Pentameric ligand-gated ion channels control synaptic neurotransmission via an allosteric mechanism, where agonist binding induces global protein conformational changes that open an ion-conducting pore. This family of channels is the target of general anesthetics, such that understanding their function and modulation mechanisms could lead to new anesthetics with better safety margins and reduced neurodevelopmental and cognitive effects. Here we report results using an atomistic molecular dynamics string method to solve for the minimum free energy gating pathways for the proton-activated GLIC channel. We describe stable open and closed states, and uncover conformational changes associated with communication between agonist-binding extracellular and ion-conducting trans-membrane domains. Transition analysis is used to compute free energy surfaces that suggest pathways, allosteric stabilization with pH, and intermediate states that facilitate channel closing in the presence of agonist. We have repeated simulations with general anesthetic propofol bound to potentiating and inhibitory sites, observing the effects on gating energetics and revealing atomic-level details of the modulation mechanisms that underscore general anesthetic activity.

Atomistic string method solution for ion channel gating and modulation by general anesthetics

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.