Molecular basis for the regulation of membrane proteins through preferential lipid solvation

The mechanism by which lipids regulate membrane proteins remains an open question. While many protein structures reveal associated lipids, neither binding nor regulatory mechanisms can be gleaned from frozen static snapshots, as these processes occur in the context of a dynamic membrane at equilibrium. In this study, we combine single-molecule experiments with computational analyses of lipid dynamics and lipid-solvation energetics to understand how changes in the lipid composition of the membrane influence the dimerization of the CLC-ec1 chloride/proton antiporter. We find this influence does not result from long-lived lipid binding at specific sites, but instead from an inherently dynamic effect known as preferential lipid solvation, which ultimately determines the relative thermodynamic stability of associated and dissociated dimers. This study provides a foundation for linking lipid composition to the modulation of membrane protein conformational equilibria and a framework for discriminating among different lipid regulation mechanisms in membranes.