Computational studies of RNA and DNA (eBook)

CONTENTS 6
PREFACE 9
Chapter 1 BASICS OF NUCLEIC ACID STRUCTURE 12
1. BACKGROUND 12
2. THE BUILDING BLOCKS 13
2.1 Chemical Composition 13
2.2 Structure 14
3. NUCLEIC ACID CONFORMATIONS 20
3.1 Double Helical Forms 22
3.2 Other Nucleic Acid Conformations 27
3.3 Nucleic Acids with Modified Components 28
3.4 Folded Single-Stranded Nucleic Acids 29
4. NUCLEIC ACIDS IN COMPLEXES 32
4.1 Recognition of Nucleic Acids by Small Molecules 34
4.2 Recognition Between Nucleic Acids and Proteins 36
5. WEB RESOURCES FOR NUCLEIC ACID STRUCTURES 42
5.1 The Primary Archives of Experimental Molecular Structures – PDB and NDB 43
5.2 Content of the NDB 44
5.3 Structural Classification of RNA (SCOR) 45
ACKNOWLEDGEMENTS 45
REFERENCES 46
Chapter 2 USING AMBER TO SIMULATE DNA AND RNA 56
1. AMBER APPLIED TO NUCLEIC ACIDS 56
1.1 Setting up AMBER MD Simulations 57
1.2 AMBER Dynamics 58
1.3 AMBER Analysis 61
2. MOLECULAR DYNAMICS OF NUCLEIC ACIDS 67
3. CHALLENGES FOR THE FUTURE 74
ACKNOWLEDGEMENTS 75
REFERENCES 76
Chapter 3 THEORETICAL STUDIES OF NUCLEIC ACIDS AND NUCLEIC ACID-PROTEIN COMPLEXES USING CHARMM 83
1. INTRODUCTION 83
2. CHARMM AS A TOOL FOR MODELING STUDIES OF NUCLEIC ACIDS 85
3. CHARMM NUCLEIC ACID FORCE FIELDS 87
4. COMPUTATIONAL STUDIES OF SMALL NUCLEIC ACIDS AND RELATED COMPOUNDS 88
5. SIMULATIONS STUDIES OF OLIGONUCLEOTIDES 90
6. SIMULATION STUDIES OF PROTEIN NUCLEIC ACID COMPLEXES 93
7. SUMMARY 95
ACKNOWLEDGEMENTS 96
REFERENCES 96
Chapter 4 CONTINUUM SOLVENT MODELS TO STUDY THE STRUCTURE AND DYNAMICS OF NUCLEIC ACIDS AND COMPLEXES WITH LIGANDS 105
1. INTRODUCTION 106
2. COMPUTER SIMULATION OF NUCLEIC ACIDS USING CONTINUUM SOLVENT MODELS 107
2.1 Molecular Mechanics Force Fields to Study Biomolecular Structure and Dynamics 107
2.2 Continuum Solvent Modeling 108
2.3 Molecular Dynamic Simulation on Nucleic Acids Using Continuum Models 115
2.4 DNA and RNA as Drug Targets 117
2.5 Application of Continuum Solvent Models to Nucleic Acid Motif Structure Prediction 119
2.6 Docking of Ligands to Nucleic Acids 121
2.7 Conclusions and Outlook 123
ACKNOWLEDGEMENTS 124
REFERENCES 124
Chapter 5 DATA MINING OF MOLECULAR DYNAMIC TRAJECTORIES OF NUCLEIC ACIDS 130
1. INTRODUCTION 130
2. THE CLASSICAL APPROACH 131
2.1 Level of Representation 132
2.2 The Force Field 133
2.3 Simulation Methods 135
2.4 Analysis of MD Trajectories 136
3. CHALLENGES FOR THE FUTURE 150
3.1 Force-Field Refinement 150
3.2 Reactivity in Nucleic Acids 151
3.3 Complexes with Proteins 151
3.4 Unusual and Non-Regular Structures 151
3.5 Transfer to Mesoscopic Levels 151
REFERENCES 152
Chapter 6 ENHANCED SAMPLING METHODS FOR ATOMISTIC SIMULATION OF NUCLEIC ACIDS 155
1. INTRODUCTION 155
2. METHODS FOR IMPROVING SAMPLING EFFICIENCY 158
2.1 Continuum Solvation with Low Viscosity 158
2.2 Locally Enhanced Sampling 160
2.3 Replica Exchange Molecular Dynamics 165
3. SUMMARY 172
ACKNOWLEDGEMENT 173
REFERENCES 173
Chapter 7 MODELING DNA DEFORMATION 176
1. DNA DEFORMATION AND ITS BIOLOGICAL INTEREST 176
2. MODELING STRATEGIES 179
2.1 Building Models of DNA 179
2.2 Controlling Deformations 183
2.3 Enthalpy and Free Energy 185
3. PRACTICAL APPLICATIONS - FROM THE MACROSCOPIC TO THE MICROSCOPIC 189
3.1 Large Scale Helical Deformations 189
3.2 Deformations of the Base Pairs 194
3.3 Deformations of the Phosphodiester Backbone 201
3.4 Deformation and Recognition 204
3.5 Sequence Induced Fluctuations 208
REFERENCES 209
Chapter 8 MOLECULAR DYNAMICS SIMULATIONS AND FREE ENERGY CALCULATIONS ON PROTEIN-NUCLEIC ACID COMPLEXES 218
1. INTRODUCTION 218
1.1 Protein-Nucleic Acid Complexes 219
1.2 Molecular Dynamics 220
1.3 Molecular Dynamics of Protein-Nucleic Acid Complexes 221
2. CASE STUDIES 225
2.1 Catabolite Activator Protein (CAP)-DNA Complex 225
2.2 U1A RNA Complex 229
3. FREE ENERGY CALCULATIONS 232
4. SUMMARY 234
ACKNOWLEDGEMENTS 234
REFERENCES 234
Chapter 9 DNA SIMULATION BENCHMARKS AS REVEALED BY X-RAY STRUCTURES 242
1. INTRODUCTION 243
2. METHODS 244
2.1 Database 244
2.2 Conformational Analysis 245
2.3 Deformability 245
2.4 Hydration Patterns 246
2.5 Protein-DNA Contacts 246
3. RESULTS 247
3.1 Torsion Angles 247
3.2 Base-pair Parameters 249
3.3 Dimeric Structural Variability 254
3.4 Effects of Sequence Context on Dimeric Properties 255
3.5 DNA Hydration 257
3.6 Protein Recognition 259
4. CONCLUDING REMARKS 261
ACKNOWLEDGMENTS 262
REFERENCES 262
Chapter 10 RNA: THE COUSIN LEFT BEHIND BECOMES A STAR 265
1. INTRODUCTION 265
2. RNA AT ATOMIC RESOLUTION 266
3. RNA’s DIVERSITY 268
4. RECENT DISCOVERIES CONCERNING RNA’s STARRING ROLE 269
5. MAJOR CHALLENGES IN RNA RESEARCH 273
5.1 RNA Gene Location 273
5.2 RNA Gene Function 274
5.3 RNA’s Structural Repertoire 274
5.4 The RNA Folding Problem 275
5.5 Designing Novel RNAs 281
6. INVITATION TO COMPUTATIONAL BIOLOGISTS 281
ACKNOWLEDGEMENTS 283
REFERENCES 283
Chapter 11 MOLECULAR DYNAMICS SIMULATIONS OF RNA SYSTEMS: IMPORTANCE OF THE INITIAL CONDITIONS 288
1. INTRODUCTION 288
2. VARIOUS ISSUES RELATED TO MD SETUPS 291
2.1 Choosing an Appropriate Starting Structure … 291
2.2 … and Checking it 292
3. CONCLUSIONS 297
ACKNOWLEDGEMENTS 298
REFERENCES 298
Chapter 12 MOLECULAR DYNAMICS SIMULATIONS OF NUCLEIC ACIDS 306
1. GUANINE QUADRUPLEX MOLECULES 307
1.1 Quadruplex Structure 307
1.2 Behavior of the Quadruplex Stem 309
1.3 Behavior of the Quadruplex Loops 313
1.4 Quadruplex Stem Formation 315
2. MD SIMULATIONS OF RNA MOLECULES 318
ACKNOWLEDGEMENTS 326
REFERENCES 326
Chapter 13 USING COMPUTER SIMULATIONS TO STUDY DECODING BY THE RIBOSOME 331
REFERENCES 344
Chapter 14 BASE STACKING AND BASE PAIRING 347
1. INTRODUCTION, METHODS AND PRINICPLES 347
1.1 The Advantage of Ab Initio Studies 347
1.2 The Electron Correlation 351
1.3 Fast Variants of MP2 353
1.4 Basis Set of Atomic Orbitals 354
1.5 Energetics of Molecular Interactions – The Main Task 358
1.6 What QM Calculations Tell About DNA and RNA? 358
1.7 Interplay Between Intrinsic and Environmental Effects 359
1.8 Definition of Interaction Energy and its Components 365
1.9 What is Basis Set Superposition Error (BSSE)? 366
1.10 What are Deformation Energies of Monomers? 367
1.11 Nonplanarity of Amino Groups 369
1.12 Can Strength of Individual H-Bonds be Dissected? 370
1.13 What are the Many Body Effects? 371
1.14 Gradient Optimization vs. Single Points 371
1.15 Atomic Charges 373
1.16 Advance of High-Level Ab Initio Calculations 374
2. SELECTED RECENT RESULTS 375
2.1 H-bonded Base Pairs 375
2.2 RNA Base Pairing 379
2.3 Nature of Base Stacking 380
2.4 Future Directions: Combined Quantum Mechanical and Molecular Mechanical Approaches 381
REFERENCES 383
Chapter 15 INTERACTION OF METAL CATIONS WITH NUCLEIC ACIDS AND THEIR BUILDING UNITS 393
1. INTRODUCTION 393
2. METAL-NUCLEOBASE INTERACTIONS 394
3. METAL-PHOSPHATE INTERACTIONS 396
4. METAL-NUCLEOTIDE INTERACTIONS 398
5. INTERACTION OF METAL CATIONS WITH BASE PAIRS 399
6. NUCLEIC ACIDS AND METALLODRUGS 401
6.1 Platinated Nucleobases 402
6.2 Interaction Strength of Platinated Base Pairs 404
6.3 Studies on Cisplatin Binding to Nucleobases 405
7. CATION-INTERACTIONS 407
8. SITE-SPECIFIC BINDING OF CATIONS TO NUCLEIC ACIDS 408
9. COMMENT ON THE ACCURACY OF FORCE FIELD CALCULATIONS FOR CATIONS 409
10. CONCLUSIONS 410
ACKNOWLEDGEMENTS 411
REFERENCES 411
Chapter 16 PROTON TRANSFER IN DNA BASE PAIRS 415
1. INTRODUCTION 415
2. NEUTRAL BASE PAIRS 416
3. EXCITED BASE PAIRS 419
4. IONIZED BASE PAIRS 423
5. PROTONATED BASE PAIRS 425
6. METAL CATION BINDING 427
7. CONCLUSIONS 430
REFERENCES 431
Chapter 17 COMPARATIVE STUDY OF QUANTUM MECHANICAL METHODS RELATED TO NUCLEIC ACID BASES: ELECTRONIC SPECTRA, EXCITED STATE STRUCTURES AND INTERACTIONS 437
1. INTRODUCTION 438
2. GROUND STATE PROPERTIES OF NUCLEIC ACID BASES AND BASE PAIRS 440
3. EXCITED STATE PROPERTIES OF NUCLEIC ACID BASES 441
3.1 Electronic Transitions 442
3.2 Geometries 451
4. EXCITED STATE PROPERTIES OF WATSON-CRICK BASE PAIRS 456
5. CONCLUDING REMARKS 458
ACKNOWLEDGEMENTS 458
REFERENCES 459
Chapter 18 SUBSTITUENT EFFECTS ON HYDROGEN BONDS IN DNA 466
1. INTRODUCTION 466
2. HYDROGEN BONDS IN NATURAL WATSON-CRICK BASE PAIRS 468
2.1 Structure and Strength of Watson-Crick Hydrogen Bonds 468
2.2 Nature of Watson-Crick Hydrogen Bonds 469
2.3 Orbital Interactions versus Electrostatic Attraction 472
3. SUBSTITUTIONS IN X–H•••Y HYDROGEN BONDS 474
4. REMOTE SUBSTITUTIONS AT DNA BASES 477
5. SUPRAMOLECULAR SUBSTITUENT EFFECTS 482
6. CONCLUSIONS 485
ACKNOWLEDGEMENT 486
REFERENCES 486
Chapter 19 COMPUTATIONAL MODELING OF CHARGE TRANSFER IN DNA 488
1. INTRODUCTION 489
2. BASICS OF ET THEORY 493
3. MODELS AND COMPUTATIONAL METHODS 496
3.1 DNA Models 496
3.2 Methods 497
4. CALCULATION OF CHARGE TRANSFER PARAMETERS 498
4.1 The Driving Force 498
4.2 Effect of DNA Environment on the Free Energy of Charge Transfer 499
4.3 Electronic Coupling 500
4.4 Reorganization Energy 502
4.5 Quantum Chemical Study of CT Rate in DNA 503
5. EXCESS CHARGE DELOCALIZATION 505
6. CHARGE TRANSFER MECHANISMS 507
7. CONCLUDING REMARKS 509
ACKNOWLEDGEMENTS 510
REFERENCES 511
Chapter 20 QUANTUM CHEMICAL CALCULATIONS OF NMR PARAMETERS 515
1. INTRODUCTION 515
2. PARAMETERS OF THE NMR SPECTRUM 516
2.1 Signal Position – Chemical Shift 516
2.2 The Hyperfine-Structure of the NMR Signal 517
2.3 Signal Line-Width and Intensity – Relaxation of Nuclear Spin 520
3. CALCULATION OF NMR PARAMETERS 525
3.1 Chemical Shift 527
3.2 The Indirect Spin-Spin Coupling Constant 528
3.3 Comments on Calculations of NMR Properties 531
3.4 Practical Examples 532
ACKNOWLEDGEMENT 536
REFERENCES 536
Chapter 21 THE IMPORTANCE OF ENTROPIC FACTORS IN DNA BEHAVIOUR: INSIGHTS FROM SIMULATIONS 539
1. INTRODUCTION 539
2. DNA DYNAMICS AND INFORMATION TRANSFER 545
2.1 A Cooperative Ligand-DNA Interaction 545
2.2 Experimental Studies of the Ligand-DNA Complex 546
2.3 Computer Simulations of the Ligand-DNA Complex 547
2.4 Mechanism of Information Transfer 548
3. ENTROPY AND THE BIOMECHANICS OF DNA 550
3.1 The Biological Importance of DNA Mechanics 550
3.2 The Disagreement between Nanomanipulation Experiments and MD Simulation 550
3.3 Quasi-static Simulations of DNA Stretching 554
3.4 The Entropic Instability of S-ladder DNA 556
3.5 Implications for the Action of Molecular Motors 558
4. CONCLUSIONS 558
REFERENCES 559
Chapter 22 SEQUENCE-DEPENDENT HARMONIC DEFORMABILITY OF NUCLEIC ACIDS INFERRED FROM ATOMISTIC MOLECULAR DYNAMICS 561
1. HIGH-DIMENSIONAL AND REDUCED MODELS 561
2. INFERRING DNA SHAPE AND DEFORMABILITY FROM STRUCTURAL FLUCTUATIONS 566
3. APPLICATIONS 571
4. COMPARISON TO EXPERIMENTALLY BASED FORCE FIELDS 573
5. CONCLUSIONS AND PERSPECTIVES 576
ACKNOWLEDGEMENTS 577
REFERENCES 577
CHROMATIN SIMULATIONS 606
1. INTRODUCTION 606
2. COARSE-GRAINED MODELS OF DNA 609
2.1 DNA flexible Wormlike Chain – Nanomechanical Parameters 609
3. SIMULATION PROCEDURES 612
3.1 Monte-Carlo Simulations 612
3.2 Brownian Dynamics Simulations 613
4. NUCLEOSOMES 614
4.1 Nucleosome Structure 614
4.2 Nucleosome Unwrapping – Analytical Model 615
4.3 Brownian Dynamics Simulation of Nucleosome Unwrapping 618
4.4 A Possible Mechanism for Nucleosome Unwrapping 619
5. COARSE-GRAINED MODELS OF CHROMATIN 621
5.1 Persistence Length of Chromatin 622
5.2 Tail Bridging for Nucleosome Attraction 623
5.3 Simulation of Chromatin Fiber Stretching 625
REFERENCES 629
INDEX 636

Chapter 7 MODELING DNA DEFORMATION (p. 169-170)

Péter Várnai1,2 and Richard Lavery11Laboratoire de Biochimie Théorique, CNRS UPR 9080, Institut de Biologie Physico-Chimique, 13 rue Pierre et Marie Curie, Paris 75005, France
2University of Cambridge,Department of Chemistry, Lensfield Road, Cambridge CB2 1EW, United Kingdom

Abstract: Deformations of DNA contribute to its essential biological function. In our laboratory, we have been studying both local and global deformations of DNA and their relationship to base sequence by molecular modeling and simulation techniques. In the current chapter, we first give an overview of the various approaches used in our laboratory to build DNA models and to control DNA deformations. Notably, we discuss the JUMNA program that uses internal and helicoidal variables, and also umbrella sampling free energy simulations used to follow DNA deformations. In the second part, we summarize the results these techniques enabled us to obtain, starting from the large scale deformations, such as stretching, twisting and bending, down to the more local changes involving base opening and flipping and backbone conformations. A separate section deals with the sequence specific recognition of DNA by proteins and the role of DNA deformation in the process. We hope to show the reader that theoretical studies can play a significant role in obtaining a better understanding of this fascinating biopolymer.

Key words: DNA deformation, recognition, base flipping, single molecule manipulation, internal coordinates, JUMNA, AMBER, umbrella sampling, free energy, MMPBSA

1. DNA DEFORMATION AND ITS BIOLOGICAL INTEREST
At first sight, DNA seems to be a relatively simple biopolymer. While it is a heteropolymer, it is composed of only four different nucleotides, a small number compared to the 20 amino acids which constitute the polypeptide chain of proteins. This simplicity led early researchers to initially reject DNA as the potential carrier of genetic information. While the beautiful double helical structure proposed by Watson and Crick1,2 and the subsequent discovery of the triplet genetic code,3,4 explained how DNA could stock enormous amounts of information, it again suggested that structurally there was not much to study. At the core of the double helical structure was the observation that the spiral phosphodiester backbones could accommodate any Watson-Crick base pair sequence without deformation.

The first step to refining this viewpoint comes from realizing that DNA must be packed quite densely to fit into a cell. This is easily illustrated in the case of human cells which contain around 1 m of DNA (corresponding to 4 x 109 base pairs) in a nucleus within a diameter of only a few microns. Within sperm heads, the packing density is even higher. A partial explanation of how this is achieved comes from modeling DNA as a flexible rod, which naturally forms a random coil to increase its conformational entropy. But this factor alone only is not enough to account for the packing that occurs within the nucleus. As we now know, the remainder is due to protein-induced superhelical compaction leading to the complex and hierarchical structure of chromatin.

A second type of deformation was detected early in the study of DNA and concerns its overall helical form. Fiber diffraction studies already showed that the double helical structure could be modified as a function of its solvent and counterion environment. The A and B forms of the double helix first named by Rosalind Franklin5 are now structurally well-characterized and they have been joined by many other conformational families which go even further in tampering with DNA structure, by modifying its helical chirality, changing its number of strands, its base pairing and its relative strand orientations. In recent years, structural studies have been joined by single molecule manipulation experiments which offer us a new way to directly probe the mechanical properties of DNA.6 These experiments have again showed that DNA is more complex than initially expected and that, when pulled or twisted, it can undergo transitions to new and unexpected conformations.