Publications associated with Ion Channels

Identification of Hydrophobic Gates by Simulation-Enabled Analysis of the Ion Channel Structural Proteome


S Rao, G Klesse, P Stansfeld, S Tucker, MSP Sansom

Abstract Ion channel proteins control ionic flux across biological membranes through conformational changes in their transmembrane pores. An increasing number of channel structures captured in different conformational states are being determined as a result of advances in membrane protein structural biology. However, newly resolved structures are commonly classified as either open or closed based solely on the physical dimensions of their pore and it is now known that more accurate annotation of their conductive state requires an additional assessment of the effect of pore hydrophobicity. A narrow hydrophobic gate region may disfavour liquid-phase water, leading to local de-wetting and an energetic barrier to water and ion permeation without steric occlusion of the pore. Here we quantify the combined influence of radius and hydrophobicity on pore de-wetting by applying molecular dynamics-based calculations to nearly 200 ion channel structures. Using machine learning, we propose a simple heuristic model that allows the rapid prediction of the state of hydrophobic gates based on analysis of both local radius and hydrophobicity in ion channel structures and nanopores.

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