Quantitative Analysis of Membrane Deformation by Multi-Helical Transmembrane Proteins

Abstract

Increasing evidence suggests that the function of G-protein coupled receptors (GPCRs), ion channels, and other membrane proteins depends on their lipid membrane environments. Several such observations have been explained in terms of hydrophobic mismatch effects in protein/membrane interactions. We have developed a novel multi-scale approach to examine this problem, in which we combine the continuum elastic theory of membrane deformations with atomistic molecular dynamics (MD) simulations to quantify the hydrophobic mismatch-driven bilayer remodeling around membrane insertions, and calculate the corresponding energetics. Allowing for radially asymmetric bilayer deformations and for irregular membrane-protein boundary, our approach enables the study of membrane remodeling by multi-helical membrane proteins. The standard Euler-Lagrange formulation is used to calculate the equilibrium membrane shape that minimizes the system's free energy functional, with energy terms including membrane compression-expansion, splay-distortion and surface tension, as well as the residual mismatch energy contribution occurring from partial alleviation of the hydrophobic mismatch. We solve the partial differential equation self-consistently; the protein-membrane boundary contour, and the boundary conditions on bilayer thickness at the membrane/protein interface and in the “bulk” are obtained from cognate MD simulations. The approach is illustrated with calculations for rhodopsin in lipid bilayers of different thicknesses, for the serotonin 5-HT2A GPCR in complex with different ligands, and the leucine transporter in its three key conformations viz., outward-facing, inward-facing, and occluded. Our analysis has identified quantitatively, for the first time, 1) the key role of the residual mismatch at specific transmembrane domains in hydrophobic mismatch-driven oligomerization of GPCRs; and 2) a new mechanistic hypothesis about the manner in which the distinct ligand or substrate-induced conformations of GPCRs, or transporters, can result in differential function of these proteins through differential effects on the membrane environment.