Molecular Dynamics Computations for Proteins: A Case Study in Membrane Ion Permeation

Abstract

AbstractComputer simulation can provide an atomic‐level view of protein structure and function that is unattainable with experiments alone. In this chapter, we demonstrate how molecular dynamics (MD) simulation can reveal the microscopic mechanisms of biomolecular activity. In particular, we illustrate the quantitative value of MD simulation by exploring ion channel proteins that allow selective permeation of charged molecules across cell membranes to control our nervous systems and chemical activity in the body. We begin by introducing the basic statistical mechanical formulation and methodological aspects of modern day MD simulations. We then discuss how to analyze a simulation to obtain mechanistic insight through calculation of various molecular properties. Special attention is given to quantitative thermodynamic calculations, which are the driving forces of protein function. We explain how to calculate free energies and equilibrium constants using potential of mean force (PMF) and free energy perturbation (FEP) techniques as well as the use of more advanced sampling approaches. These methods are then used to study ion permeation through the gramicidin A (gA) channel as well as the energetics of arginine side chain translocation across a lipid bilayer to assess models of voltage‐gated ion channel activation.