Preorganized Electric Fields in Voltage‐Gated Sodium Channels

Abstract

Enzymes are reported to catalyze reactions by generating electric fields that promote the evolution of the reaction in the active site. Although seldom used outside enzymatic catalysis, electrostatic preorganization theory and language of electric fields can be generalized to other biological macromolecules. Herein, we performed molecular dynamics simulations of human Nav1.5, Nav1.6, and Nav1.7 with the atomic multipole optmimized energetics for biomolecular applications polarizable force field. We show that in the absence of an external potential, charged and uncharged residues generate strong electric fields that assist in Naþ motion in the pore. This work emphasizes the importance of charge–dipole interactions in modulating Naþ dynamics, in addition to charge–charge interactions, the focus of a majority of previous studies. Finally, we find that residues share a high level of mutual information through electric fields that can enable the optimization of allosteric pathways.