title: Functional Annotation of Ion Channel Structures by Molecular Simulation.
abstract: Ion channels play key roles in cell membranes, and recent advances are yielding an increasing number of structures. However, their functional relevance is often unclear and better tools are required for their functional annotation. In sub-nanometer pores such as ion channels, hydrophobic gating has been shown to promote dewetting to produce a functionally closed (i.e., non-conductive) state. Using the serotonin receptor (5-HT3R) structure as an example, we demonstrate the use of molecular dynamics to aid the functional annotation of channel structures via simulation of the behavior of water within the pore. Three increasingly complex simulation analyses are described: water equilibrium densities; single-ion free-energy profiles; and computational electrophysiology. All three approaches correctly predict the 5-HT3R crystal structure to represent a functionally closed (i.e., non-conductive) state. We also illustrate the application of water equilibrium density simulations to annotate different conformational states of a glycine receptor.
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
authors.forename: Jemma L
authors.initials: JL
authors.lastname: Trick
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK.
authors.forename: Sivapalan
authors.initials: S
authors.lastname: Chelvaniththilan
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK.
authors.forename: Gianni
authors.initials: G
authors.lastname: Klesse
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK; OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford, UK.
authors.forename: Prafulla
authors.initials: P
authors.lastname: Aryal
authors.affiliation: Oxford Nanopore Technologies Ltd., Oxford OX4 4GA, UK.
authors.forename: E Jayne
authors.initials: EJ
authors.lastname: Wallace
authors.affiliation: Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK; OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tucker
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford, UK. Electronic address: mark.sansom@bioch.ox.ac.uk.
authors.forename: Mark S P
authors.initials: MSP
authors.lastname: Sansom
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D007473:Ion Channels / Q000737:chemistry*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry*; D014867:Water / Q000737:chemistry*
chemical_list: D007473:Ion Channels; D044406:Receptors, Serotonin, 5-HT3; D014867:Water
keywords: annotation; hydrophobic gating; ion channel; membrane protein; molecular dynamics