Advances in biomolecular simulations: methodology and recent applications

Abstract

1. Introduction 258

2. Set-up of MD simulations 260

2.1 Constant-pressure dynamics 260

2.2 Grand-canonical dynamics 261

2.3 Boundary conditions 261

3. Force fields 262

3.1 Proteins 262

3.2 Nucleic acids 265

3.3 Carbohydrates 266

3.4 Phospholipids 266

3.5 Polarization 267

4. Electrostatics 267

4.1 Spherical truncation methods 268

4.2 Ewald summation methods 269

4.3 Fast multipole (FM) methods 271

4.4 Reaction-field methods 271

5. Implicit solvation models 271

6. Speeding-up the simulation 273

6.1 SHAKE and its relatives 273

6.2 Multiple time-step algorithms 274

6.3 Other algorithms 275

7. Conformational space sampling 275

7.1 Multiple copy simultaneous search (MCSS) and locally enhanced sampling (LES) 275

7.2 Steered or targeted MD 276

7.3 Self-guided MD 276

7.4 Leaving the standard 3D Cartesian coordinate system: 4D MD and internal coordinate MD 277

7.5 Temperature variations 277

8. Thermodynamic calculations 278

8.1 Lambda (λ) dynamics 278

8.2 Extracting thermodynamic information from simulations 279

8.3 Non-Boltzmann thermodynamic integration (NBTI) 279

8.4 Other methods 279

9. QM/MM calculations 282

10. MD simulations of protein folding and unfolding 283

10.1 High-temperature effects 284

10.2 Co-solvent and polarization effects 288

10.3 External force effects 288

11. On the horizon 291

12. Acknowledgements 292

13. References 292

Molecular dynamics simulations are widely used today to tackle problems in biochemistry and molecular biology. In the 25 years since the first simulation of a protein computers have become faster by many orders of magnitude, algorithms and force fields have been improved, and simulations can now be applied to very large systems, such as protein–nucleic acid complexes and multimeric proteins in aqueous solution. In this review we give a general background about molecular dynamics simulations, and then focus on some recent technical advances, with applications to biologically relevant problems.