A heuristic derived from analysis of the ion channel structural proteome permits the rapid identification of hydrophobic gates

Significance

Ion channels are nanoscale protein pores in cell membranes. An exponentially increasing number of structures for channels means that computational methods for predicting their functional state are needed. Hydrophobic gates in ion channels result in local dewetting of pores, which functionally closes them to water and ion permeation. We use simulations of water behavior within nearly 200 different ion channel structures to explore how the radius and hydrophobicity of pores determine their hydration vs. dewetting behavior. Machine learning-assisted analysis of these simulations allowed us to propose a simple model for this relationship and present an easy method for rapidly predicting the functional state of new channel structures as they emerge.

Abstract

Ion channel proteins control ionic flux across biological membranes through conformational changes in their transmembrane pores. An exponentially increasing number of channel structures captured in different conformational states are now being determined; however, these 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 additional assessment of the effect of pore hydrophobicity. A narrow hydrophobic gate region may disfavor liquid-phase water, leading to local dewetting, which will form 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 dewetting by applying molecular dynamics simulations and machine learning to nearly 200 ion channel structures. This allows us to propose a simple simulation-free heuristic model that rapidly and accurately predicts the presence of hydrophobic gates. This not only enables the functional annotation of new channel structures as soon as they are determined, but also may facilitate the design of novel nanopores controlled by hydrophobic gates.