Allosteric Gating Pathways for the Pentameric Ligand-Gated Ion Channel Glic

Abstract

Pentameric ligand-gated ion channels (pLGICs) play essential roles in the transmission and interpretation of synaptic signals. The recent solution of multiple X-ray structures of pLGICs has allowed detailed examination of the molecular mechanisms of synaptic transduction at the atomic level. We have described the mechanism of activation for the proton-gated ion channel GLIC, shedding light on the allosteric mechanisms for the entire family of pLGICs. Using a large-scale string method to explore pathways connecting open and the closed state structures, we have described the conformational changes in the agonist-binding extracellular domain, the ion-conducting trans-membrane domain, and the gating interface that communicates the change. We have observed switching of key interactions, allowing for the sensing of agonist/proton binding, leading to a discrete change in the channel pore. These changes involve several residues conserved across the pLGIC family. We have employed transition analysis of data, collected during millions of short path sampling simulations, to compute free energy surfaces that suggest multiple possible pathways, quantitatively reproduce allosteric stabilization of the open state at low pH, and reveal intermediates that are promising as target states for new drugs and anesthetics.