Functional Annotation of Ion Channel Structures by Molecular Simulation

• Published in: Structure (London) Vol. 24; no. 12; pp. 2207 - 2216
• Main Authors: Trick, Jemma L., Chelvaniththilan, Sivapalan, Klesse, Gianni, Aryal, Prafulla, Wallace, E. Jayne, Tucker, Stephen J., Sansom, Mark S.P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 06.12.2016; Cell Press
• Subjects: annotation; Cell Membrane - metabolism; Hydrophobic and Hydrophilic Interactions; hydrophobic gating; ion channel; Ion Channels - chemistry; membrane protein; Models, Molecular; molecular dynamics; Molecular Dynamics Simulation; Protein Conformation; Receptors, Serotonin, 5-HT3 - chemistry; Resource; Water - chemistry; annotation; hydrophobic gating; membrane protein; molecular dynamics; ion channel
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2016.10.005

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. [Display omitted] •Hydrophobic gating can close ion channels via dewetting of the central pore•We functionally annotate channel structures via simulation of water within the pore•The 5-HT3 receptor is shown by simulation to be in a functionally closed state•Three states of the glycine receptor are compared via their pore water density Hydrophobic gating can generate functionally closed ion channel states. Trick et al. show that molecular dynamics simulations can aid functional annotation of channel structures by revealing the behavior of water within transmembrane pores. They describe increasingly complex simulation analyses: water equilibrium densities; single-ion free-energy profiles; and computational electrophysiology.