Contents
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Preface (PDF) | ||
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Prelude (PDF) | ||
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Table of Contents (PDF) | ||
| 1 |
Biomolecular Structure and Modeling: Historical Perspective | |
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1.1 A Multidisciplinary Enterprise 1.1.1 Consilience 1.1.2 What is Molecular Modeling 1.1.3 Need For Critical Assessment 1.1.4 Text Overview 1.2 Molecular Mechanics 1.2.1 Pioneers 1.2.2 Simulation Perspective 1.3 Experimental Progress 1.3.1 Protein Crystallography 1.3.2 DNA Structure 1.3.3 Crystallography 1.3.4 NMR Spectroscopy 1.4 Modern Era 1.4.1 Biotechnology 1.4.2 PCR and Beyond 1.5 Genome Sequencing 1.5.1 Sequencing Overview 1.5.2 Human Genome |
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| 2 | Biomolecular Structure and Modeling: Problem and Application Perspective | |
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2.1 Computational Challenges 2.1.1 Bioinformatics 2.1.2 Structure From Sequence 2.2 Protein Folding 2.2.1 Folding Views 2.2.2 Folding Challenges 2.2.3 Folding Simulations 2.2.4 Chaperones 2.2.5 Unstructured Proteins 2.3 Protein Misfolding 2.3.1 Prions 2.3.2 Infectious Proteins? 2.3.3 Hypotheses 2.3.4 Other Misfolding Processes 2.3.5 Function From Structure 2.4 Practical Applications 2.4.1 Drug Design 2.4.2 AIDS Drugs 2.4.3 Other Drugs 2.4.4 A Long Way To Go 2.4.5 Better Genes 2.4.6 Designer Foods 2.4.7 Designer Materials 2.4.8 Cosmeceuticals |
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| 3 | Protein Structure Introduction | |
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3.1 Machinery of Life 3.1.1 From Tissues to Hormones 3.1.2 Size and Function Variability 3.1.3 Chapter Overview 3.2 Amino Acid Building Blocks 3.2.1 Basic C  Unit3.2.2 Essential and Nonessential Amino Acids 3.2.3 Linking Amino Acids 3.2.4 The Amino Acid Repertoire 3.3 Sequence Variations in Proteins 3.3.1 Globular Proteins 3.3.2 Membrane and Fibrous Proteins 3.3.3 Emerging Patterns from Genome Databases 3.3.4 Sequence Similarity 3.4 Protein Conformation Framework 3.4.1 The Flexible phi and psi and Rigid omega Dihedral Angles 3.4.2 Rotameric Structures 3.4.3 Ramachandran Plots 3.4.4 Conformational Hierarchy |
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| 4 | Protein Structure Hierarchy | |
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4.1 Structure Hierarchy 4.2 Helices 4.2.1 Classic - Helix4.2.2 310 and  Helices4.2.3 Left - Handed - Helix4.2.4 Collagen Helix 4.3  - Sheets: A Common Secondary Structural Element4.4 Turns and Loops 4.5 Supersecondary and Tertiary Structure 4.5.1 Complex 3D Networks 4.5.2 Classes in Protein Architecture 4.5.3 Classes are Further Divided into Folds 4.6 - Class Folds4.6.1 Bundles 4.6.2 Folded Leafs 4.6.3 Hairpin Arrays 4.7 - Class Folds4.7.1 Anti - Parallel Domains4.7.2 Parallel and Antiparallel Combinations 4.8 / and
+ - Class Folds4.8.1 / Barrels4.8.2 Open Twisted / Folds4.8.3 Leucine-Rich / Folds4.8.4 + Folds4.8.5 Other Folds 4.9 Number of Folds 4.9.1 Finite Number? 4.10 Quaternary Structure 4.10.1 Viruses 4.10.2 From Ribosomes to Dynamic Networks 4.11 Structure Classification | ||
| 5 | Nucleic Acids Structure Minitutorial | |
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5.1 DNA, Life's Blueprint 5.1.1 The Kindled Field of Molecular Biology 5.1.2 DNA Processes 5.1.3 Challenges in Nucleic Acid Structure 5.1.4 Chapter Overview 5.2 Basic Building Blocks 5.2.1 Nitrogenous Bases 5.2.2 Hydrogen Bonds 5.2.3 Nucleotides 5.2.4 Polynucleotides 5.2.5 Stabilizing Polynucleotide Interactions 5.2.6 Chain Notation 5.2.7 Atomic Labeling 5.2.8 Torsion Angle Labeling 5.3 Conformational Flexibility 5.3.1 The Furanose Ring 5.3.2 Backbone Torsional Flexibility 5.3.3 The Glycosyl Rotation 5.3.4 Sugar/Glycosyl Combinations 5.3.5 Basic Helical Descriptors 5.3.6 Base - Pair Parameters 5.4 Canonical DNA Forms 5.4.1 B-DNA 5.4.2 A-DNA 5.4.3 Z-DNA 5.4.4 Comparative Features |
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| 6 | Topics in Nucleic Acids Structure: DNA Interactions and Folding | |
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6.1 Introduction 6.2 DNA Sequence Effects 6.2.1 Local Deformations 6.2.2 Orientation Preferences in Dinucleotide Steps 6.2.3 Orientation Preferences in Dinucleotide Steps With Flanking Sequence Context: Tetranucleotide Studies 6.2.4 Intrinsic DNA Bending in A-Tracts 6.2.5 Sequence Deformability Analysis Continues 6.3 DNA Hydration and Ion Interactions 6.3.1 Resolution Difficulties 6.3.2 Basic Patterns 6.4 DNA/Protein Interactions 6.5 Cellular Organization of DNA 6.5.1 Compaction of Genomic DNA 6.5.2 Coiling of the DNA Helix Itself 6.5.3 Chromosomal Packaging of Coiled DNA 6.6 Mathematical Characterization of DNA Supercoiling 6.6.1 DNA Topology and Geometry 6.7 Computational Treatments of DNA Supercoiling 6.7.1 DNA as a Flexible Polymer 6.7.2 Elasticity Theory Framework 6.7.3 Simulations of DNA Supercoiling | ||
| 7 | Topics in Nucleic Acids Structure: Noncanonical Helices and RNA Structure | |
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7.1 Introduction 7.2 Variations on a Theme 7.2.1 Hydrogen Bonding Patterns in Polynucleotides 7.2.2 Hybrid Helical/Nonhelical Forms 7.2.3 Overstretched and Understretched DNA 7.3 RNA Structure and Function 7.3.1 DNA's Cousin Shines 7.3.2 RNA Chains Fold Upon Themselves 7.3.3 RNA's Diversity 7.3.4 Non-Coding and Micro-RNAs 7.3.5 RNA at Atomic Resolution 7.4 Current Challenges in RNA Modeling 7.4.1 RNA Folding 7.4.2 RNA Motifs 7.4.3 RNA Structure Prediction 7.5 Application of Graph Theory to Studies of RNA Structure and Function 7.5.1 Graph Theory 7.5.2 RNA-As-Graphs (RAG) Resource | ||
| 8 | Theoretical and Computational Approaches to Biomolecular Structure | |
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8.1 Merging of Theory and Experiment 8.1.1 Exciting Times for Computationalists! 8.1.2 The Future of Biocomputations 8.1.3 Chapter Overview 8.2 QM Foundations 8.2.1 The Schrodinger Wave Equation 8.2.2 The Born-Oppenheimer Approximation 8.2.3 Ab Initio 8.2.4 Semi-Empirical QM 8.2.5 Recent Advances in Quantum Mechanics 8.2.6 From Quantum to Molecular Mechanics 8.3 Molecular Mechanics Principles 8.3.1 The Thermodynamic Hypothesis 8.3.2 Additivity 8.3.3 Transferability 8.4 Molecular Mechanics Formulation 8.4.1 Configuration Space 8.4.2 Functional Form 8.4.3 Some Current Limitations | ||
| 9 | Force Fields | |
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9.1 Formulation of the Model and Energy 9.2 Normal Modes 9.2.1 Characteristic Motions 9.2.2 Spectra of Biomolecules 9.2.3 Spectra As Force Constant Sources 9.2.4 In-Plane and Out-of-Plane Bending 9.3 Bond Length Potentials 9.3.1 Harmonic Term 9.3.2 Morse Term 9.3.3 Cubic and Quartic Term 9.4 Bond Angle Potentials 9.4.1 Harmonic and Trigonometric Terms 9.4.2 Cross Bond Stretch / Angle Bend Terms 9.5 Torsional Potentials 9.5.1 Origin of Rotational Barriers 9.5.2 Fourier Terms 9.5.3 Torsional Parameter Assignment 9.5.4 Improper Torsion 9.5.5 Cross Dihedral/Bond Angle and Improper/Improper Dihedral Terms 9.6 van der Waals Potential 9.6.1 Rapidly Decaying Potential 9.6.2 Parameter Fitting From Experiment 9.6.3 Two Parameter Calculation Protocols 9.7 Coulombic Potential 9.7.1 Coulomb's Law: Slowly Decaying Potential 9.7.2 Dielectric Function 9.7.3 Partial Charges 9.8 Parameterization 9.8.1 A Package Deal 9.8.2 Force Field Comparisons 9.8.3 Force Field Performance | ||
| 10 | Nonbonded Computations | |
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10.1 Computational Bottleneck 10.2 Reducing Computational Cost 10.2.1 Simple Cutoff Schemes 10.2.2 Ewald and Multipole Schemes 10.3 Spherical Cutoff Techniques 10.3.1 Technique Categories 10.3.2 Guidelines for Cutoff Functions 10.3.3 General Cutoff Formulations 10.3.4 Potential Switch 10.3.5 Force Switch 10.3.6 Shift Functions 10.4 Ewald Method 10.4.1 Periodic Boundary Conditions 10.4.2 Ewald Sum and Crystallography 10.4.3 Morphing a Conditionally Convergent Sum 10.4.4 Finite-Dielectric Correction 10.4.5 Ewald Sum Complexity 10.4.6 Resulting Ewald Summation 10.4.7 Practical Implementation 10.5 Multipole Method 10.5.1 Basic Hierarchical Strategy 10.5.2 Historical Perspective 10.5.3 Expansion in Spherical Coordinates 10.5.4 Biomolecular Implementations 10.5.5 Other Variants 10.6 Continuum Solvation 10.6.1 Need for Simplification! 10.6.2 Potential of Mean Force 10.6.3 Stochastic Dynamics 10.6.4 Continuum Electrostatics | ||
| 11 | Multivariate Minimization in Computational Chemistry | |
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11.1 Optimization Applications 11.1.1 Algorithmic Understanding Needed 11.1.2 Chapter Overview 11.2 Fundamentals 11.2.1 Problem Formulation 11.2.2 Independent Variables 11.2.3 Function Characteristics 11.2.4 Local and Global Minima 11.2.5 Derivatives 11.2.6 Hessian Matrix 11.3 Basic Algorithms 11.3.1 Greedy Descent 11.3.2 Line Searches 11.3.3 Trust Region Methods 11.3.4 Convergence Criteria 11.4 Newton's Method 11.4.1 Newton in One Dimension 11.4.2 Newton's Method for Minimization 11.4.3 Multivariate Newton 11.5 Large-Scale methods 11.5.1 Quasi-Newton (QN) 11.5.2 Conjugate Gradient (CG) 11.5.3 Truncated-Newton (TN) 11.5.4 Simple Example 11.6 Software 11.6.1 Popular Newton and CG 11.6.2 CHARMM's ABNR 11.6.3 CHARMM's TN 11.6.4 Comparative Performance on Molecular Systems 11.7 Recommendations 11.8 Future Outlook | ||
| 12 | Monte Carlo Techniques | |
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12.1 Monte Carlo Popularity 12.1.1 A Winning Combination 12.1.2 From Needles to Bombs 12.1.3 Chapter Overview 12.1.4 Importance of Error Bars 12.2 Random Number Generators 12.2.1 What is Random? 12.2.2 Properties of Generators? 12.2.3 Linear Congruential Generators 12.2.4 Other Generators 12.2.5 Artifacts 12.2.6 Recommendations 12.3 Gaussian Random Variates 12.3.1 Manipulation of Uniform Random Variables 12.3.2 Normal Variates in Molecular Simulations 12.3.3 Odeh/Evans 12.3.4 Box/Muller/Marsaglia 12.4 Monte Carlo Means 12.4.1 Expected Values 12.4.2 Error Bars 12.4.3 Batch Means 12.5 Monte Carlo Sampling 12.5.1 Probability Density Function 12.5.2 Equilibria or Dynamics 12.5.3 Ensembles 12.5.4 Importance Sampling 12.6 MC Applications 12.6.1 General attractiveness 12.6.2 Biased MC 12.6.3 MC and MD 12.6.4 Parallel Tempering and Other MC Variants | ||
| 13 | Molecular Dynamics: Basics | |
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13.1 Introduction 13.1.1 Why Molecular Dynamics? 13.1.2 Background 13.1.3 Outline of MD Chapters 13.2 Laplace's Vision 13.2.1 The Dream 13.2.2 Deterministic Mechanics 13.2.3 Neglect of Electronic Motion 13.2.4 Critical Frequencies 13.2.5 Electronic/Nuclear Treatment 13.3 Basics 13.3.1 Following Motion 13.3.2 Trajectory Quality 13.3.3 Initial System Setting 13.3.4 Trajectory Sensitivity 13.3.5 Simulation Protocol 13.3.6 High-Speed Implementations 13.3.7 Analysis and Visualization 13.3.8 Reliable Numerical Integration 13.3.9 Computational Complexity 13.4 Verlet Algorithm 13.4.1 Position and Velocity Propagation 13.4.2 Leapfrog, Velocity Verlet, and Position Verlet 13.5 Constrained Dynamics 13.6 Various MD Ensembles 13.6.1 Ensemble Types 13.6.2 Simple Algorithms 13.6.3 Extended System Methods | ||
| 14 | Molecular Dynamics: Further Topics | |
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14.1 Introduction 14.2 Symplectic Integrators 14.2.1 Symplectic Transformation 14.2.2 Harmonic Oscillator Example 14.2.3 Linear Stability 14.2.4 Timestep-Dependent Rotation in Phase Space 14.2.5 Resonance Condition for Periodic Motion 14.2.6 Resonance Artifacts 14.3 Multiple-Timestep (MTS) Methods 14.3.1 Basic Idea 14.3.2 Extrapolation 14.3.3 Impulses 14.3.4 Resonances in Impulse Splitting 14.3.5 Resonance Artifacts in MTS 14.3.6 Resonance Consequences 14.4 Langevin Dynamics 14.4.1 Uses 14.4.2 Heat Bath 14.4.3 Effect of  14.4.4 Generalized Verlet for Langevin Dynamics 14.4.5 LN Method 14.5 Brownian Dynamics (BD) 14.5.1 Brownian Motion 14.5.2 Brownian Framework 14.5.3 General Propagation Framework 14.5.4 Hydrodynamics 14.5.5 BD Propagation 14.6 Implicit Integration 14.6.1 Implicit vs. Explicit Euler 14.6.2 Intrinsic Damping 14.6.3 Computational Time 14.6.4 Resonance Artifacts 14.7 Enhanced Sampling Methods 14.7.1 Overview 14.7.2 Harmonic-Analysis Based Techniques 14.7.3 Other Coordinate Transformations 14.7.4 Coarse Graining Models 14.7.5 Biasing Approaches 14.7.6 Variations in MD Algorithm and Protocol 14.7.7 Other Rigorous Approaches for Deducing Mechanisms, Free Energies, and Reaction Rates 14.8 Future Outlook 14.8.1 Integration Ingenuity 14.8.2 Current Challenges | ||
| 15 | Similarity and Diversity in Chemical Design | |
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15.1 Introduction to Drug Design 15.1.1 Chemical Libraries 15.1.2 Early Days 15.1.3 Rational Drug Design 15.1.4 Automated Technology 15.1.5 Chapter Overview 15.2 Database Problems 15.2.1 Database Analysis 15.2.2 Similarity and Diversity Sampling 15.2.3 Bioactivity 15.3 General Problem Definitions 15.3.1 The Dataset 15.3.2 The Compound Descriptors 15.3.3 Biological Activity 15.3.4 The Target Function 15.3.5 Scaling Descriptors 15.3.6 The Similarity and Diversity Problem 15.4 Data Compression and Cluster Analysis 15.4.1 PCA compression 15.4.2 SVD compression 15.4.3 PCA and SVD 15.4.4 Projection Application 15.4.5 Example 15.5 Future Perspectives | ||
| Appendix A Syllabus | ||
| Appendix B Article Reading List | ||
| Appendix C Supplementary Course Texts | ||
| Appendix D Homeworks | ||
| Bibliography | ||
| References | ||
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