Quantitative Characterization of Membrane Protein-Lipid Interactions

Abstract

Protein-lipid interactions are important for membrane protein (MP) structure, function, and organization. Qualitatively, bilayer regulation of MP function or sorting has been under stood in terms of the hydrophobic match between MP and the lipid bilayer. However, due to difficulties in quantitative characterization of protein-lipid interactions (even in computational studies), it is difficult to understand, even on a case-by-case basis, how much and why protein stability differs from bilayer to bilayer, and how much protein-lipid interactions and a bilayer deformation penalty (caused by inclusion of the protein) contribute to such stability difference. As a first step of quantitative characterization, we calculated the transfer free energy of gramicidin A (gA) in binary lipid systems. To obtain insight into the impact of bilayer thickness and curvature on gA-lipid interactions, we have chosen two types of binary lipid systems: (1) DLPC DMPC and (2) DLPC DLPE. In order to improve sampling and accuracy of the potential of mean force (PMF), we employed window exchange umbrella sampling molecular dynamics (WEUSMD) technique with an optimal parameter set. We will discuss the preference of gA (channel) dimer to be in DLPC compared to DMPC and DLPE bilayers. For consistency check, transfer free energy calculation is required for the binary lipid system: DMPC → DLPE. Agreement will validate that the separately calculated transfer free energy profiles can be combined to characterize the changes of the gA-lipid interactions in any two chosen bilayer types. This will allow us to quantitatively map the equilibrium states of gA in bilayers with different properties and to quantitatively elucidate the consequences by the free energy decomposition method.