Molecular Modeling and Simulation

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1 Tamar Schlick Molecular Modeling and Simulation An Interdisciplinary Guide With 147 Full-Color Illustrations Springer

2 Contents About the Cover Book URLs Preface Prelude List of Figures List of Tables Acronyms, Abbreviations, and Units v ix xi xix xxxi xxxviii xli 1 Biomolecular Structure and Modeling: Historical Perspective A Multidisciplinary Enterprise Consilience What is Molecular Modeling? Need For Critical Assessment Text Overview Molecular Mechanics Pioneers Simulation Perspective Experimental Progress Protein Crystallography 12

3 xxii Contents DNA Structure Crystallography NMR Spectroscopy Modern Era Biotechnology PCR and Beyond Genome Sequencing Sequencing Overview Human Genome 27 2 Biomolecular Structure and Modeling: Problem and Application Perspective Computational Challenges Bioinformatics Structure From Sequence Protein Folding Folding Views Folding Challenges Folding Simulations Chaperones Unstructured Proteins Protein Misfolding Prions Infectious Proteins? Hypotheses Other Misfolding Processes Function From Structure Practical Applications Drug Design AIDS Drugs Other Drugs A Long Way To Go Better Genes Designer Foods Designer Materials Cosmeceuticals 59 3 Protein Structure Introduction Machinery of Life From Tissues to Hormones Size and Function Variability Chapter Overview Amino Acid Building Blocks Basic C Q Unit Essential and Nonessential Amino Acids 67

4 Contents xxiii Linking Amino Acids The Amino Acid Repertoire Sequence Variations in Proteins Globular Proteins Membrane and Fibrous Proteins Emerging Patterns from Genome Databases Sequence Similarity Protein Conformation Framework The Flexible 4> and ip and Rigid w Dihedral Angles Rotameric Structures Ramachandran Plots Conformational Hierarchy 86 Protein Structure Hierarchy Structure Hierarchy Helices Classic a-helix io and TT Helices Left-Handed a-helix Collagen Helix /3-Sheets: A Common Secondary Structural Element Turns and Loops Supersecondary and Tertiary Structure Complex 3D Networks Classes in Protein Architecture Classes are Further Divided into Folds a-class Folds Bundles Folded Leafs Hairpin Arrays /3-Class Folds Anti-Parallel (3 Domains Parallel and Antiparallel Combinations a//3 and a+/3-class Folds a//3 Barrels Open Twisted a//3 Folds Leucine-Rich a/(3 Folds a+(3 Folds Number of Folds Finite Number? Concerted Target Selection: Structural Genomics Quaternary Structure Viruses From Ribosomes to Dynamic Networks Structure Classification Ill

5 xxiv Contents 5 Nucleic Acids Structure Minitutorial DNA, Life's Blueprint The Kindled Field of Molecular Biology DNA Processes Challenges in Nucleic Acid Structure Chapter Overview Basic Building Blocks Nitrogenous Bases Hydrogen Bonds Nucleotides Polynucleotides Stabilizing Polynucleotide Interactions Chain Notation Atomic Labeling Torsion Angle Labeling Conformational Flexibility The Furanose Ring Backbone Torsional Flexibility The Glycosyl Rotation Sugar/Glycosyl Combinations Basic Helical Descriptors Base-Pair Parameters Canonical DNA Forms B-DNA A-DNA Z-DNA Comparative Features Topics in Nucleic Acids Structure Introduction DNA Sequence Effects Local Deformations Orientation Preferences in Dinucleotide Steps Intrinsic DNA Bending in A-Tracts Sequence Deformability Analysis Continues DNA Hydration and Ion Interactions Resolution Difficulties Basic Patterns DNA/Protein Interactions Variations on a Theme Hydrogen Bonding Patterns in Polynucleotides Hybrid Helical/Nonhelical Forms Overstretched and Understretched DNA RNA Structure RNA Chains Fold Upon Themselves 175

6 Contents xxv RNA's Diversity RNA at Atomic Resolution Emerging Themes in RNA Structure and Folding Cellular Organization of DNA Compaction of Genomic DNA Coiling of the DNA Helix Itself Chromosomal Packaging of Coiled DNA Mathematical Characterization of DNA Supercoiling DNA Topology and Geometry Computational Treatments of DNA Supercoiling DNA as a Flexible Polymer Elasticity Theory Framework Simulations of DNA Supercoiling Theoretical and Computational Approaches to Biomolecular Structure Merging of Theory and Experiment Exciting Times for Computationalists! The Future of Biocomputations Chapter Overview QM Foundations The Schrodinger Wave Equation The Born-Oppenheimer Approximation Ab Initio Semi-Empirical QM Recent Advances in Quantum Mechanics From Quantum to Molecular Mechanics Molecular Mechanics Principles The Thermodynamic Hypothesis Additivity : Transferability Molecular Mechanics Formulation Configuration Space Functional Form Some Current Limitations Force Fields Formulation of the Model and Energy Normal Modes Characteristic Motions Spectra of Biomolecules Spectra As Force Constant Sources In-Plane and Out-of-Plane Bending Bond Length Potentials Harmonic Term 233

7 xxvi Contents Morse Term Cubic and Quartic Terms Bond Angle Potentials Harmonic and Trigonometric Terms Cross Bond Stretch / Angle Bend Terms Torsional Potentials Origin of Rotational Barriers Fourier Terms Torsional Parameter Assignment Improper Torsion Cross Dihedral/Bond Angle and Improper/Improper Dihedral Terms van der Waals Potential Rapidly Decaying Potential Parameter Fitting From Experiment Two Parameter Calculation Protocols Coulomb Potential Coulomb's Law: Slowly Decaying Potential Dielectric Function Partial Charges Parameterization A Package Deal Force Field Performance Nonbonded Computations Computational Bottleneck Reducing Computational Cost Simple Cutoff Schemes Ewald and Multipole Schemes Spherical Cutoff Techniques Technique Categories Guidelines for Cutoff Functions General Cutoff Formulations Potential Switch Force Switch Shift Functions Ewald Method Periodic Boundary Conditions Ewald Sum and Crystallography Morphing A Conditionally Convergent Sum Finite-Dielectric Correction Ewald Sum Complexity Resulting Ewald Summation Practical Implementation Multipole Method 284

8 Contents xxvii Basic Hierarchical Strategy Historical Perspective Expansion in Spherical Coordinates Biomolecular Implementations Other Variants Continuum Solvation Need for Simplification! Potential of Mean Force Stochastic Dynamics Continuum Electrostatics Multivariate Minimization in Computational Chemistry Optimization Applications Algorithmic Understanding Needed Chapter Overview Fundamentals Problem Formulation Independent Variables Function Characteristics Local and Global Minima Derivatives Hessian Matrix Basic Algorithms Greedy Descent Line Searches Trust Region Methods Convergence Criteria Newton's Method Newton in One Dimension Newton's Method for Minimization Multivariate Newton Large-Scale methods Quasi-Newton (QN) Conjugate Gradient (CG) Truncated-Newton (TN) Simple Example Software Popular Newton and CG CHARMM'sABNR CHARMM'sTN Comparative Performance on Molecular Systems Recommendations Future Outlook 342

9 xxviii Contents 11 Monte Carlo Techniques Monte Carlo Popularity A Winning Combination From Needles to Bombs Chapter Overview Importance of Error Bars Random Number Generators What is Random? Properties of Generators? Linear Congruential Generators Other Generators Artifacts Recommendations Gaussian Random Variates Manipulation of Uniform Random Variables Normal Variates in Molecular Simulations Odeh/Evans Box/Muller/Marsaglia Monte Carlo Means Expected Values ErrorBars Batch Means Monte Carlo Sampling Probability Density Function Equilibria or Dynamics Ensembles Importance Sampling Hybrid MC MCandMD Basic Idea Variants and Other Hybrid Approaches Molecular Dynamics: Basics Introduction Why Molecular Dynamics? Background Outline of MD Chapters Laplace's Vision The Dream Deterministic Mechanics Neglect of Electronic Motion Critical Frequencies Electron/Nuclear Treatment Basics Following Motion 392

10 Contents xxix Trajectory Quality Initial System Settings Trajectory Sensitivity Simulation Protocol High-Speed Implementations Analysis and Visualization Reliable Numerical Integration Computational Complexity Verlet Algorithm Position and Velocity Propagation Leapfrog, Velocity Verlet, and Position Verlet Constrained Dynamics Various MD Ensembles Ensemble Types Simple Algorithms Extended System Methods Molecular Dynamics: Further Topics Introduction Symplectic Integrators Symplectic Transformation Harmonic Oscillator Example Linear Stability Timestep-Dependent Rotation in Phase Space Resonance Condition for Periodic Motion Resonance Artifacts Multiple-Timestep (MTS) Methods Basic Idea Extrapolation Impulses Resonances in Impulse Splitting Resonance Artifacts in MTS Resonance Consequences Langevin Dynamics Uses Heat Bath Effect of Generalized Verlet for Langevin Dynamics LN Method Brownian Dynamics (BD) Brownian Motion Brownian Framework General Propagation Framework Hydrodynamics BD Propagation 450

11 xxx Contents 13.6 Implicit Integration Implicit vs. Explicit Euler Intrinsic Damping Computational Time Resonance Artifacts Future Outlook Integration Ingenuity Current Challenges Similarity and Diversity in Chemical Design Introduction to Drug Design Chemical Libraries Early Days Rational Drug Design Automated Technology Chapter Overview Database Problems Database Analysis Similarity and Diversity Sampling Bioactivity General Problem Definitions TheDataset The Compound Descriptors Biological Activity The Target Function Scaling Descriptors The Similarity and Diversity Problems Data Compression and Cluster Analysis PCA compression SVD compression PCA and SVD Projection Application Example Future Perspectives 492 Epilogue 497 Appendix A. Molecular Modeling Sample Syllabus 499 Appendix B. Article Reading List 501 Appendix C. Supplementary Course Texts 505 Appendix D. Homework Assignments 511 Index 621

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