Impact of bilayer composition on the dimerization properties of the Slg1 stress sensor TMD from a multiscale analysis †

ABSTRACT Mutual interactions between the transmembrane domains of membrane proteins and lipids on the bilayer properties has gained major interest. Most simulation studies of membranes rely on the Martini force field, which has proven extremely helpful in providing molecular insights into realistic systems. Accordingly, an evaluation of the accuracy of Martini is crucial to be able to correctly interpret the reported data. In this study, we combine atomistic and coarse-grained Martini simulations to investigate the properties of transmembrane domains (TMDs) in a model yeast membrane. The results show that the TMD binding state (monomeric, dimeric with positive or negative crossing angle) and the membrane composition significantly influence the properties around the TMDs and change TMD-TMD and TMD-lipid affinities. Furthermore, ergosterol (ERG) exhibits strong affinity to TMD dimers. Importantly, the right-handed TMD dimer configuration is stabilized via TMD-TMD contacts by addition of asymmetric anionic PS. The CG simulations corroborate many of these findings, with two notable exceptions: a systematic overestimation of TMD-ERG interaction and lack of stabilization of the right-handed TMD dimers with the addition of PS. Atomistic simulation results suggest that a meaningful comparison of dimer formation and experimentally-determined network factor may require to additionally take into account the precise conformation and thermodynamic relevance of multimeric TMD clusters.