State-specific morphological deformations of the lipid bilayer explain mechanosensitive gating of MscS ion channels

The so-called force-from-lipids hypothesis of cellular mechanosensation posits that ion channel gating directly responds to changes in the physical state of the membrane induced for example by lateral tension. Here, we investigate the molecular basis for this transduction mechanism by studying the mechanosensitive ion channel MscS from Escherichia coli and its eukaryotic homolog, MSL1 from Arabidopsis thaliana . First, we use single-particle cryo-EM to determine the structure of a novel open conformation of wild-type MscS, stabilize in thinned lipid nanodisc. Compared with the closed state, the structure shows a reconfiguration of helices TM1, TM2 and TM3a, resulting in widening of the central pore. Based on these structures, we examined how the morphology of the lipid bilayer is altered upon gating, using molecular dynamics simulations. The simulations reveal that, in the absence of extrinsic forces, closed-state MscS causes drastic protrusions in the inner leaflet of the lipid bilayer. These deformations develop to provide adequate solvation to hydrophobic features of the protein surface, and clearly reflect a high energy conformation for the membrane. Strikingly, the protrusions are largely eradicated upon channel opening. An analogous computational study of open and closed states of MSL1 recapitulates these findings. The gating equilibrium of MscS channels thus appears to be dictated by two opposing conformational preferences, namely those of the lipid membrane and of the protein structure. We theorize that membrane tension controls this balance because it increases the energetic cost of the membrane deformations that specifically stabilize the closed channel, shifting the gating equilibrium towards the conductive form. ### Competing Interest Statement The authors have declared no competing interest.