Atomistic Simulation Analyses of Sequence-nonspecific Effects of Lipid Composition on Transmembrane Helical Peptide Dimerization

For the dimerization/multimerization of transmembrane (TM) proteins, specific peptide motifs mediate the interactions between transmembrane domains (TMDs).However, the sequence-nonspecific interactions among TMDs as well as between TMDs and lipids may also be important in determining the basal propensities for the association of TM proteins.For this, experimental and computational analyses using model peptides with simple amino acid sequences have been previously used.Recently, we performed an extensive set of united-atom (totaling ~1300 µs) and all-atom simulations (~200 µs), mainly computing free energy for the dimerization of TM model peptides.In this mini-review, we discuss our findings on the sequence-nonspecific effects of lipids on the dimerization of TM helical peptides.An increase in cholesterol in the membranes stiffens the membranes and stabilizes the dimeric state of the TM helical peptides.Cholesterol increased the order parameter of the phospholipid acyl chains and, intriguingly, increased the number of the chains in contact with both peptides, resulting in the better solvation of the peptides in the dimeric state.In contrast, in cholesterol-free phospholipids bilayers, the monomeric state was stabilized because the good coordination of the lipid headgroup atoms with the peptides lowered the electrostatic potential energy.Our analysis also demonstrated the limited parameter transferability of the united-atom force-fields, which caused erroneous results in the simulation analyses of the TMD associations.