ArticleBiophysical journal2026
Membrane insertion and dimerization of glycophorin-A mutations studied by free energy simulations.
Article in Biophysical journal, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Numerous proteins are associated with cellular membranes and often contain single or multiple membrane-spanning helices. These helices can mediate membrane protein interactions to form functional complexes involved in enzymatic or signaling processes. A detailed understanding of interactions and driving forces is essential for the understanding of membrane protein association and for membrane protein complex design. The glycophorin-A transmembrane helical dimer has been studied extensively by biochemical and structural methods, including mutagenesis of dimer interface residues. We use alchemical free energy simulations to investigate the effect of amino acid substitutions on the binding free energy and the change in membrane insertion free energy. Simulations on more than 30 substitutions were performed in different lipid environments and resulted in overall good agreement with experimental data, both for the change in membrane insertion and dimerization free energies. For the membrane insertion, the simulations slightly underestimated the stabilization due to larger nonpolar residues and overestimated the destabilization by substitution with polar residues. Interestingly, very little influence of the lipid type on changes in membrane insertion free energy was observed. The influence of lipid environment on the calculated binding free energy changes was also modest for most substitutions but significant for mutations that affect the glycine residues in the central GxxxG interaction motif. Enhanced lipid dynamics of unsaturated lipids may compensate for conformational changes in the case of mutations of interface glycine to larger residues. Mutations, especially of residues V84 and T87 to other polar and nonpolar residues, allowed us to estimate the contribution of additional hydrogen bonds (∼-1.0 kcal/mol) and removal of methyl groups (∼0.5 kcal/mol) to dimerization. Our study also demonstrates the usefulness of alchemical free energy simulations to quantify the influence of amino acid substitutions on membrane helix association and could be valuable for the design of new membrane protein interactions.
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