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

Potassium (K+) channels are widely distributed in many types of organisms. Potassium channels combine high efficiency (K+ ions permeation rates ~100 pS) and exquisite K+/Na+ selectivity by a conserved selectivity filter (SF) with four adjacent potassium-binding sites. Molecular Dynamics (MD) simulations can, in principle, provide a detailed, atomistic mechanism of this sophisticated ion permeation. However, currently there are clear inconsistencies between computational and experimental predictions. 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 from single-channel electrophysiology. This discrepancy is in part because the force fields used in MD simulations of potassium channels do not account for explicit electronic polarization. One of the proposed solutions is the Electronic Continuum Correction (ECC), a force field modification that scales down formal atomic charges, to introduce the polarization in a mean-field way. In this work, we apply the ECC to MD simulations of K+ channels under applied voltage. When the ECC is used in conjunction with the Charmm36m force field, the simulated K+ conductance increases 13-fold, whereas applying the ECC to Amber14 seemingly has no major effect. Following the analysis of ion occupancy states using Hamiltonian Replica Exchange (HRE) simulations, we propose a new parameter set for Amber14sb, that 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 tested, for three K+ channels. In all simulated systems, the direct knock-on permeation mechanism with near-full K+ ion occupancy of the SF is consistently observed. In general, our ECC-enabled simulations are in excellent agreement with experimental data, in terms of ion occupancy, conductance, current-voltage response, and K+/Na+ selectivity. These simulations thus form a robust basis to study structure-function relations in K+ channels on the atomistic level with unprecedented accuracy, as exemplified by deciphering the rectification mechanism of the MthK channel.