Dimerization of a membrane transporter is driven by differential energetics of lipid solvation of dissociated and associated states

Over two-thirds of membrane proteins of known structure assemble into oligomers. Yet, the forces that drive the association of these proteins in the membrane remain to be delineated, as the lipid bilayer is a solvent environment that is both structurally and chemically complex. In this study we reveal how the lipid solvent defines the dimerization equilibrium of the CLC-ec1 Cl-/H+ antiporter. Integrating experimental and computational approaches, we show that monomers associate to avoid an energetic penalty for solvating a thinned-membrane defect caused by their exposed dimerization interfaces. Supporting this theory, we demonstrate that this penalty is drastically reduced with minimal amounts of short-chain lipids, which stabilize the monomeric state by preferentially solvating the defect rather than altering the physical state of the membrane. We thus posit that the energy differentials for local lipid-solvation define membrane-protein association equilibria, and describe a molecular-level physical mechanism for lipid regulation of such processes in biological conditions.