Anthony K. Rappe'
Professor of Chemistry
Colorado State University
and
Carla J. Casewit
Calleo Scientific
Fort Collins, Colorado
Available from University Science Publishers January 1997
Dedicated to our children
Mollie, Kelly and Charles
Preface Chapter 1 Overview 1.1. Introduction 1.2. Energy Expressions in Molecular Mechanics 1.2.1. Bond Stretch 1.2.2. Angle Bend 1.2.3. Torsions 1.2.4. van der Waals 1.2.5. Electrostatics 1.2.6. Other terms 1.2.7. Example 1.3. Minimization Techniques 1.3.1. Newton-Raphson 1.3.2. Steepest descents 1.3.3. Fletcher-Powell 1.3.4. Conjugate gradient method 1.3.5. Comparison of the methods 1.4. Conformational Searching 1.4.1. Grid Searches 1.4.2. Monte Carlo 1.4.3. Molecular Dynamics 1.5. Energetics 1.6. Applications 1.7. Homework 1.8. References 1.9. Further Reading Chapter 2 Organics 2.1. Introduction 2.2. Allinger's MM2 and MM3 2.2.1. Bond Stretch 2.2.2. Angle Bend 2.2.3. Torsions 2.2.4. Inversion 2.2.5. Cross terms 2.2.6. van der Waals 2.2.7. Electrostatics 2.2.8. Hydrogen bonding 2.2.9. Heats of formation 2.2.10. Transferability of parameters 2.2.11. Examples 2.3. Conformational Analysis 2.3.1 Background 2.3.2 Isomer Energies of Hydrindanes and Hydrindanones 2.3.3 Solution Conformations of Cinchona Alkaloids Box 2.1 Nuclear Overhauser Effect Box 2.2 Three Bond Proton-Proton Couplings---the Karplus Relations 2.3.4. Assignment of Stereogenic Centers by a Combination of NOESY and Restrained Molecular Dynamics Box 2.3 Distance dependence of NOE 2.4. Transition State Modeling 2.4.1 Background 2.4.2 Carbonyl Reduction 2.5. Diastereomeric Energy Differences 2.5.1 Background 2.5.2 Chiral Chromatography 2.5.3 Diastereomeric Salt Formation Box 2.4 Periodic Boundary Conditions 2.6. Homework 2.7. References 2.8. Further Reading 2.9. Supplemental Case Studies Chapter 3 Peptides and Proteins 3.1. Introduction 3.1.1. Amino Acids 3.1.2. Protein and Peptide Structure Primary Structure Secondary Structure Tertiary Structure Quaternary Structure Determining Structures of Peptides and Proteins 3.1.3. Dynamics of Proteins and Peptides 3.1.4. Prediction of Protein Structure Comparing Structures Applications 3.2. Biological Force Fields 3.2.1. Comparison with MM2 and MM3 3.2.2. Inversion 3.2.3. van der Waals 3.2.4. Electrostatic Interactions 3.2.5. Nonbonded Approximations 3.2.6. Hydrogen Bonding 3.2.7. Force Field Parameters 3.2.8. Solvation 3.3. Minimizations of Proteins 3.3.1. Crambin Box 3.1 OPLS 3.3.2. Carbonic Anhydrase Box 3.2 Modeling Metal-Ligand Bonds 3.4. Site-Directed Mutagenesis 3.4.1 Background 3.4.2 Mutagenesis of Insulin 3.5. Conformational Analysis 3.5.1 Background 3.5.2 Tuftsin 3.6. Dynamics 3.6.1 Background 3.6.2 HIV-1 Protease 3.7. Protein Structure by NMR and Molecular Modeling 3.7.1 Background Sequence Assignment NOE-Derived Distances Dihedral Angles Hydrogen Bonds Structure 3.7.2 Tendamistat 3.7.3 Lac Repressor Headpiece 3.7.4 Discussion 3.8. Protein Homology Modeling 3.8.1 Background 3.8.2 Hypervariable Loop Region of Immunoglobulins 3.9. Homework 3.10. References 3.11. Further Reading 3.12. Supplemental Case Studies Chapter 4 Drug Design 4.1. Introduction 4.2. X-ray Crystal Structure Assisted Design of HIV-1 Protease Inhibitors 4.2.1 Peptide-Based Inhibitors 4.2.2 C2 Symmetric Inhibitors 4.2.3 Non-Peptide Inhibitors by Structural Database Searching 4.3. Conformational Analysis in Hormone Drug Design 4.3.1 Background 4.3.2 Somatostatin Analogs 4.4. QSAR 4.4.1 Background 4.4.2 Dihydrofolate Reductase Inhibitors 4.5. Pharmacaphore Modeling 4.5.1 Background 4.5.2 CNS Drugs 4.6. Homework 4.7. References 4.8. Further Reading 4.9. Supplemental Case Studies Chapter 5 DNA 5.1. Introduction 5.1.1 Structural Nomenclature Backbone Sugar Helix DNA Helix Types 5.1.2. DNA Motion 5.1.3. DNA Modeling 5.2. Dynamics 5.2.1 DNA in Vacuo 5.2.2 DNA In Water 5.3. Binding to the Minor Groove 5.3.1 Background 5.3.2 Netropsin Binding 5.4. Dynamics of Intercalation 5.4.1 Background 5.4.2 Proflavine Intercalation 5.5. Covalent Bonding 5.5.1 Background 5.5.2 Cisplatin Binding 5.6. Homework 5.7. References 5.8. Further Reading 5.9. Supplemental Case Studies Chapter 6 Synthetic Polymers 6.1. Introduction 6.1.1 Polymer Types 6.1.2 Polymer Simulation 6.2. Crystalline Structure Determination 6.2.1 Background 6.2.2 Poly(ethylene oxybenzoate) 6.2.3 Poly(oxymethylene), use of Helical Coordinates 6.2.4 Poly(vinylidene fluoride), a General Structure Solution 6.3. Estimation of Elastic Modulii 6.3.1 Background 6.3.2 Poly(ethylene oxybenzoate) and Poly(ethylene terephthalate) 6.3.3 Polyethylene and Poly(oxymethylene) 6.3.4 Syndiotactic Polystyrene 6.4. Rotational Isomeric State Analysis 6.4.1 Background Box 6.1 The Rotational Isomeric State Model 6.4.2 Polyethers 6.5. Polymer Solutions and Blends 6.5.1 Background Box 6.2 Development of Flory-Huggins Theory 6.5.2 Molecular Mechanics-Based Flory-Huggins 6.6. Estimation of Glass Transition Temperatures 6.6.1 Background Box 6.3 Group Additivities 6.6.2 Molecular Mechanics-Based Group Additivity 6.7. Homework 6.8. References 6.9. Further Reading 6.10. Supplemental Case Studies Chapter 7 Inorganics 7.1. Introduction 7.1.1 p Block Elements 7.1.2 d Block Elements 7.1.3 Transition Metal Applications 7.2. Acid Sites in Zeolites 7.2.1 Shell Model Study of Faujasite and ZSM-5. Box 7.1 Shell Model 7.2.2 Force Field Study of Faujasite and ZSM-5. 7.3. Electronic Sources of Octahedral and Square Planar Coordination 7.3.1 Electronic Structure of Octahedral Coordination 7.3.2 Electronic Structure of Square Planar Coordination 7.4. Conformational Analysis 7.4.1 Background 7.4.2 Co(III) Chelate Complexes 7.5. Ziegler-Natta Olefin Polymerization 7.5.1 Background Box 7.2 Pseudo-atoms 7.5.2 Stereoregular Polypropylene Catalysis 7.6. Asymmetric Hydrogenation 7.6.1 Background 7.6.2 Shape of the Active Site. Box 7.3 SHAPES Force Field 7.7. Conformational Flexibility 7.7.1 Simulation of the Plasticity of Copper(II). Box 7.4 First Order Jahn-Teller Effect 7.7.2 Simulation of the Coordination Geometries of Hexaamine Cage Complexes. Box 7.5 Six Coordination Revisited 7.8. Homework 7.9. References 7.10. Further Reading 7.11. Supplemental Case Studies Chapter 8 Force Fields 8.1. Introduction 8.2. Sources of Parameterization Data 8.2.1 Experimental Sources 8.2.2 Theoretical Sources 8.3. Force Field Augmentation and Design 8.3.1 Parameterization Approaches Fitting Experimental Data Fitting Electronic Structure Data Rule Based Parameterization Simple Assignment 8.3.2 Augmentation Strategies 8.3.3 Design Strategies 8.4. Homework 8.5. References 8.6. Further Reading Appendix A. Stereochemical Terms Appendix B. Thermodynamic Corrections Appendix C. Molecular Dynamics Appendix D. Monte Carlo Sampling Appendix E. Conformational Searching Appendix F. Answers to Homework Index