A membrane-embedded pathway delivers general anesthetics to two interacting binding sites in the Gloeobacter violaceus Ion Channel [Molecular Biophysics]

General anesthetics exert their effects on the central nervous system by acting on ion channels, most notably pentameric ligand−gated ion channels (pLGICs). Although numerous studies have focused on pLGICs, the details of anesthetic binding and channel modulation remains debated. A better understanding of anesthetic mechanism of action is necessary for the development of safer and more efficacious drugs. Herein, we present a computational study identifying two anesthetic binding sites in the transmembrane domain of the GLIC channel, characterize the putative binding pathway, and observe structural changes associated with channel function. Molecular simulations of desflurane reveal a binding pathway to GLIC via a membrane−embedded tunnel utilizing an intrasubunit protein lumen as the conduit, an observation that explains the Meyer−Overton hypothesis, or why the lipophilicity of an anesthetic and its potency are generally proportional. Moreover, employing high concentrations of ligand led to the identification of a second transmembrane site (TM2) which inhibits dissociation of anesthetic from the TM1 site, and is consistent with the high concentrations of anesthetics required to achieve clinical effects. Finally, asymmetric binding patterns of anesthetic to the channel were found to promote an iris−like conformational change that constricts and dehydrates the ion pore, creating a 13.5 kcal/mol barrier to ion translocation. Together with previous studies, the simulations presented herein demonstrate a novel anesthetic binding site in GLIC which is accessed through a membrane-embedded tunnel and interacts with a previously known site, resulting in conformational changes that produce a non−conductive state of the channel.

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