BPS2026 – Membrane mechanics of the mechanosensitive channel MscS

Mechanosensitive ion channels are membrane proteins that open and close in response to physical forces in their environment. While some, like the spring-shaped NompC channel involved in soft touch, sense external force perpendicular to the membrane directed along the long axis of the channel, many open in response to tension in the plane of the membrane. A model for energetic coupling of in-plane tension to channel opening was initially developed for the mechanosensitive channel of large conductance (MscL) and posited that the energy of opening is the product of protein area expansion and tension. Cryogenic electron microscopy (cryo-EM) structures of the mechanosensitive channel of small conductance (MscS) in lipid nanodiscs, corroborated by molecular dynamics (MD) simulations, suggest that the MscS conformational change is dominated by large membrane deformations induced by the closed state that resolve as the channel opens to increase cross-sectional surface area. Using a combination of coarse-grained MD simulation and continuum mechanics, we show that the deformation of the putative closed state produces a large out-of-plane area expansion, akin to the PIEZO model of tension sensing, that reproduces experimental open probability curves. Continuum estimates of the mean and Gaussian curvature energies between the open and closed conformations reveal large bending energies, though not as large as one would expect given the extent of the deformation. Additional MD simulations show that charge-neutralizing key basic residues at the solvent-bilayer interface facilitates adoption of a new closed state due to closure of hydrophobic pockets, and this new state relieves much of the membrane deformation.