Modeling of Electrostatic Interactions inside Human Voltage-Gated Sodium Channels

Abstract

In this project, we focus on the permeation of Na+ through human voltage-gated sodium channels (Navs). Despite their biological significance, the selective permeation mechanism of Nav channels remains poorly understood at the molecular level. Here, we calculated electric fields inside the channel pore of Nav1.5, 1.6, and 1.7 to gain insights into the components that control the selectivity and permeation of Nav channels. We found that water inside the channel pore aligns vertically in response to the electric fields created by the channel residues. The regions with stronger electric field, characterized by stronger water alignment, correlate to Na+ binding sites identified by Na+ free energy profile. Residues in the P-loop, including the selectivity filter and outer ring residues, generate strong electric fields acting on pore Na+ ions, showing their significance in Na+ binding and permeation. Future study with different ions can identify their roles in ion selectivity. Overall, we have shown that electric fields computed from molecular dynamics simulations using the AMOEBA force field serve as effective indicators for identifying residues crucial to protein function.