title: Conformational gating dynamics in the GluCl anion-selective chloride channel.
abstract: Cys-loop receptors are central to propagation of signals in the nervous system. The gating of the membrane-spanning pore is triggered by structural rearrangements in the agonist-binding site, located some 50 Å away from the pore. A sequential conformational change, propagating from the ligand-binding site to the pore, has been proposed to govern gating in all Cys-loop receptors. Here, we identify structural and dynamic components of the conformational gating in the eukaryotic glutamate-gated chloride channel (GluCl) by means of molecular dynamics (MD) simulations with and without the l-glutamate agonist bound. A significant increase in pore opening and accompanying hydration is observed in the presence of glutamate. Potential of mean force calculations reveal that the barrier for ion passage drops from 15 kcal/mol to 5-10 kcal/mol with the agonist bound. This appears to be explained by agonist binding that leads to significant changes in the intersubunit hydrogen-bonding pattern, which induce a slight tilt of the extracellular domain relative to the transmembrane domain in the simulations. This rearrangement is subtle, but correspond to the direction of the quaternary twist observed as a key difference between open and closed X-ray structures. While the full reversible gating is still a much slower process, the observed structural dynamics sheds new light on the early stages of how the agonist influences the extracellular domain, how the extracellular domain interacts with the transmembrane domain, and how changes in the transmembrane domain alter the free energy of ion passage.
authors.affiliation: †Science for Life Laboratory, Stockholm and Uppsala, 171 21 Stockholm, Sweden.|‡Theoretical and Computational Biophysics, Department of Theoretical Physics, KTH Royal Institute of Technology, 106 91 Stockholm, Sweden.
authors.forename: Özge
authors.initials: Ö
authors.lastname: Yoluk
authors.affiliation: †Science for Life Laboratory, Stockholm and Uppsala, 171 21 Stockholm, Sweden.|‡Theoretical and Computational Biophysics, Department of Theoretical Physics, KTH Royal Institute of Technology, 106 91 Stockholm, Sweden.|§Department of Biochemistry and Biophysics, Center for Biomembrane Research, Stockholm University, 114 18 Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Lindahl
authors.affiliation: †Science for Life Laboratory, Stockholm and Uppsala, 171 21 Stockholm, Sweden.|‡Theoretical and Computational Biophysics, Department of Theoretical Physics, KTH Royal Institute of Technology, 106 91 Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Andersson
mesh_terms: D018118:Chloride Channels / Q000737:chemistry / Q000378:metabolism*; D018698:Glutamic Acid / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D007559:Ivermectin / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation
chemical_list: D018118:Chloride Channels; C109777:glutamate-gated chloride channels; D018698:Glutamic Acid; D007559:Ivermectin
keywords: Membrane protein; cys-loop receptor; ligand-gated ion channel; molecular dynamics simulations