Activation Mechanism of the Mechanosensitive OSCA Channel: A Molecular Dynamics Study

Mechanosensitive ion channels are widely distributed from bacteria to humans and are involved in many crucial physiological processes. Recently, the structures of a new family of the mechanosensitive ion channels, OSCA, which play an essential role in responding to the osmotic pressures across membranes, were resolved by cryo-electron microscopy. We used molecular dynamics (MD) simulations to investigate the activation mechanism of OSCA. We applied a 50-mN/m surface tension to the lipid bilayer in our MD simulations and observed a clear dilation of the OSCA pore. Interestingly, when we put additional LPC (a conical like lipid) into the extracellular side of the bilayer, we also found the OSCA pore dilated. Based on our MD results, we determine that two transmembrane helixes, M0 and M6, are directly related to the activation of OSCA, and we reveal why both surface tension and addition of LPC can lead to the dilation of the pore. Furthermore, we identified a critical salt bridge that can regulate the gating behavior of OSCA, which may act as a lock in addition to the hydrophobic gate during opening of the pore.