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

Bogdan Lev (1) , Samuel Murail (2) , Frédéric Poitevin (3, 4) , Brett A Cromer (1) , Marc Baaden (2) , Marc Delarue (5) , Toby W. Allen (1)

1 RMIT University - Royal Melbourne Institute of Technology University
2 LBT (UPR_9080) - Laboratoire de biochimie théorique [Paris]
3 Stanford University
4 PULSE Institute
5 Département de Biologie structurale et Chimie - Department of Structural Biology and Chemistry

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.

Mots clés: allosteric modulation; string method molecular dynamics; pentameric ligand-gated ion channel; pH activation; ion channel gating; pentameric ligand-gated ion channel ion channel gating string method molecular dynamics allosteric modulation pH activation

Domaines: Bio-Informatique, Biologie Systémique [q-bio.QM]

Bogdan Lev, Samuel Murail, Frédéric Poitevin, Brett A Cromer, Marc Baaden, et al.. String method solution of the gating pathways for a pentameric ligand-gated ion channel. Proceedings of the National Academy of Sciences of the United States of America, 2017, 114 (21), pp.E4158 - E4167. ⟨10.1073/pnas.1617567114⟩. ⟨hal-01644525⟩