Coarse-Grained Molecular Dynamics Simulations Reveal the Membrane Dependence of MscL Gating

Abstract

Membrane proteins are solvated in a lipid bilayer; with the proteins' hydrophobic area covered by the bilayer's hydrophobic core. The strong bilayer-protein hydrophobic interactions effectively couple the protein to the bilayer and vice versa. Therefore, membrane protein function can be influenced with changes in bilayer properties.A coarse-grained MARTINI molecular dynamics model is used to explore the lipid bilayer influence on the mechanosensitive channels of large conductance (MscL). Among the mechanosensitive channels MscL is the most studied and often used as a model for how proteins sense membrane tension. We characterize the MscL gating kinetics dependence on bilayer properties by simulating MscL embedded in bilayers of different composition and with systematic addition of straight chain alcohols. Both bulk bilayer properties and local properties/deformation around the proteins are analysed in addition to MscL time to opening after applied tension (ko). The in-silico predictions are compared with experimental data determined using reconstituted MscL in a liposomal fluorescent efflux assay. The in-silico model correctly predicts known MscL behaviour, like longer ko in thicker bilayers. Surprisingly, the model also predicted longer ko with the addition of octanol, a finding which was experimentally confirmed.View Large Image | View Hi-Res Image | Download PowerPoint Slide