Charge Scaling in Potassium Channel Simulations: Conductance, Ion Occupancy, Voltage Response, and Selectivity

Abstract

Potassium (K+) channels are widely distributed in many types of organisms. They combine high efficiency ([~]100 pS) and K+/Na+ selectivity by a conserved selectivity filter (SF). Molecular Dynamics (MD) simulations can provide detailed, atomistic mechanisms of this sophisticated ion permeation. However, currently there are clear inconsistencies between computational predictions and experimental results. Firstly, the ion occupancy of the SF in simulations is lower than expected ([~]2.5 in MD compared to [~]4 in X-ray crystallography). Secondly, in many reported MD simulations of K+ channels, K+ conductance is typically an order of magnitude lower than experimental values. This discrepancy is in part because the force fields used in MD simulations of potassium channels do not account for polarization. One of the proposed solutions is the Electronic Continuum Correction (ECC), a force field modification that scales down formal charges, to introduce the polarization in a mean-field way. When the ECC is used in conjunction with the Charmm36m force field, the simulated K+ conductance increases 13-fold. Following the analysis of ion occupancy states using Hamiltonian Replica Exchange (HRE) simulations, we propose a new parameter set for Amber14sb, that also leads to a similar increase in conductance. These two force fields are then used to compute, for the first time, the full current-voltage (I-V) curves from MD simulations, approaching quantitative agreement with experiments at all voltages. In general, the ECC-enabled simulations are in excellent agreement with experiment, in terms of ion occupancy, conductance, current-voltage response, and K+/Na+ selectivity. Significance StatementPotassium (K+) channels are essential membrane proteins that facilitate the selective conduction of K+ ions while excluding Na+ ions. Incorporation of electronic polarization effects through the Electronic Continuum Correction (ECC) method enables molecular dynamics simulations to reproduce rapid K+ permeation under physiological voltage conditions. In this study, we demonstrate that employing ECC approximated polarization in molecular dynamics simulations allows for the prediction of multiple channel properties: conductance, ion occupancy, voltage response, and selectivity, with unprecedented accuracy. Furthermore, our simulations provide atomistic insights into the asymmetrical current-voltage (I-V) relationship observed in the MthK channel.