Atomistic Simulations of Membrane Ion Channel Conduction, Gating, and Modulation

Abstract

Membrane ion channels are the fundamental electrical components in the nervous system. Recent developments in X-ray crystallography and cryo-EM microscopy have revealed what these proteins look like in atomic detail but do not tell us how they function. Molecular dynamics simulations have progressed to the point that we can now simulate realistic molecular assemblies to produce quantitative calculations of the thermodynamic and kinetic quantities that control function. In this review, we summarize the state of atomistic simulation methods for ion channels to understand their conduction, activation, and drug modulation mechanisms. We are at a crossroads in atomistic simulation, where long time scale observation can provide unbiased exploration of mechanisms, supplemented by biased free energy methodologies. We illustrate the use of these approaches to describe ion conduction and selectivity in voltage-gated sodium and acid-sensing ion channels. Studies of channel gating present a significant challenge, as activation occurs on longer time scales. Enhanced sampling approaches can ensure convergence on minimum free energy pathways for activation, as illustrated here for pentameric ligand-gated ion channels that are principal to nervous system function and the actions of general anesthetics. We also examine recent studies of local anesthetic and antiepileptic drug binding to a sodium channel, revealing sites and pathways that may offer new targets for drug development. Modern simulations thus offer a range of molecular-level insights into ion channel function and modulation as a learning platform for mechanistic discovery and drug development.

Determinants of ion selectivity in ASIC1a- and ASIC2a-containing acid-sensing ion channels

“…While the precise ion-carboxylate LJ parameter will affect ion free energies within the ASIC pores, we have previously shown that selective binding is maintained regardless of the choice (Lynagh et al, 2017a). Modified LJ parameters, however, were used to describe the interactions between cations and carbonyl oxygen atoms of the protein to reproduce free energies of solvation in protein backbone mimetic, N -methyl-acetamide (Bernèche and Roux, 2001; Noskov et al, 2004; Allen et al, 2006; Flood, 2019).…”

Queueing arrival and release mechanism for K+ permeation through a potassium channel

“…Permeating K + ions cannot occupy adjacent binding sites in the SF because of the electrostatic repulsion, and water molecules are intercalated between ions such that K + and water molecules (w) are aligned in alternating arrays, denoted as w-K + -w-K + and K + -w-K + -w. Morais-Cabral et al considered that the interconversion between the alternating arrays yielded rapid permeation. Molecular dynamics (MD) simulations reproduced the alternating arrays, and the simulation results were interpreted as an incoming ion that forced the expulsion of the downstream ion [17][18][19][20][21][22][23][24][25] via the three-ion-occupied intermediate (K + -w-K + -w-K + ; the "knock-on intermediate" [19]; Fig. 1, right lower snapshot) [15,16].…”

Simulating ion channel activation mechanisms using swarms of trajectories

“…Over the last two decades, advances in X‐ray crystallography, and more recently in cryogenic electron microscopy (cryo‐EM), have provided atomic‐level ion channel structures to allow simulation studies of ion permeation, selectivity, gating and drug modulation . Each of these processes represents a challenge to simulation, because the time scales are either comparable to, or exceed that achievable with present day computers.…”