A Deep Learning Approach to Uncover Voltage-Gated Ion Channels’ Intermediate States.

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Abstract

Owing to recent advancements in cryo-electron microscopy, voltage-gated ion channels have gained a greater comprehension of their structural characteristics. However, a significant enigma remains unsolved for a large majority of these channels: their gating mechanism. This mechanism, which encompasses the conformational changes between open and closed states, is pivotal to their proper functioning. Beyond the binary states of open and closed, an ensemble of intermediate states defines the transition path in-between. Due to the lack of experimental data, one might resort to molecular dynamics simulations as an alternative to decipher these states and the transitions between them. However, the high-energy barriers and the colossal time scales involved hinder access to the latter. We present here an application of deep learning as a reliable pipeline for a comprehensive exploration of voltage-gated ion channel conformational rearrangements during gating. We showcase the pipeline performance specifically on the Kv1.2 voltage sensor domain and confront the results with existing data. We demonstrate how our physics-based deep learning approach contributes to the theoretical understanding of these channels and how it might provide further insights into the exploration of channelopathies.