All-Atom Simulation and Continuum Elastic Theory of Gramicidin a in Binary Component Lipid Bilayers

Abstract

The linear gramicidins are a group of peptides with alternating L and D chirality that fold into β-helices. The prototypical gramicidin is [Val1] gramicidin A (gA), which has been extensively studied using electrophysiology, spectroscopy, and molecular dynamics simulations. gA channels form by transmembrane dimerization and have been used to examine the interactions between membrane proteins and their host bilayer. This study focuses on gA channels in lipid bilayers composed of two phosphatidylcholines with different acyl chain lengths. The bilayers were formed from equimolar mixtures of DC16:1PC+DC24:1PC or DC18:1PC+DC22:1PC mixture, as well as pure DC20:1PC, all of which have the same average tail length. These gA-bilayer systems were simulated for 3.5 μs to explore the characteristics and energetics of lateral lipid redistribution around a protein. The simulations indicate: i) the overall bilayer thickness profile adjacent to the channel is similar in the three systems tested; ii) in the DC16:1PC+DC24:1PC mixture, the shorter DC16:1PC is enriched by nearly a factor of two in the first lipid shell around the channel; iii) thickness matching is dominant, even when the disparity between lengths is large; and iv) the acyl chains adopt non-native conformations in order to match achieve hydrophobic matching between the gA dimer and the bilayer core. In contrast to the results in the DC16:1PC+DC24:1PC mixture, enrichment in the DC18:1PC+DC22:1PC mixture is statistically insignificant. The preference for the better matching lipid (DC16:1PC) near the channel in the DC16:1PC+DC24:1PC mixture can be explained by a continuum model that accounts for the energetic penalty associated with compressing the longer lipid (DC24:1PC) to match the channel's hydrophobic length.