Ligand-Gated Ion Channel Opening and Closing Mechanism from Molecular Simulations

Abstract

Pentameric Ligand Gated Ion Channels comprise key receptors for neurotransmitters including acetylcholine, GABA, and serotonin. They are thus targets for many anesthetics, alcohol, and other drugs such as antipsychotics and antidepressants. The channels typically open after physiologic ligand binding to a site in the extracellular domain, but the channels are also highly susceptible to allosteric modulation at sites in the transmembrane domain, the mechanism utilized by many drugs. To better understand ligand and drug action, we are studying ion channel gating using Gloebacter violaceus (GLIC) channels. GLIC is a prokaryotic homologue believed to share all the important characteristics of metazoan channels, but with several structures available. We have previously(1) shown a single closing event for GLIC at neutral pH in molecular simulations. Here, we have employed ensemble molecular dynamics simulations to systematically explore the conformational dynamics of the channel, starting from both open and locally-closed conformations. We observe a large number of both opening and closing events. We have also simulated multiple functional mutants of the GLIC channel and observe shifts in opening or closing propensity that agree well with the functional data. Mutants strongly biased towards opening remained open for greater than one microsecond in our simulations. Based on our results, we generate a structural model for which portions of the channel can close sufficiently to restrict water and ion flow.(1) Samuel Murail, Rebecca J. Howard, James R. Trudell, Edward Bertaccini, Erik Lindahl, Tracing the Closing of a Ligand-Gated Ion Channel in Atomic Detail: An Unconstrained Four-Microsecond Simulation of GLIC Leads to a Closed State Remarkably Similar to ELIC, Biophysical Journal, Volume 102, Issue 3, Supplement 1, 31 January 2012, Pages 113a-114a, ISSN 0006-3495, 10.1016/j.bpj.2011.11.639. (http://www.sciencedirect.com/science/article/pii/S0006349511019874)