Exploring Hydrophobic Mismatch's Impacts on Dissociation of Gramicidin a Channels using Molecular Dynamics Free Energy Simulations

Abstract

Gramicidin A (gA) channels, formed by trans-bilayer association of two non-conducting subunits, have been used as probes to explore how changes in lipid bilayer composition, including the adsorption of small molecules, alter lipid bilayer properties through measurements of gA channels’ appearance frequency, lifetime, conductance, and gating. However, the molecular mechanism of the channel association/dissociation remains an enigma. Because the gA channel's association/dissociation can be a multi-dimensional reaction coordinate problem, it also is challenging to computationally explore these mechanisms in a fully atomistic system. As a first step, based on our previous molecular dynamics (MD) simulation systems of gA in DLPC, DMPC, DOPC, and POPC bilayers, we have performed umbrella sampling MD free energy simulations (MD/FES) of gA dissociation along the membrane normal (i.e., the Z axis). In this presentation, the MD/FES results of gA dissociation in the four different bilayers will be discussed in terms of (1) the resulting free energy profiles, (2) gA subunits’ structure, orientation, and XY displacement, (3) the subunit-subunit hydrogen bonding (number and pattern), (4) the pore water molecules’ distribution and (5) the bilayer properties (thickness, per-lipid surface area, lateral compressibility, and order parameters) along the reaction coordinate.