In-Silico Electrophysiology: On the Activation of Voltage-Gated Ion Channels using Molecular Dynamics Simulations

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The working cycle of voltage gated ion channels involves the complex conformational change of modular protein units called voltage sensor domains (VSDs). For over forty years, these rearrangements have been recorded as “gating” currents, intensities and kinetics of which are unique signatures of VGC function. Here we show, for the potassium VGC Kv1.2, that the atomistic description of VSD activation obtained by molecular dynamics simulations and free energy calculations is consistent with the phenomenological models adopted so far to account for the macroscopic observables measured by electrophysiology. The properties of the computed single channel current traces, as well as “whole-cell” gating currents under several voltage clamped protocols are in agreement with experiments. Hence, by providing a connection between microscopic and macroscopic dynamics, our results pave the way for a deeper understanding of the molecular level factors affecting VSD activation, such as lipid composition, amino acid mutations, and binding of endogenous ligands.