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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.

Original publication

DOI

10.1016/j.str.2016.10.005

Type

Journal article

Journal

Structure

Publication Date

06/12/2016

Volume

24

Pages

2207 - 2216

Keywords

annotation, hydrophobic gating, ion channel, membrane protein, molecular dynamics, Cell Membrane, Hydrophobic and Hydrophilic Interactions, Ion Channels, Models, Molecular, Molecular Dynamics Simulation, Protein Conformation, Receptors, Serotonin, 5-HT3, Water