Introduction to Atomistic Modeling and Simulation of Biomolecular Systems

Molecular dynamics (MD) and related techniques have been used for computer simulations of biomolecular systems for over 40 years, but only recently, due to advances in computer hardware, simulation software, and methodologies, as well as breakthroughs in structural biology, have they become a widely used tool for studying the molecular mechanisms of biological function and its modulation. In this chapter, we will discuss the statistical-mechanical foundations and general theory of MD simulations, such as numerical integrators, simulation ensembles, periodic boundary conditions, the efficient treatment of long-range nonbonded interactions, and temperature and pressure control. Emphasis will be placed on the empirical force fields used in biomolecular simulations and recent advances, such as explicit polarizability, force field development for a variety of drug-like molecules, and automated parameterization strategies. Popular MD simulation software and system-building tools will be described as well. We will also discuss enhanced sampling techniques actively used in biomolecular MD simulations, such as umbrella sampling; replica exchange; metadynamics; steered, targeted, and accelerated MD; and free-energy perturbation (FEP). Efficient ways to obtain thermodynamic information such as free-energy profiles and kinetic information such as diffusion coefficients and rates from both unbiased and enhanced sampling MD simulations will be described as well. Illustrative examples based on recently published studies will be provided for those topics.