Poor Person's pH Simulation of Membrane Proteins

Abstract

pH conditions are central to the functioning of all biomolecules. However, implications of pH changes are nontrivial on a molecular scale. Though a rigorous microscopic definition of pH exists, its implementation in classical molecular dynamics (MD) simulations is cumbersome, and more so in large integral membrane systems. In this chapter, an integrative pipeline is described that combines Multi-Conformation Continuum Electrostatics (MCCE) computations with MD simulations to capture the effect of transient protonation states on the coupled conformational changes in transmembrane proteins. The core methodologies are explained, and all the software required to set up this pipeline are outlined with their key parameters. All associated analyses of structure and function are provided using two case studies, namely those of bioenergetic complexes: NADH dehydrogenase (complex I) and V_o domain of V-type ATPase. The hybrid MCCE-MD pipeline has allowed the discovery of hydrogen bond networks, ligand binding pathways, and disease-causing mutations.

Keywords: Complex I; Hydrogen bond network; Molecular dynamics; Multi-Conformation Continuum Electrostatics; Potential of mean force; Proton transfer; V-ATPase.