String method solution of the gating pathways for a pentameric ligand-gated ion channel.

TitleString method solution of the gating pathways for a pentameric ligand-gated ion channel.
Publication TypeJournal Article
Year of Publication2017
AuthorsLev B, Murail S, Poitevin F, Cromer BA, Baaden M, Delarue M, Allen TW
JournalProc Natl Acad Sci U S A
Date Published2017 05 23
KeywordsComputer Simulation, Ligand-Gated Ion Channels, Models, Biological, Models, Chemical

Pentameric ligand-gated ion channels control synaptic neurotransmission by converting chemical signals into electrical signals. Agonist binding leads to rapid signal transduction via an allosteric mechanism, where global protein conformational changes open a pore across the nerve cell membrane. We use all-atom molecular dynamics with a swarm-based string method to solve for the minimum free-energy gating pathways of the proton-activated bacterial GLIC channel. We describe stable wetted/open and dewetted/closed states, and uncover conformational changes in the agonist-binding extracellular domain, ion-conducting transmembrane domain, and gating interface that control communication between these domains. Transition analysis is used to compute free-energy surfaces that suggest allosteric pathways; stabilization with pH; and intermediates, including states that facilitate channel closing in the presence of an agonist. We describe a switching mechanism that senses proton binding by marked reorganization of subunit interface, altering the packing of β-sheets to induce changes that lead to asynchronous pore-lining M2 helix movements. These results provide molecular details of GLIC gating and insight into the allosteric mechanisms for the superfamily of pentameric ligand-gated channels.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
Citation Key2017|2096
PubMed ID28487483
PubMed Central IDPMC5448215
Grant ListP41 RR006009 / RR / NCRR NIH HHS / United States
R35 GM122543 / GM / NIGMS NIH HHS / United States
U01 HL126273 / HL / NHLBI NIH HHS / United States