azide to alpha,beta-unsaturated carbonyls reported by Miller. Thus, a flexible peptide organocatalyst was reverse-docked to a rigid transition-state representation of the catalyst-free azidation reaction. Analysis of the highest scoring docking poses revealed a well-defined structural motif for the peptide/transition-state complex that accounts for the observed enantioselectivities. This represents an important step toward the rational in silico design of peptide catalysts and other molecular devices.

COMP 194 [773649]:  Theoretical studies of atmospheric chemistry and developments in coupled-cluster theory
Timothy J. Lee, Computational Chemistry Group, NASA Ames Research Center, MS T27B-1, Moffett Field, CA 94035-1000, Fax: 650-604-1095,

Recent work in our laboaratory on the application of computational quantum chemistry methods to the study of atmospheric chemistry and some recent interesting developments in coupled-cluster theory will be discussed.

COMP 195 [773078]:  Computational studies of molecular frame photoelectron angular distributions
Robert R. Lucchese, Department of Chemistry, Texas A&M University, College Station, TX 77843-3255,

We will examine recent experiments on dissociative photoionization that use coincidence measurements to detect both the photoelectron and the ionic photofragment in order to measure the molecular frame photoelectron angular distributions (MFPAD). We will consider the level of agreement between theory and experiment obtained with current computational methods for valence ionization of NO, O2 and N2O and innervalence ionization of N2O and CO2. Additionally, a discussion will be given of the broad features of the MFPADs and their relationships to the nature of the bound states in the photoionization process and to the photoelectron scattering dynamics.

COMP 196 [762305]:  Modeling molecular interactions in MALDI mass spectrometry
Dennis S. Marynick, Department of Chemistry and Biochemistry, University of Texas at Arlington, Box 19065, Arlington, TX 76019, Fax: 817-272-3808

Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is an important technique for mass analysis of large molecules. In this talk, we explore the possible molecular interactions between a matrix (typically a small functionalized aromatic molecule) and an analyte (typically a protein) that are important in MALDI-MS. Model systems to be discussed include proline/2,5-dihydroxybenzoic acid (25DHB), arginine/25DHB and a number of di- and tripeptides interacting with 25DHB. Of particular interest is the ionization energy lowering of 25DHB upon binding to proline or arginine, which can be over 1.0 eV. The nature of the proton transfer between 25DHB and proline or arginine will also be discussed. Docking studies of 25DHB and other MALDI matrices with whole proteins such as insulin will also be reported.

COMP 197 [747355]:  Two face-to-face benzenes and o,o'-dibenzene: Electronic states and photochemical interconversion
Joern Tonne1, Marc Schottelius1, Jakub Chalupsky2, Zdenek Havlas2, Horst Prinzbach3, and Josef Michl1. (1) Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309-0215,,, (2) Institute of Organic Chemistry and Biochemistry, Academy of Sciences of Czech Republic, (3) Institut für Organische Chemie und Biochemie, Albert-Ludwigs-University Freiburg

We describe the electronic spectroscopy and temperature-dependent photophysical and photochemical behavior of (i) a molecule in which two benzene rings are held face-to-face, and (ii) a molecule produced from it by a photochemical 6+6 cycloaddition, in which the benzene rings have been converted to planar 1,3-cyclohexadienes joined through a cyclobutane ring. An interpretation of the observations is based on MS-CASPT2 calculations.

COMP 198 [770844]:  Theoretical design of ion selective receptors
Kwang S. Kim, Department of Chemistry, Pohang University of Science and Technology, San31, Hyoja Dong, Namgu, Pohang 790784, South Korea, Fax: 82-54-279-8137,

Quantum chemistry has now evolved to the stage of designing new chemicals and materials. Given the fact that ions play important roles as cofactors, substrates, and signaling devices in both biological and chemical systems, there has been a lot of interest to design ion selective receptors. In this talk, we highlight our recent efforts in the design and development of ion selective receptors. In particular, we show how a design strategy based on quantum mechanical calculations enables us to design a wide range of dipodal, tripodal and imidazolium-calix based cation/anion receptors exhibiting excellent affinity of the biologically important ions, K+, NH4+, Acetycholine, F-, Cl-, H2PO4-, CH3COO-, ATP, GDP, etc. Apart from a discussion of the experimental verification of our predicted affinities, we also elaborate on the role of N•••cation/(N-H)•••anion/N(C-H)+•••anion H-bonding, dipole-charge, charge-charge interactions in the ion-selective receptor design. We also discuss the design of amphi-ionophores (receptors capable of binding anions or cations alternatively).

COMP 199 [756304]:  Computational studies of the O-O bond activation and olefin epoxidation catalyzed by Mn-Salen complexes
Keiji Morokuma, Ilja V. Khavrutskii, Robby R. Rahim, and Djamaladdin G. Musaev, Cherry L. Emerson Center for Scientific Computation and Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, GA 30322, Fax: 404-727-7412,

Enantioselective epoxidation catalyzed by chiral transition metal complexes has been attracting a major attention as an efficient pathway for production of enantiomerically pure epoxides. This talk presents density functional computational studies on the O-O bond activation of peracid oxidant and olefin epoxidation catalyzed by (Salen)MnIII. Specifically, the presentation will focus on (1) the acylperoxo complexes of the (Salen)MnIII, as precursors for the subsequent O-O bond activation to form the MnV-oxo species; (2) the effect of the axial ligands (L), push-effect, on the O-O bond breaking of the trans-L acylperoxo complexes; (3) the so-called pull-effect, modeled by protonating the acylperoxo complexes. Finally, (4) the mechanism of epoxidation of unfunctionalized olefins by Mn(Salen) catalyst with organic peracids will be examined in two regimes: with and without axial ligands.

COMP 200 [788729]:  Development of an improved four-site water model for bio-molecular simulations: TIP4P-Ew
Hans W. Horn1, William Swope1, Jed Pitera1, Jeffry D. Madura2, Thomas J. Dick3, Greg L.B. Hura4, and Teresa Head-Gordon5. (1) IBM Almaden Research Center, San Jose, CA 95120,, (2) Department of Chemistry & Biochemistry, Center for Computational Sciences and Duquesne University, (3) Department of Chemistry and Biochemistry, Duquesne University, (4) BioPhysics Group, University of Califonia at Berkeley, (5) Department of Bioengineering, University of California, Berkeley

A re-parameterization of the standard TIP4P water model for use with Ewald techniques is introduced, providing an overall global improvement in water properties relative to several popular non-polarizable and polarizable water potentials. Using high precision simulations, and careful application of standard analytical corrections, we show that the new TIP4P-Ew potential has a density maximum at approximately 1oC, and reproduces experimental bulk-densities and the enthalpy of vaporization, dHvap, from -37.5 to 127 oC at 1 atm with an absolute average error of less than 1%. Structural properties are in very good agreement with X-ray scattering intensities at temperatures between 0 and 77oC and dynamical properties such as self-diffusion coefficient are in excellent agreement with experiment. The parameterization approach used can be easily generalized to rehabilitate any water force field using available experimental data over a range of thermodynamic points.

COMP 201 [771975]:  Studies of brine using TIP4P-Ew and DYNAMO
Peter E Krouskop, Department of Chemistry and Biochemistry, Duquesne University, 308 Mellon Hall, 600 Forbes Ave., Pittsburgh, PA 15282,, and Jeffry D. Madura, Department of Chemistry and Biochemistry, Center for Computational Sciences, Duquesne University

One proposed method of sequestering carbon dioxide (CO2) from the atmosphere is to inject the gas into underground brine aquifers. However, very little is known about brine solutions on a molecular or atomic level so the effect of adding CO2 to the aquifer can not be predicted. The molecular structure of brine has recently been probed through molecular dynamics simulations using water models (e.g. TIP3P, TIP4P, SPC, etc.) that are parameterized using specific cut-offs. These models do not adequately account for the long range interactions we expect to be dominant in the brine solutions. Thus, we have adapted the DYNAMO library to simulate brine using the new water model (TIP4P-Ew) which has been re-parameterized to incorporate long-range electrostatic interactions using the Ewald sums technique. The molecular structure of a brine using the new water model will be presented and compared with previous results.

COMP 202 [768117]:  Molecular level studies of water-mediated interactions between ions and their relevance to biomolecular interactions
Sowmianarayanan Rajamani, Tuhin Ghosh, and Shekhar Garde, Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, Fax: 518-276-4030,

Charge-density dependent ionic hydration and association preferences in aqueous media are central to many biophysical phenomena, including protein stability, salt and additive effects on proteins, and biomolecular interactions in solution. At the fundamental level, these interactions arise from the peculiar structure of water olecules near interacting solutes. We will present calculations of free energies of hydration and interactions between ions of various sizes, shapes and charge densities in water. Specifically, we focus on the ion pairing preferences in solution, which are raditionally represented using the well-known Volcano relationships. Our development of similar ``molecular Volcano plot'' allows us to relate differences in ion hydration free energies to their tendency to associate in solution. For example, oppositely-charged ions with imilar free energies of hydration (e.g., Cs+,I-) favor the formation of long-lived contact pairs, whereas ion pairs with large differences in their free energies of hydration (e.g., Na+,I-) prefer solvent-separated or dissociated configurations in solution. The thermodynamics of ion pair formation as a function of size of the two ions, studied by calculating the enthalpy and entropy contributions to ion-ion association will be presented. In addition, pressure effects on these ion pairing preferences and their relevance to pressure denaturation of proteins will be discussed.

COMP 203 [762232]:  Reaction mechanism, free energy profiles and structural changes along the reaction path of catalysis in the wild type and two active site mutants of medium chain acyl-CoA dehydrogenase
Sudeep Bhattacharyay, Marian T. Stankovich, and Jiali Gao, Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, MN 55455-0431, Fax: (612)626-7541,

Potential of mean force calculations have been performed on the wild type medium chain acyl-CoA dehydrogenase (MCAD) and two of its mutant forms. The catalytic a,b-dehydrogenation of fatty acid acyl-CoAs follow a two step mechanism - a proton abstraction followed by a hydride transfer step. Energy profiles of the two reaction steps indicate that they follow a stepwise mechanism rather than concerted. Simulation of the active site of the T168A mutant of this enzyme shows some loss of the flavin ring interactions, however, this did not translate into the energetics of the reaction steps. The computed over all reaction barrier for this mutant remains unchanged which is quite agreeable to the experimental results. Analysis of the equilibrated active site of the enzyme reveals an arginine residue (R256), conserved in the substrate binding domain of this group of enzyme (R248 for short chain enzyme and R255 for isovaleryl CoA dehydrogenase), to exist in two alternate conformations, only one of which makes the enzyme active. Mutation of this residue to glutamine substantially increases the activation barrier of the hydride transfer reaction. Analyses of structural changes along reaction path reveal a large hydrogen bonding network encompassing the reaction center thioester carbonyl group which is responsible for stabilization of transition state(s) as well as the intermediate formed between the two steps.

COMP 204 [772942]:  Novel "linear" Monte Carlo approach to free energy calculations
Matthew Clark, Igor Shkurko, and Qiang Wang, Scientific Computation, Locus Pharmaceuticals, Four Valley Square, 512 Township Line Road, Blue Bell, PA 19422, Fax: 214 358 2020

Abstract text not available.

COMP 205 [764126]:  A structure and thermodynamic model of the binding of botulinum neurotoxin Type A inhibitors computed by Monte Carlo methods of docking and thermodynamic evaluation
Louis Carlacci, Department of Cell Biology and Biochemistry, USAMRIID/NetwokCS, 1425 Porter St., Fort Detrick, MD 21702, Fax: (301)619-8067,, and Mark Olson, Department of Cell Biology and Biochemistry, USAMRIID

Recently, a series of peptide inhibitors of botulinum neurotoxin (BotNT) Type A were discovered. In binding experiments, derivates of the peptide with the 1-letter amino acid code sequence ACE-CRATKML-NH2 revealed the sequence dependence of the inhibitor constant, Ki. In this study, the computed thermodynamic properties of the complexes and the free peptides were used to obtain the relative binding free energies of a series of peptide inhibitors of BotNT Type A. The structural model revealed the binding sites on the protein (Pi), and on the ligand (Li). The peptides were docked by the Monte Carlo simulated annealing approach. Before the thermodynamic characterization, the free energy landscape was optimized by the use of low temperature simulated annealing and room-temperature random walks. An estimate of the vibrational and configurational entropy of the free peptide was determined by root mean square deviation clustering and the quasi harmonic model. The errors in the relative binding free energies are reported.

COMP 206 [772582]:  Liquid-liquid phase transitions in phosphorus: Insight from simulations
R. O. Jones, I F F, Forschungszentrum Juelich, 52425 Juelich, Germany, Fax: 01149-2461-612850,, and P. Ballone, Department of Physics, University of Messina

The structural properties of elemental phosphorus have been a challenge for many decades, and the many allotropes reflect the variety of possible coordinations for this element. Interest in the phase diagram has been revived by the recent observation of a molecular (P_4) to polymer transition in the liquid phase upon increasing pressure P and/or temperature T. A classical force field (FF) has been developed on the basis of density functional computations of the energy, equilibrium geometry and reactivity of small phosphorus aggregates. The model describes the system in terms of atoms and covalent bonds, where bonds are dynamical variables that break and form as the system evolves. Monte Carlo simulations reproduce the reversible polymerization transition observed, and the model provides a mapping of structural features to a few energy and entropy contributions. It allows us to investigate the origin of the polymerization transition, and its computational efficiency allows us to investigate the polymerization process and related properties. We predict the existence of two polymeric states: one with predominantly cubic symmetry obtained by increasing P at constant T (near 1400 K), the other with mainly tetrahedral coordination obtained at low P by increasing T. We suggest that these phases are separated by a non-metal to metal transition.

COMP 207 [773387]:  Systematic method for identifying reaction coordinates in complex systems
Ao Ma and Aaron R. Dinner, James Franck Institute, University of Chicago, 5640 Ellis Ave., Chicago, IL 60637,

To interpret simulations of a complex system to obtain a physical mechanism for a dynamical process, it is necessary to identify the small number of coordinates that distinguish the transition states from the reactants and products. Here we develop a systematic method for identifying these coordinates that uses a neural network combined with a genetic algorithm to predict the committor values of structures obtained with transition path sampling. The method is successfully applied to isomerization reactions of the alanine dipeptide in vacuum and in aqueous solution.

COMP 208 [774480]:  Directly calculated ligand binding free energies using Folding@Home
Michael R. Shirts1, Guha Jayachandran2, Christopher D. Snow3, and Vijay S. Pande1. (1) Department of Chemistry, Stanford University, Stanford, CA 94305,, (2) Department of Computer Science, Stanford University, (3) Biophysics Program, Stanford University

Current computational methods cannot reliably calculate free energies with chemical accuracy (e.g. within 1 kcal/mol). Are the models not sufficiently accurate or is the sampling not sufficiently thorough? To answer this question, we a combination of improved methods for calculating binding free energies and extensive sampling obtainable using the Folding@Home distributed computing infrastructure. These advances have made it possible to compute the free energies of solvation of large flexible ligands with a precision of 0.1-0.2 kcal/mol. We also use these methods to directly calculate the binding free energy of these ligands to FKBP12 with a precision of approximately 0.5 kcal/mol. The results qualitatively match experimental binding energies (as estimated from inhibition constants), but are still not accurate enough to serve as direct predictors of free energies. This implies that the current generation molecular mechanics models may not be able to match all the biochemical detail of binding interactions.

COMP 209 [773435]:  Validation of a complete polarizable force field for proteins by computing geometric and energetic properties of isolated and solvated systems
George A. Kaminski, Department of Chemistry, Central Michigan University, Mount Pleasant, MI 48859, Fax: 989-774-3883,

A recently developed complete polarizable empirical force field for proteins has been validated by a series of isolated-molecule and solvated calculations on proteins and protein complexes. First, single side-chain conformational decoys have been generated and followed by geometry optimizations. The overall success rates in returning back to the experimentally determined values of chi1 and chi2 side-chain dihedrals were found to be ca. 90% and 75%, respectively. Then a single apolipoprotein A molecule was simulated by geometry optimizations in gas-phase and in solution. Total RMS deviations from the corresponding experimental geometries were 1.65 Å and 1.02 Å, respectively, with the corresponding benchmarking OPLS-AA deviations being 2.06 Å and 1.47 Å. Finally, simulation of a barnase-barstar complex in water has been performed with the polarizable force field and with the standard OPLS-AA. The results will be discussed during the presentation of this work.

COMP 210 [762942]:  Ab initio and empirical model simulation studies of "neat" liquid water and of a solvated peptidic fragment in aqueous solution
Yves A. Mantz1, Bin Chen2, Helene Gerard3, Radu Iftimie4, and Glenn J. Martyna1. (1) Physical Science Division, IBM Research, TJ Watson Research Center, PO Box 218, Yorktown Heights, NY 10598, Fax: 914-945-4506,, (2) Department of Chemistry, Louisiana State University, (3) Laboratoire de Chimie Théorique, Université Pierre et Marie Curie, (4) Department of Chemistry, New York University

The structure of water, and how it is affected by the presence of solute, is of long-standing interest but is generating intense new scrutiny based on recent experimental studies [Phys. Rev. Lett. 90, 075502 (2003), Nature 416, 829 (2002)]. In this presentation, the temperature dependence of the structure predicted by a variety of theoretical methods is compared, including the first Car-Parrinello ab initio MD study. In addition, the cis-trans isomerization of a simple peptidic fragment, N-methylacetamide [CH3-C(O)-N(H)-CH3], is examined via umbrella sampling ab initio and classical MD [YA Mantz et al., J. Am. Chem. Soc. 126, 4080 (2004)]. A new interpretation of the C(O)-N bond restructuring in terms of maximally localized Wannier function centers and ELF isosurfaces is presented. Additionally, a full analysis of the solvation shell including the orientational structure is given, complementing our studies of the "neat" liquid and offering data for comparison to anticipated new experiments.

COMP 211 [788712]:  High performance computing in the Blue Gene project at IBM Research
William Swope, IBM Almaden Research Center, 650 Harry Road, San Jose, CA 95120,

In 1999 IBM announced the Blue Gene project( with plans to begin a research program to develop a large parallel computer system that could be used to perform biomolecular simulations. The goal is to use this capability to study biological processes at a molecular level, and, in particular, to help improve the understanding of the phenomenon of protein folding.

The IBM BlueGene science team has been working with the computational chemistry and biology communities in academia and government to outline meaningful research projects that can make effective use of the Blue Gene resource. There are several thrusts to the scientific effort, including: thermodynamics and kinetics related to the protein folding process, and force field validation and assessment. We are particularly concerned with making as strong a connection as possible with experimental results. This talk will give an update on the program and present some results.

COMP 212 [788708]:  Folding@Home: Can a grid of 100,000 CPUs tackle fundamental barriers in molecular simulation?
Vijay S. Pande, Department of Chemistry, Stanford University, MS 5080, Stanford, CA 94305-5080, Fax: 650-725-0259,

Molecular simulation is greatly restricted by the limitations of modern computer power. Indeed, accurate, atomic-level simulation of the folding of proteins or the accurate calculation of the free energy of drug binding would require hundreds of years on the fastest computers. By coupling novel grid-computing algorithms and over 100,000 CPUs located throughout the world, the Folding@Home project ( has been able to make significant advances in molecular simulation, including the first simulations of protein folding in full atomic detail with quantitative agreement with experiment as well as high precision free energy calculation. Finally, applications of this technology to the study of disease, including Alzheimer's Disease, cancer, and Osteogenesis Imperfecta will be discussed.

COMP 213 [788714]:  Asymptotic improvement in the parallel evaluation of pairwise particle interactions
David E. Shaw, D.E. Shaw Research and Development LLC, 120 W. 45th St., 39th Floor, New York, NY 10036,

Biomolecular simulations often require the pairwise evaluation of interactions between all pairs of particles separated by no more than some distance R, with more distant interactions either ignored or accounted for using some less expensive method. On a massively parallel computer system, the distance limit for pairwise interactions may be exploited to reduce inter-processor communication using methods that partition the space being simulated into a number of regions equal to the number of available processors, with each processor responsible for calculating the forces on all atoms residing within a single region. In the standard approach to such simulations, the time required for inter-processor communication is proportional to R3 (assuming a large number of processors). This talk introduces a novel method whose communication requirements are instead proportional to R2. Moreover, the constants are such that the method should offer substantial performance advantages in many cases of practical significance.

COMP 214 [788764]:  Turbo-charged applications on ClearSpeed's streaming processors
Simon McIntosh-Smith, ClearSpeed Technology Ltd, 3110 Great Western Court, Hunts Ground Road Stoke Gifford, Bristol BS34 8HP, United Kingdom,

Current commodity computing architectures are no longer providing the focus for expected increases in performance for scientific applications such as Structural Biology or Computational Chemistry. Additionally the heat dissipation associated with every increasing clock speeds are compounding the impracticality of large installations. ClearSpeed Technology Inc. provides a very high performance complimentary technology, targeted at scientific applications, designed to occupy unused slots within any compute platform. This adds significant performance benefit without structural changes or risk to any present or planned installations. Using a high performance data parallel streaming processor architecture, the technology is inherently low power, so that tens of processors can occupy the same thermal environment of a single commodity processor. Conventional software compilation development tools and methods provide a familiar environment for development.

COMP 215 [772886]:  Evolution of the Locus "Titan" computing cluster
Keith Milligan, Scientific Computation, Locus Pharmaceuticals, Four Valley Square, 512 Township Line Road, Blue Bell, PA 19422, Fax: 215 358 2020, and Matthew Clark, Scientific Computation, Locus Pharmaceuticals

Assembling a large computing cluster for scientific computations can present many issues, some anticipated, some not. The Locus cluster of 1,000 dual processor nodes has evolved from a special-purpose system to a general purpose computing resource via a series of configuration changes and software changes driven by our experience. Some of the issues discussed will be the Locus experience with electricity requirements, cooling, network bandwidth, various job scheduling software, maintainability and troubleshooting, failure-tolerance of various hardware software components, and design of algorithms to make best use of the system limitations.

COMP 216 [788705]:  High performance computing at Novartis Institutes for Biomedical Research
Dmitri Mikhailov, In Silico Sciences, Novartis Institutes for Biomedical Research, Cambridge, MA 02139,

The evolution of drug discovery technology has produced an increasing amount of experimental data. Understanding this data is further complicated by its complex character and emerging new data types. Most of these challenges call for powerful computational tools and, as result, HPC is becoming an integral part of pharmaceutical research. At Novartis, HPC strategy has been developed over recent years that accounts for scientific application diversity and for need to offer a variety of computing resources. Bio- and cheminformatics, CAMM, computational pharmacology and toxicology and clinical trial simulation, all require combination of computing paradigms: from distributed Linux clusters to large shared memory systems to special hardware accelerators. This presentation explains our HPC strategy in the acquisition of the right mix of computer hardware and efficiently using existing hardware bound in a computational GRID, to address large scale computing problems. This strategy requires deep understanding of scientific applications and how well they fit for a given computational paradigm. Process by which these applications are evaluated will also be discussed.

COMP 217 [746061]:  Semiclassical correction to quantum energy levels
William H. Miller, Department of Chemistry, University of California, Berkeley, CA 94720, Fax: 510-642-6262,, Alexey L. Kaledin, Department of Chemistry, Emory University, and C William McCurdy, Computing Sciences Division, Lawrence Berkeley National Lab

It is shown how semiclassical theory can be used to construct a correction to an approximate quantum mechanical calculation of energy eigenvalues (i.e., energy levels) for molecular systems. Various applications are presented to illustrate the approach.

COMP 218 [774050]:  Linear-scaling methods for large molecules: Development and application
Christian Ochsenfeld, Theoretical Chemistry, Universität Tübingen, Tübingen D-72076, Germany, Fax: +49-7071-295490,

For the investigation of large molecular systems it is crucial to reduce the increase of the computational effort with molecular size. In this talk linear scaling Hartree-Fock (HF) and Density Functional Theory (DFT) methods are presented, which allow to compute molecular systems of 1000 and more atoms on simple one-processor workstations. At the same time the accuracy and reliability of conventional ab initio methods is preserved. Both theoretical aspects as well as applications to large molecular systems are discussed. Here, in particular the computation of NMR chemical shifts provide a useful link to the experiment. Examples studying molecular recognition processes are presented, where systems in the solid-state and in solution are considered.

COMP 219 [785528]:  Fritz Schaefer and the periodic table
Russell M. Pitzer, Department of Chemistry, Ohio State University, 100 W. 18th Ave., Columbus, OH 43210,

H. F. Schaefer's career in quantum chemistry has been marked by progress is a number of dimensions, including computational methods, range of applications, choice of hardware, size of molecule, and predictions of the future. Another dimension is progress downward in the periodic table. This progress will be described briefly with respect to other measures.

Some sample quantum chemistry methods and applications from still further down the periodic table will be described, particularly with respect to electronic spectroscopy problems.

COMP 220 [770935]:  Thermochemistry of calcium-containing molecules: An examination of the performance of high-level theoretical procedures
Leo Radom1, Michael B. Sullivan2, Naomi L. Haworth1, Angela K. Wilson3, Larry A. Curtiss4, and Jan ML Martin5. (1) School of Chemistry, University of Sydney, Building F11, Sydney NSW, 2006, Australia, Fax: +61 (2) 9351-3329, (2) Research School of Chemistry, Australian National University, (3) Department of Chemistry, University of North Texas, (4) Materials Science and Chemistry Divisions, Argonne National Laboratory, (5) Department of Organic Chemistry, The Weizmann Institute of Science

The calculation of reliable thermochemistry has become almost a routine task for many molecules, through the use of techniques such as the Gn procedures of Curtiss, Raghavachari and Pople, the CBS procedures of Petersson, and the Wn procedures of Martin. However, in recent studies of alkali and alkaline earth oxides and hydroxides, we found that the application of these methods in their standard formulations can sometimes lead to errors greater than 100 kJ/mol. Special modifications need to be introduced to avoid such errors. In this presentation, I will discuss our most recent work on the topic, focusing particularly on calcium-containing molecules.

COMP 221 [782217]:  Resonant electron scattering by soft box CCSD(T) calculations
Wilfried Meyer, Department of Chemistry, Universität of Kaiserslautern, Erwin-Schrödinger-Strasse, FB Chemie Geb.52/527, Kaiserslautern D-67663, Germany, Fax: 49-631-205-2750,, and Dirk Spelsberg, Department of Chemistry, University of Kaiserslautern

A reliable ab inito characterization of resonant electronic states has proven very difficult: resonance energies and resonance-continuum coupling vary strongly even if orbital spaces, configuration spaces or projection algorithms are only slightly changed. We show how a CCSD(T) treatment of a molecul + electron in a soft box potential may be used for a direct (variational) determination of electron phase shifts from energy shifts with respect to empty box energies, without requiring continuum boundary conditions or Feshbach projections. By non-linear fitting, the phase shifts furnish the resonant potential Vr(R) and the width function Γ(E,R) which form the input to a non-local Feshbach procedure for calculating total scattering cross sections as well as vibrational excitation cross sections and/or dissociative attachment cross sections. For important resonances of small molecules we demonstrate excellent agreement with experiment, e.g. resonance peak positions with an accuracy of about 20 meV.

COMP 222 [772561]:  Electroweak quantum chemical kinetics and molecular parity violation
Martin Quack, Laboratory for Physical Chemistry, ETH Zurich, ETH Hoenggerberg, HCI, Wolfgang Pauli Strasse 10, CH-8093 Zurich, Switzerland, Fax: +41-1-632-10-21,

Quantum Chemistry is usually founded on the electromagnetic force together with the Schrödinger and Dirac equations or equivalent representations (“it's all Coulomb’s law”). This research program is one of the greatest success stories of the last decades [1]. However, there is evidence that for certain chemical phenomena related to molecular chirality the weak nuclear force as encoded in the more general “electroweak quantum chemistry” is of crucial importance, particularly after our discovery, about ten years ago, that its effects are 1 to 2 orders of magnitude larger than anticipated previously [2]. We shall introduce the general background and then discuss the most recent results from our group in the setting of quantum chemical kinetics and high resolution molecular spectroscopy covering now phenomena between less than yoctoseconds and more than days [3]. [1] H.F. Schaefer III, Quantum Chemistry, Oxford University Press (1984), [2] M. Quack, Angew. Chem. Int. Ed. (Engl.) 41, 4618 (2002), [3] M. Quack, Chimia 57 (4), 147 (2003)

COMP 223 [763707]:  The ages of quantum chemistry
W. Graham Richards, Department of Chemistry, University of Oxford, Central Chemistry Laboratory, South Parks Road, Oxford OX 1 3QH, United Kingdom, Fax: 44 1865 275905,

Fritz Schaefer was the herald of the third age of quantum chemistry. By the late 1970s he was providing theoretical calculations more accurate than experiment, or at least sufficiently accurate to be indispensible for interpretation. Earlier ages had only come within an order of magnitude of experiment, and then secondly, only really useful when experiment was precluded. In the present era the chief virtue of ab initio calculations is in telling us where electrons are and as such providing, amongst other things, the basis for the crude but fast methods capable of being applied to such areas as drug discovery.

COMP 224 [788718]:  Kinematic view of loop closure
Evangelos A. Coutsias, Department of Mathematics and Statistics, University of New Mexico, Albuquerque, NM 87131,, and Chaok Seok, Department of Pharmaceutical Chemistry, University of California at San Francisco

We consider the problem of loop closure, i.e., of finding the ensemble of possible backbone structures of a chain segment of a protein molecule that is geometrically consistent with preceding and following parts of the chain whose structures are given. We reduce this problem of determining the loop conformations of six torsions to finding the real roots of a 16th degree polynomial in one variable, based on the robotics literature on the kinematics of the equivalent rotator linkage in the most general case of oblique rotators. We provide a simple intuitive view and derivation of the polynomial for the case in which each of the three pairs of torsional axes has a common point. Our method generalizes previous work on analytical loop closure in that the torsion angles need not be consecutive, and any rigid intervening segments are allowed between the free torsions. The method of resultants is used to eliminate variables, and the BKK theorem is used to obtain the bounds to the number of solutions. We present applications to three problems. First, we show that this analytical loop closure algorithm can be efficiently combined with an existing loop-construction algorithm to sample loops longer than three residues. Second, we show that Monte Carlo Minimization is made several-fold more efficient by employing the local moves generated by loop closure algorithm, when applied to the global minimization of an eight-residue loop. Lastly, we show that the loop closure move set can be used in a rigorous Monte Carlo simulation to efficiently simulate cyclopeptides.

COMP 225 [788721]:  Symbolic generation of perturbation equations for the vibrational-rotational analysis of potential energy surfaces
Walter C. Ermler, George Mason University and National Science Foundation, Research, Evaluation, and Communication Division, Fairfax, VA 22030,

The Schrödinger equation for vibrational motion is solved to arbitrary order of Rayleigh-Schrödinger perturbation theory by means of symbolic formula generation. It is demonstrated that by using Mathematica® the lengthy algebraic equations resulting from high-order perturbation theory can be accurately and efficiently treated to the appropriate level of approximation as dictated by the accuracy of Born-Oppenheimer potential energy surfaces. In this work the theoretical details necessary to calculate arbitrary-order anharmonicity, non-rigid rotator and vibration-rotation coupling correction terms to vibrational-rotational energies, wave functions and expectation values are presented. The requisite correction formulae in terms of universal constants, molecular constants, and quantum numbers are derived by symbolic computation using a compact procedural program. FortranForms of the resulting expressions are subsequently incorporated into a general-purpose code. It is demonstrated that symbolic calculation can be used for computer-generated algebra that will apply arbitrarily high-order perturbation theory successfully to the problem of intramolecular nuclear motion.

COMP 226 [788853]:  Enzyme kinetics using manifold theory
Simon J. Fraser, Department of Chemistry, University of Toronto at Scarborough, Toronto, ON M1C 1A4,

Chemical reactions show a separation of time scales (rapid transient decay) due to the stiffness of the ordinary differential equations (ODEs) describing their evolution. In enzyme kinetics time scale separation allows the steady-state evolution of such systems to be represented on a hierarchy of smooth, slow manifolds embedded in the full phase space of concentration variables for the complete reaction. Typically such manifolds are dynamically stable in the sense that they attract the surrounding phase flow exponentially fast; this relates to their confinement within regions of phase space bounded by the nullclines of the system. The slow manifolds also contain the true attractors of the system. Explicit formulas for manifolds of this kind can be found by iterating functional equations using a symbolic language like Maple. It has been proved that, using sufficiently smooth starting functions, e.g., the expressions for the nullclines, the nth iteration of the functional equation provides expressions for the slow manifolds is accurate to the nth power in the singular perturbation parameter(s) that appear in the ODEs. However, the iteration procedure may diverge. This can be related to the geometry of the phase flow, e.g., the phase-space region in question does not lie between system nullclines and is not locally exponentially attracting. Nevertheless, if the local phase flow has the correct properties iteration can be stabilized. The iterative method provides global formulas for the manifolds in cases where series methods diverge. There are many advantages to such reduced descriptions: the corresponding ODEs describe the system evolution on the slow manifolds; consequently, bifurcations of the system can be analysed on the manifolds: changes in the dimensionality associated with the system evolution can be expressed as structural, geometrical changes within the slow-manifold hierarchy.

COMP 227 [788856]:  Conventional and unconventional symbolic computation in chemistry
Frank E. Harris, Department of Physics, University of Utah, Quantum Theory Project, University of Florida, 115 S 1400 E Rm 201, Salt Lake City, UT 84112-0830,

Modern symbolic computation systems have enough flexibility for it to be possible to define operators with a non-commutative algebra and to provide rules for the manipulation and simplification of expressions involving several different kinds of such quantities. Operators of interest for chemistry and physics include boson and fermion creation/annihilation operators, symmetry operators, and also conventional differential and integral operators. These capabilities enable the automatic reduction of expressions such as arise in the computation of relativistic and quantum electrodynamic effects. Practical potential applications include high-precision studies of few-body systems such as the He atom (where relativistic perturbation-theoretic expansions can involve very large numbers of terms, even at fairly low order). These same ideas have been used by the author (and with great success by others) in automating algebraic processes such as arise in coupled-cluster and other approaches to ab inito electronic structurer studies. These and more conventional applications of symbolic computation will be presented.

COMP 228 [788857]:  Symbolic calculations in the theory of atoms
Juha Javanainen, Department of Physics, University of Connecticut, Storrs, CT 06269-3046,

We discuss the use of symbolic manipulations in two examples drawn from studies of interactions of light with atoms: analysis of temperature limit for laser cooling of atoms, and derivation of split-operator methods for numerical integration of variations of the Schroedinger equation.

COMP 229 [746854]:  Towards a universal potential for water
Richard J. Saykally, Department of Chemistry, University of California, Berkeley, CA 94720-1460, Fax: 510-642-8369,

A new polarizable potential energy surface, VRT(ASP-W)-III, has been determined by fitting water dimer spectroscopic data to Stone’s ASP-W surface. This new surface correctly describes the vibrational ground states of water clusters through hexamer (via DQMC calculations) and yields good structural properties for room temperature liquid water (via MC simulations), although very long simulation times are required.

COMP 230 [774573]:  Towards an understanding of 3-D aromaticity
Paul v. R. Schleyer, Zhongfang Chen, and R. B. King, Department of Chemistry, University of Georgia, Computational Chemistry Annex, Athens, GA 30602-2525, Fax: 706-542-7514,

Molecular “clusters” with globular shapes often have delocalized electronic structures and exhibit properties associated with aromaticity. Computed nucleus–independent chemical shifts (NICS) are particularly effective probes into the three-dimensional aromatic (diatropic) or antiaromatic (paratropic) character, especially since NICS can be dissected into localized as well as canonical MO contributions. Numerous puzzles can be clarified: the well-known icosahedral borane, B12H12(2-), is aromatic, but its unknown isoelectronic Ih Si12(2-) analog is antiaromatic. NICS changes magnitude and then sign down group 14: Pb12(2-) is aromatic. The effects of substituents can be equally dramatic. The neutral B4H4, B8H8, and B9H9 clusters are antiaromatic and unknown, but their known perhalogenated analogs are aromatic. Although the basic MO symmetries and the number of skeletal electrons are the same, the contributions of individual sets of MOs differ quantitatively. This is responsible for the disparate behavior. Electron count rules for stability or aromaticity provide insights, but are oversimplified.

COMP 231 [768500]:  How to "Cope" with biradicals from enediynes and the like
Peter R. Schreiner, Department of Chemistry, Justus-Liebig-University, Heinrich-Buff-Ring 58, Giessen D-35392, Germany, Fax: 0641-99-34309,

Quantum chemical studies of the cyclizations of enediynes and enyne-allenes have proven to be computationally tractable thanks to the success of modern DFT and multi-reference methods. In particular, it is now possible to unify these fascinating reactions under the header of the family of Cope-reactions. A systematic study will present simple (empirical) predictive rules to determine whether biradicals are expected as intermediates in these types of reactions that are characterized by aromatic transition structures or biradical intermediates.

Lit.: Schreiner, P. R.; Navarro-Vazquez, A.; Prall, M. Acc. Chem. Res. 2004, submitted.

COMP 232 [751696]:  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 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 233 [774406]:  Potential energies of weakly and strongly interacting systems: From pi-stacking to bond-breaking
C. David Sherrill, School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400,

Current ab initio quantum mechanical methods are challenged by weakly interacting systems such as van der Waals clusters, and strongly interacting systems such as those in bond-breaking reactions. The theoretical requirements (basis set, electron correlation) for both types of problems will be explored. Applications of high-level methods to pi-pi interactions will be discussed; a deeper understanding of these interactions is crucial for the rational design of supramolecular assemblies and intercalating drugs. These computations show that substituent effects are not determined by electrostatics alone. New benchmark potential energy curves will be used to compare various strategies for the reliable and efficient modeling of bond-breaking reactions.

COMP 234 [781130]:  Thermodynamic and kinetic simulations of protein folding at IBM Research
William Swope, IBM Almaden Research Center, 650 Harry Road, San Jose, CA 95120,

In 1999 IBM announced the Blue Gene project ( with plans to begin a research program to develop a large parallel computer system that could be used to perform biomolecular simulations. The goal is to use this capability to study biological processes at a molecular level, and, in particular, to help improve the understanding of the phenomenon of protein folding. This ambitious project will also push the state of the art in large scale computer design and in the software tools that will be needed to exploit the associated hardware architecture.

The IBM BlueGene science team has been working with the computational chemistry and biology communities in academia and government to outline meaningful research projects that can make effective use of the Blue Gene resource. There are several thrusts to the scientific effort, including: thermodynamics related to the protein folding process, kinetics of the protein folding process, and force field validation and assessment. We are particularly concerned with making as strong a connection as possible with experimental results. This talk will give a report on the program and present some results, including: an improved model for water for use with Ewald simulation protocols; precise solvation free energies of small molecule amino acid side chain analogs; folding studies of the thermodynamics of small mini-proteins; and a methodology and its application for the computation of folding rates (kinetics) from molecular dynamics simulations.

COMP 235 [773330]:  Quantum mechanical studies of HIV-1 protease inhibitors and drug design based on full ab initio MFCC computation
Dawei Zhang and John Z.H. Zhang, Department of Chemistry, New York University, 100 Washington Square East, New York, NY 10003,

Full quantum mechanical studies of detailed binding interactions between HIV-1 protease and six FDA approved drugs are carried out using a recently developed MFCC (Molecular Fractionation with Conjugate Caps) method. The MFCC calculation gives quantum mechanical interaction spectrum for each protease-drug binding complex. Detailed quantitative analysis on binding of Lopinavir to specific residues of the protease is obtained. The dominant binding of Lopinavir to the protease is due to a strong hydrogen bonding between the central hydroxyl group of the drug to the aspartate oxygen of Asp25 in the A chain. This is followed by binding to Asp29 in the B chain as well as Gly27, Gly48, and Ile50. The ab initio binding energies at HF/3-21G method for six protease drugs are ¨C90.24 kcal/mol for Saquinavir, -92.91 kcal/mol for Indinavir, -109.97 kcal/mol for Nelfinavir, -111.19 kcal/mol for Lopinavir, -118.29 kcal/mol for Amprenavir, and ¨C119.81 for Ritonavir respectively. By partitioning all six drugs into four building blocks besides the central component containing the hydroxyl group, MFCC calculation finds that block III has no effect of binding to the protease. The major binding interactions of these drugs are from blocks II and IV, in addition to the central hydroxyl group. Based on this rational, for each subsite of binding, we choose a building block that has strong binding to this particular subsite and construct a series of new inhibitors (T1-T5) that have 'super strong' bindings to the protease. The MFCC calculations at HF/3-21G method give the binding energies of ¨C123.91 kcal/mol for T1, -137.97 kcal/mol for T2, -142.04 kcal/mol for T3, -152.75 kcal/mol for T4, and ¨C247.80 kcal/mol for T5 respectively.

COMP 236 [774475]:  PREDICT modeling and in silico screening for GPCR: From amino acid sequence to the clinic
Sharon Shacham1, Yael Marantz2, Silvia Noiman2, Oren, M Becker2, and Michael, G Kauffman1. (1) Predix Pharmaceuticals, 10K Gill St, Woburn, MA 01801, Fax: 781-376-0822,, (2) Predix Pharmaceuticals Ltd

GPCRs constitute a major family of drug targets, involved in many physiological responses. Predix Pharmaceuticals has developed a suite of algorithms that permit the structure-based discovery and optimization of drug candidates binding to GPCRs and Ion Channels. Predix' discovery platform includes a novel technology for modeling the 3D structure of any GPCR based solely on its amino-acid sequence (PREDICT); The model is then used initially for in-silico screening against any library and in several programs the initial hits were converted into early drug candidates . The accuracy of the PREDICT models, was extensively validated, including: (a) agreement with rhodopsin X-ray structure; (b) reproduction of site-directed mutagenesis data: (c) PREDICT models yield novel hits with nanomolar activity in binding assays. (d) Novel, non-azapirone lead clinical candidate and backup 5-HT1A agonists with preclinical activity in anxiety and attention deficit hyperactivity disorder were created, and are now in Phase I clinical trails.

COMP 237 [774632]:  QMQSAR: A semi-empirical (PM3) field-based QSAR program
Steve Dixon1, Kenneth M. Merz Jr.2, Giorgio Lauri3, James Ianni4, and Marisa C Kozlowski4. (1) Schrodinger, 120 West Forty-Fifth Street, 32nd Floor, Tower 45, New York, NY 10036-4041, Fax: 1 646 366-9550,, (2) Department of Chemistry, Pennsylvania State University, (3) Giorgio Lauri Inc, (4) Department of Chemistry, University of Pennsylvania

A semiempirical quantum mechanical approach to the creation of molecular field-based QSAR models is implemented in the QMQSAR software. Each aligned ligand is characterized by a set of probe interaction energy (PIE) values computed at optimized grid points located near the surface. Single-point semiempirical PM3 calculations using the DIVCON software efficiently provide the required PIE values. The best n-variable linear fit is determined by forward stepwise regression followed by a simulated annealing procedure. An average model based on all accepted n-variable models is also constructed, yielding predictions of greater accuracy and stability without overfitting. The ability of the semiempirical potential to accurately represent electronic interactions for non-first-row elements underlies our interest in this method for the correlation of enantiomeric excesses with catalyst structure. For this application using a set of 18 beta-aminoalcohol chiral catalysts QMQSAR gave an overall r^2 of 0.85 in a leave-out-two cross validation.

COMP 238 [769074]:  Computational investigations on novel catalytic antibodies: Aldolase and anti-cocaine
Yunfeng Hu and Arthur Olson, Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, MB5, La Jolla, CA 92037,

Catalytic aldolase antibodies catalyze the aldol reaction with the efficiency of natural enzymes, but accept a much broader range of substrates. Two separate groups of aldolase antibodies catalyzing the same aldol reactions with antipodal selectivity were analyzed computationally with flexible receptor dockings. The reactive lysine residues in each group of antibodies are located on different chains in the opposite orientation (VH, VL) but within a similar hydrophobic environment.

More than 40,000,000 Americans have used cocaine since 1980 and at least two million people have cocaine addiction. Current treatments are still not satisfying. An alternative peripheral-blockade approach is using antibody to bind cocaine and disassemble it eventually. Computationally predicted transition state binding mode agrees with the transition state analog in the crystal structures. A hydroxide ion conducts a nucleophilic attack on cocaine carbonyl to form a methyl ester and benzoic acid.

COMP 239 [756416]:  Importance of electric charges in molecular docking: QM/MM approach
Art E. Cho1, Victor Guallar2, Bruce J. Berne1, and Richard A. Friesner3. (1) Department of Chemistry, Columbia University, Mail Code 3158, New York, NY 10027, Fax: 212-854-7454,, (2) Biochemistry and Molecular Biophysics, Washington University at St Louis. School of Medicine, (3) Department of Chemistry and Center for Biomolecular Simulation, Columbia University

The extent to which accuracy of electric charges plays a role in protein docking is investigated through development of a docking algorithm, which incorporates quantum mechanical/molecular mechanical (QM/MM) calculations. In this algorithm, fixed charges of ligands from force field parameters are replaced by QM/MM calculations treating only the ligands as quantum region. The algorithm is tested on a set of 40 test crystallographic data and illustrates strong evidence that use of non-fixed charges is important. An algorithm, dubbed "Survival of the Fittest" (SOF) algorithm, is implemented to incorporate QM/MM charge calculations without any knowledge of native structures. Potential energy surfaces seem to be modified by this substitution of charges by QM/MM calculations to speed up the search of global minimum. This study strongly suggests that use of polarizable force field in fast docking will be productive.

COMP 240 [769054]:  Computer-aided design of novel natural-product-based matrix metalloproteinase-3 inhibitors
Elizabeth A. Amin, Department of Chemistry, University of Minnesota, 139 Smith Hall, 207 Pleasant St SE, Minneapolis, MN 55416, Fax: 612-626-7541,, and William J. Welsh, Pharmacology, UMDNJ-RWJMS

Matrix metalloproteinases (MMPs) constitute a class of structurally related, zinc-binding enzymes which mediate the breakdown of extracellular matrix proteins such as collagen, gelatin and proteoglycan. MMPs have been identified in tissue surrounding invasive carcinoma, and directly enable tumor metastasis through proteolysis and blood vessel formation (angiogenesis). Degenerative and inflammatory diseases such as osteoarthritis also depend on MMPs to spread to unaffected tissue. These enzymes are therefore attractive targets for small-molecule synthetic inhibitors (MMPIs) which would serve as adjuncts to traditional cancer treatments such as radiation and chemotherapy. A series of computational techniques, including comparative molecular field analysis (CoMFA), has been applied to the design and optimization of several new nonpeptidic, bioavailable, natural-product-based MMPI lead series which demonstrate high predicted biological activity against stromelysin-1 (MMP-3).

COMP 241 [773003]:  High quality homology models for structure-based drug design: A comparative study
Akbar Nayeem, Doree Sitkoff, 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,

The goal of this study is to evaluate the commercial protein homology modeling software in the context of model utility for virtual screening, molecular docking and structure-based drug design. Proteins used as templates and models were derived from therapeutically interesting target classes and include serine proteases, kinases, aspartyl proteases, matrix metallloproteases, nuclear hormone receptors, and cytochrome P450s. The relative strengths and weaknesses of the modeling approaches are compared. An improved protocol for protein modeling based upon a combination of methodologies will be discussed.

COMP 242 [761935]:  GQSAR: A new ab intio/DFT 3-D-QSAR program
James Ianni and Marisa Kozlowski, Department of Chemistry, University of Pennsylvania, 231 S 34th St, Philadelphia, PA 19104-6323,

A new ab initio/DFT 3D-QSAR software program named GQSAR has been developed. GQSAR implements the theoretical models available in Gaussian98 to calculate electrostatic potential fields (EPF) to produce 3D QSARs. Accurate solvent models can be utilized in combination with most available level of theories allowing for highly accurate calculations of several different types of QSARs. For example, GQSAR has been used successfully in the classic example of steroid affinities for corticosteroid binding globulin. Specifically, a leave-out-one cross validation r^2 of 0.86 was obtained for a set of 30 steroids using a B3LYP/6-31G* level of theory. Sample runs will also be presented correlating enantiomeric excesses from the asymmetric addition of diethylzinc to benzaldehyde with the structures of the chiral catalysts. For example, with a set of 18 beta-aminoalcohol chiral catalysts GQSAR calculated an overall r^2 of 0.82 in a leave-out-one cross validation.

COMP 243 [771736]:  Graph isomorphisms for computer-aided drug discovery
Noel T Southall, Trung Nguyen, and Dr Ajay, Informatics, Celera Genomics, 45 W. Gude Drive, Rockville, MD 20850,

We have implemented an algorithm for quickly identifying all (maximal) common substructures between two graphs. As opposed to most chemical searching methods which address whether a given substructure is present in or similar to another graph, finding the maximal common substructure relieves the user of having to generate an appropriate substructure to initiate the search with (Raymond JW, Willett P, J Comput Aided Mol Des 16:59-71 (2002)). In the context of small molecule drug discovery, this tool can help generate structural hypotheses as opposed to simply testing a user's hypotheses and ultimately their creativity. And in contrast to descriptor-based learning methods, here the model is a chemical graph, which is far more intuitive to chemists and straight-forward to visualize. We provide a few examples for the use of a graph isomorphism tool, including automated generation of structure-property relationships, and pharma/toxicophore perception.

COMP 244 [771673]:  Conformational consensus as a method to distinguish agonists from antagonists II: Identification of selective conformations
Gregory J. Tawa, Alan H. Katz, and Juan C. Alvarez, Chemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543, Fax: 732-274-4292,

We recently presented a method in which distributions of conformations are compared across a series of potent GPCR ligands. Through systematic shape/pharmacophore searching, we find that conformations exist that are shared predominantly by agonists or antagonists. The conformations are identified using a comprehensive suite of programs designed to manage the large amount of data generated by the systematic searches [PaccMan - Pharmacophore Analysis by Conformational Consensus - Management Tool]. We have extended this analysis suite to allow us to determine which selective conformations can best be overlapped to generate 3D Pharmacophores and starting points for ligand-based virtual screens. The method is demonstrated for a set of GPCR agonists and antagonists, and for a set of small molecules binding to two different targets

COMP 245 [758418]:  Lead docking protocol featuring improved sampling and scoring
Luciano Mueller, Macromolecular Structure, Bristol-Myers Squibb, Route 206 and Provinceline Road, P. O. Box 4000, Princeton, NJ 08543, Fax: 609 252 6030,, David R. Langley, Structural Biology and Modeling, Bristol-Myers Squibb, and Daniel L. Cheney, Department of Macromolecular Structure, Bristol Myers Squibb Pharmaceutical Research Institute

Flexible docking is a critically important tool for hit identification and binding mode prediction (lead docking). Multiple docking programs have been developed to achieve these tasks, and while considerable improvements have been reported, problems persist in computing scoring energies, adequate inclusion of solvation effects and protein flexibility (ligand-induced fit). Our study shows, that substantial improvements in sampling can be realized by the docking of lead compounds into ensembles of proteins. This led to efforts in assessing selection criteria for the choice of optimally diverse protein ensembles for molecular docking from sets of protein structures (crystal-structures and/or homology models). None of the evaluated molecular docking programs (Gold, Glide, ICM, Flo+) featured scoring functions of sufficient accuracy to reliably select correct protein-binding poses. For this reason, multiple docked conformations of lead compounds were subsequently minimized and re-scored in both IMPACT using the OPLS-AA 2001 force-field and in CHARMM using the CFF98-force-field (both IMPACT and CHARMM calculations treated solvation effects with SGB and GB implicit solvent model, respectively). Forthcoming inter-molecular interaction- and ligand strain energies proved superior to the original scores in the respective docking programs in ranking docked poses. Targeted relaxation of active site residues based on ligand-induced conformational variability during the energy minimization, further aided the scoring of docked ligand conformers.

COMP 247 [788861]:  Symbolic computation in the determination of hyperspherical harmonics
Aron Kuppermann, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125,

Abstract text not available.

COMP 249 [788865]:  Symbolic computation in coupled cluster theory
Piotr Piecuch, Department of Chemistry, Michigan State University, College of Natural Science, East Lansing, MI 48824-1322, Fax: 517-353-1793,

Abstract text not available.

COMP 250 [788867]:  Some uses of computer algebra in enzyme kinetics
Necmettin Yildirim, Department of Mathematics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3205,

The kinetic analysis of multi-enzyme systems is made difficult by the non-linearities and the number of parameters involved in the model equation. We present a method for analysis of such systems under the pseudo steady state assumption using Groebner bases theory to solve multivariate polynomial systems. This method provides a powerful approach to such problems when the assumption valid. The application of the method to some actual systems will be discussed.

COMP 251 [771063]:  Computational strategies for high-accuracy computations of hydrogen bonding and π - π stacking prototypes
Gregory S. Tschumper, Department of Chemistry and Biochemistry, University of Mississippi, University, MS 38677-1848, Fax: 662-915-7300,

Hydrogen bonding and π - π stacking are two of the most important weak chemical interactions in chemistry and biology. However, the small magnitude of these attractive interactions poses a significant computational challenge. To keep relative errors acceptably small (typically < 0.1 kcal/mol), high-accuracy computations are necessary. In some cases, this situation requires going beyond the "Gold Standard" (i.e. the CCSD(T) method) and utilizing massive basis sets (e.g. aug-cc-pV6Z and aug-cc-pV7Z). Continuing advances in computer hardware and parallel software have facilitated the application of these high-accuracy techniques to larger prototypes. Strategies based on recent successes and failures will be summarized.

COMP 252 [755410]:  Conical intersections are generalized lines not isolated points
David R. Yarkony, Department of Chemistry, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218, Fax: 410-516-8420,

Points of conical intersections are not isolated entites that are continuously connected, forming seams. When Cs symmetry is present the seam may exhibit distinct branches. Conical intersection of the 1,21A and 1,22A states of NH3 and H2COH respectively are reported over a range of nuclear coordinates. The implications for photodissociation are discussed.

COMP 253 [773963]:  High accuracy theoretical pKa calculations
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,

We have applied the sophisticated quantum chemical method of Liptak and Shields to predict the pKa values for a series of N-heterocyclic carbenes in water, dimethylsulfoxide and acetonitrile. Remarkably good agreement between the calculated and experimental pKa values has been obtained for the two available experimental numbers, confirming that this state-of-the-art theoretical approach can be used to calculate highly accurate pKa values without fitting to experimental data. The heterocyclic carbenes are predicted to be considerably more basic than common phosphine compounds used as ligands in organometallic chemistry. Results have been obtained for unsaturated as well as saturated 5-membered and 6-membered ring systems and these have allowed us to elucidate some of the electronic and steric affects operating on pKa in these systems.

COMP 254 [775083]:  Three- vs. four-coordinate phosphorus: More reasons for tight d functions
Steven S. Wesolowski, Computational Chemistry and Informatics, AstraZeneca Pharmaceuticals, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850, Fax: 302-886-5382,

Complete basis set extrapolations employing the coupled-cluster series are illustrated for phosphine oxide and its cis- and trans-phosphinous acid isomers. Incorporation of tight d functions via Dunning's core-valence or newly constructed "plus d" [cc-pV(X+d)Z] basis sets is essential for rapid convergence of core polarization effects which are evident even at the SCF level. The precision to which the phosphorus hybridization is described in the three- and four-coordinate environments ultimately determines the predicted relative energy orderings. The dramatic effect of the tight d functions on double- and triple-zeta basis sets in this prototype system suggests that tight d functions may be essential for accurate QM predictions within QM/MM simulations of biological reactions where phosphorus experiences a change in hybridization (e.g. protein phosphorylation).

COMP 255 [751802]:  Ab initio vibration-rotation spectroscopy
Walter Thiel, Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470, Mülheim an der Ruhr, Germany,

High-level ab initio calculations can provide reliable predictions for the spectroscopic properties of small molecules. In vibration-rotation spectroscopy, the required spectroscopic parameters can be determined from ab initio harmonic and anharmonic force fields using rovibrational perturbation theory. The lecture will first address the current status of this approach, in particular with regard to the convergence of the theoretical results, and then describe some recent studies on small reactive species such as bismuthine [1,2].

The second part of the talk will address variational calculations on ammonia, with particular emphasis on large amplitude inversion motion. This work [3,4] involves the computation of six-dimensional potential energy surfaces (PES) at the coupled cluster CCSD(T) level (with extrapolation to the complete basis set limit and addition of relativistic and other corrections), the generation of suitable analytical representations of these PES, and the actual variational calculations. The accuracy of the computed vibrational levels depends on the quality of the ab initio PES and of the analytical PES fits and on any approximations made in the variational treatment. The influence of these factors will be discussed for levels up to 10000 cm-1 and for inversion splittings. Results will be presented for selected rovibrational levels with high J and K values.

[1] W. Jerzembeck, H. Bürger, L. Constantin, L. Margules, J. Demaison, J. Breidung, and W. Thiel, Angew. Chem. Int. Ed. 41, 2550 (2002). [2] J. Breidung, H. Stoll, D. Figgen, and W. Thiel, J. Chem. Phys., in press. [3] H. Lin, W. Thiel, S. N. Yurchenko, M. Carvajal, and P. Jensen, J. Chem. Phys. 117, 11265 (2002). [4] H. Lin, J. J. Zheng, W. Thiel, S. N. Yurchenko, M. Carvajal, P. Jensen, T. Rajamäki, and L. Halonen, to be published.

COMP 256 [748964]:  Modeling of the CVD of 13-15 composites: From donor-acceptor complexes to rings and clusters
Alexey Y Timoshkin, Department of Chemistry, Inorganic Chemistry Group, St. Petersburg State University, Universitetskii pr. 26, Old Peterhoff, St. Petersburg 198504, Russia, Fax: 812-428-6939,

Group 13-15 binary compounds and composites are prospective materials for microelectronics. Chemical Vapor Deposition (CVD) method is widely used for their production. Despite extensive experimental studies, mechanisms of the involved gas phase processes are still unknown to chemists. Present report summarizes results of extensive ab initio quantum-chemical modeling of CVD processes from the 13-15 donor-acceptor complexes X3MYH3 (M=Al,Ga,In; Y=N,P,As; X=H,F,Cl,Br,I,CH3). It is shown that gas phase association reactions play an important role, and formation of oligomeric rings and cluster compounds [X2MYH2]2,3; [XMYH]4-16 is favorable both thermodynamically and kinetically. Results obtained open perspective for the design of novel single-source precursors for the stoichiometry-controlled CVD of 13-15 composites.

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