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Annual Reports in Computational Chemistry
Volume 2

Contributors

Preface

Section 1: Chemical Education
Section Editor: Theresa Julia Zielinski

1.   Real-World Kinetics via Simulations
      Frances A. Houle and William D. Hinsberg

1. Introduction

2. Selecting and setting up simulation studies

3. Kinetics in materials chemistry and biomimetic chemistry

3.1 Interfacila reactions on silica nanoparticles
3.2 Chemical amplification with encapsulated reagents

4. A foundation for kinetic model development

Acknowledgements

References

Section 2: Quantum Mechanical Methods
Section Editor: T. Daniel Crawford

2.   Explicitly Correlated Approaches for Electronic Structure Computations
      Edward F. Valeev

1. Introduction

2. Two-electron systems

3. Many-electron systems

3.1 Transcorrelated methods
3.2 Hylleraas-Cl method
3.3 Gaussian geminal methods
3.4 Linear R12 methods
3.5 Some recent developments

4. Outlook

Acknowledgements

References

3.   Hybrid Methods: ONIOM(QM:MM) and QM/MM
      Thom Vreven and Keiji Morokuma

1. Introduction

2. Defining the potential surface

2.1 QM/MM
2.2 ONIOM
2.3 Capping the dangling bonds

3. Investigating potential surfaces

3.1 Monte Carlo and molecular dynamics
3.2 Geometry optimization

4. Properties

5. Examples of applications

5.1 Structure and reactivity of zeolites
5.2 Enantioselectivity in transition metal-catalyzed hydrogenation
5.3 Enzymatic reaction mechanism of glutathione peroxidase (GPx)

6. Conclusions

References

4.   On the Selection of Domains and Orbital Pairs in Local Correlation Treatments
      Hans-Joachim Werner and Klaus Pfluger

1. Introduction

2. Method

2.1 Orbital spaces

3. Selection of domains using localized orbitals

3.1 Standard domains
3.2 Extended domains
3.3 Pair and triple domains
3.4 Domain merging
3.5 Redundancy check
3.6 Fixing domains
3.7 Selection of domains using energy thresholds

4. Pair classes

5. Triple excitations

6. Applications and discussion

6.1 Dependence of the correlation energy on the domain approximation
6.2 Dependence of the correlation energy on the weak-pair approximation
6.3 Reaction energies
6.4 A case study: the C6H6 + 3H2 --> C6H12 reaction

7. Conclusions

Acknowledgements

References

Section 3: Molecular Modeling Methods
Section Editor: Carlos Simmerling

5.   Simulations of Temperature and Pressure Unfolding Peptides and Proteins with Replica
          Exchange Molecular Dynamics
      Angel E. Garcia, Henry Herce, and Dietmar Paschek

1. Introduction

2. The replica exchange algorithm

2.1 Assignment of temperatures to replicas

3. Convergence of averages

4. Volume and temperature replic exchange molecular dynamics

5. Conclusions

Acknowledgements

References

6.   Hybrid Explicit/Implicit Solvation Methods
      Asim Okur and Carlos Simmerling

1. Introduction

2. Hybrid solvation methods

2.1 Solvation shell approach
2.2 Hybrid solvation with replica exchange

3. Conclusions

Acknowledgements

References

Section 4: Advances in QSAR/QSPR
Section Editor: Yvonne Martin

7.   Variable Selection QSAR and Model Validation
      Alexander Tropsha

1. Introduction

2. Building predictive QSAR models: the approaches to model validation

3. Defining model applicability domain

3.1 Extent of extrapolation
3.2 Effective prediction domain
3.3 Residual standard deviation
3.4 Similarity distance

4. Validated QSAR modeling as an empirical data modeling approach: combinatorial QSAR

5. Validated QSAR models as virtual screening tools

6. Conclusions

References

8.   Machine Learning in Computational Chemistry
      Brian B. Goldman and W. Patrick Walters

1. Introduction

2. Support vector machines

3. Bayesian methods

4. Ensemble methods

5. Conclusions

References

9.   Molecular Similarity: Advances in Methods, Applications, and Validations in Virtual Screening and QSAR
      Andreas Bender, Jeremy L. Jenkins, Qingliang Li, Sam E. Adams, Ed O. Cannon and Robert C. Glen

1. Introduction

2. Novel methods

2.1 Molecular dscriptors
2.2 Data analysis and model generation
2.3 New properties of old methods

3. Method validation

4. "Getting more from your data"

4.1 Analysis of high-throughput screening data
4.2 Consensus predictions

5. Applications

5.1 Virtual screening
5.2 Clustering
5.3 Drug-likeness and comparison of databases
5.4 Docking validations

6. Conclusions and outlook

References

Section 5: Applications of Computational Methods
Section Editor: Heather A. Carlson and Jeffry D. Madura

10.  Cytochrome P450 Enzymes: Computational Approaches to Substrate Prediction
        Andreas Verras, Irwin D. Kuntz and Paul R. Ortiz de Montellano

1. Introduction

2. P450 structures

2.1 First crystal structures, bacterial P450 enzymes
2.2 The active site channel and substrate access
2.3 Active site flexibility and promiscuity
2.4 Mammalian P450 structures

3. Computational metabolism prediction

3.1 Ligand-based techniques
3.2 Homology modeling
3.3 Structure-based design, protein-ligand docking

4. Conclusions

4.1 Summary
4.2 Future prospects

Acknowledgements

References

11.  Recent Advances in Design of Small-Molecule
        Ligands to Target Protein-Protein Interactions
        Chao-Yie Yang and Shaomeng Wang

1. Introduction

2. Computational analysis of the protein-protein interaction interface

3. Approaches in discovery and design of small molecule inhibitors targeting protein-protein interactions

3.1 Computational structure-based database screening
3.2 Experimental high-throughput screening
3.3 Structure-based design of peptidomimetics to disrupt protein-protein interactions
3.4 Lead discovery using fragment library

4. Examples in design of small molecules to target protein-protein interactions

4.1 Small-molecule inhibitors targeting Bcl-2 and Bcl-xL proteins
4.2 Small molecules targeting the inhibitors of apoproteins
4.3 Small-molecule inhibitors targeting the p53-MDM2 interaction
4.4 Antagonists of the thyroid hormone receptor
4.5 Small-molecule inhibitors targeting the interface of homodimeric proteins
4.6 Small-molecule inhibitors of the interaction between interleukin-2 and its receptor protein

5. Conclusions

References

12.  Accelerating Conformational Transitions in Biomolecular Simulations
        Donald Hamelberg and J. Andrew McCammon

1. Introduction

2. Umbrella sampling

3. Accelerated molecular dynamics

3.1 Conformational flooding
3.2 Hyperdynamics
3.3 Extension of the hyperdynamics scheme to biomolecules

4. Conclusions

Acknowledgements

References

13.  Principal Component Analysis: A Review of its Application on Molecular Dynamics Data
        Sarah A. Muller Stein, Anne E. Loccisano, Steven M. Firestine and Jeffrey D. Evanseck

1. Introduction

2. Multivariate methods

3. Principal components analysis

3.1 Background
3.2 Principal components
3.3 Covariance matrix
3.4 Index of selectivity
3.5 Eigenanalysis
3.6 Scree test dimensionality determination
3.7 Visualization

4. Essential dynamics

4.1 Background
4.2 Applications to protein systems
4.3 Applications to nucleic acids

5. Related methods

4.1 Independeny component analysis
4.2 Singular value decomposition

6. Limitations and common errors

7. Conclusions

Acknowledgements

References

14.  Solvent Effects on Organic Reactions from QM/MM Simulations
        Orlando Acevedo and William L. Jorgensen

1. Introduction

2. Methods

3. Menshutkin reaction

4. Nucleophilic aromatic substitution

5. Kemp decarboxylation

6. Conclusion

Acknowledgement

References

15.  Structure-Based Design of New Anti-Bacterial Agents
        Haihong Ni and John Wendoloski

1. Introduction

2. The design of antibacterial agents that inhibit DNA gyrase at B subunit

2.1 Background
2.2 Structural features of the GyrB active site
2.3 Hot spot identification
2.4 Overview of structure-based virtual screening
2.5 Identification of novel inhibitors by structure-based virtual screening
2.6 Structure-based improvements of existinf leads

3. The design of peptide deformylase (Pdf) inhibitors

3.1 Background
3.2 Structural features at the binding site
3.3 Rational design of novel Pdf inhibitors based on strategies used with MMP inhibitors
3.4 Structure-based design of novel macrocyclic inhibitors
3.5 Structure-based optimization

4. Conclusions

References

16.  Recent Evaluations of High-Throughput Docking Methods for Pharmaceutical
          Lead Finding - Consensus and Caveats
        Wendy D. Cornell

1. Introduction

2. Background

3. Methods

3.1 Docking programs
3.2 Scoring functions
3.3 Resource requirements
3.4 Protein structures
3.5 Ligand data sets

4. Performance Measurements

4.1 Fraction actives found in top scoring N%
4.2 Percentage of database screened to find M% of actives
4.3 Enrichment factor
4.4 Maximum enrichment factor
4.5 Percentage of databse where maximum enrichment factor occurred
4.6 Cumulative recall or accumulation curves
4.7 ROC curves
4.8 Average rank
4.9 RIE
4.10 Evaluation metric employed in this review

5. Evaluations

5.1 Bursulaya et al. (Scripps)
5.2 Schulz-Gasch et al. (Hoffmann La-Roche)
5.3 Perola et al. (Vertex)
5.4 Kellenberger et al. (CNRS)
5.5 Klon et al. (Novartis)
5.6 Muegge and Enyedy (Boehringer-Ingelheim/Bayer)
5.7 Cummings et al. (J&J)
5.8 Knotoyianni et al. (J&J)
5.9 Warren et al. (GSK)
5.10 Chen et al. (Astra-Zeneca)
5.11 Consensus and caveats

6. Post-Processing

7. Future Directions

Acknowledgements

References




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