(653c) Multiscale Simulation of Ion Channel Gating

Pentameric ligand-gated ion channels are an important family of membrane proteins with key roles in physiological processes, including signal transduction at chemical synapses. To study the conformational changes associated with the opening and closing of the channel pore, we adopt a multiscale approach that combines coarse-grained elastic models and all-atom simulations. In the first stage, based on recent crystal structures of two prokaryotic members of the family in open and closed states, respectively, mixed elastic network models are constructed for the transmembrane domain, and a course-grained transition pathway is computed that smoothly connects the closed and open conformations of the channel. In the second stage, molecular dynamics simulations are carried out to refine the coarse-grained transition pathway and to reveal the transition at atomic detail. Thermodynamic and kinetic properties of the gating transition are obtained from this multiscale study.