Ion Channel Regulation by Lipid Bilayers: Theory & Simulation of Deformed Membranes around Gramicidin A

Abstract

The energetic coupling between an integral membrane protein and its host bilayer depends on the protein structure and the bilayer material properties (e.g., hydrophobic thickness, intrinsic lipid curvature, compression modulus, and bending modulus). Therefore, if a bilayer is modulated by a membrane protein conformational change, the energetics of the protein-induced bilayer deformations must be considered. To explore this energetic coupling, gramicidin A (gA) monomer↔dimer association was used as a surrogate for conformational transitions of large membrane proteins that perturb the host bilayer. gA channels provide similar physics of bilayer modulation since they form by transmembrane dimerization, and deform the bilayer to match the hydrophobic length of the channel. gA channels were simulated in five single-component bilayers formed of mono-unsaturated lipids with increasing chain length, leading to thicker bilayers, and increased deformation around the peptide. These deformations are analyzed primarily in terms of compression (i.e., placing a tall lipid next to the shorter channel) and bending. Lipid compression and bending both cause bilayer stresses, and these stresses lead to curvature frustration of the individual leaflets. The per area free energy of bending with respect to curvature, dF/dR−1, (a sensitive measure of bilayer stress) is calculated and compared to the predictions based on a continuum elastic model (CEM). It is shown that gA monomer insertion produces similar contributions to dF/dR−1 independent of bilayer type, and gA dimerization increases dF/dR−1 systematically with bilayer thickness. The increase in dF/dR−1 is indicative of increased bilayer stresses due to dimerization. In tandem with the CEM results, the all-atom values allow for development of an improved CEM, and determination of the compression and bending energies that can be compared to experiment.