Biophysical Society Conference | Tahoe 2022

Molecular Biophysics of Membranes

Tuesday Speaker Abstracts

ELIMINATION OF MEMBRANE DEFORMATIONS DRIVES CLC-EC1 DIMERIZATION Tugba N. Ozturk 1,2 ; Rahul Chadda 1 ; Nathan Bernhardt 2 ; José D Faraldo-Gómez 2 ; Janice L Robertson 1 ; 1 Washington University, Department of Biochemistry and Molecular Biophysics, St. Louis, MO, USA 2 National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD, USA Most membrane proteins are found as oligomers. These hydrophobic proteins interact with each other instead of their hydrophobic solvent, the membrane. The physical forces driving membrane protein assemblies in the context of the membrane are not well understood. The fundamental understanding of the driving forces involved in self-assembly reactions of proteins in the membrane is essential for physiological and pharmacological modulation of membrane proteins. What causes the high affinity of membrane protein complexes in the membrane? In order to answer this question, we carried out coarse-grained molecular dynamics simulations combined with umbrella sampling and studied the dimerization of a bacterial chloride/proton antiporter, CLC-ec1. CLC-ec1 forms high affinity homodimers in the membrane in which two, large membrane-embedded and hydrophobic surfaces associate with each other. Our results show that the membrane alone can drive the assembly of two CLC-ec1 protomers to eliminate local deformations caused by the exposed dimerization interface of each subunit. The dimerization is driven by the membrane via a directional driving force that favors association at the native interface over other non-specific interfaces, prior to the formation of direct protein-protein contacts. The dimerization is governed by the structure of CLC-ec1 dimerization interface and the perturbation it imparts onto the surrounding membrane when exposed. Our physical model describes how this dimerization is initially driven by the energetics of the membrane solvating the CLC-ec1’s monomeric state and how changes in lipid composition impact the free energy of dimerization, presenting a way of quantifying lipid regulation in membranes.

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