# Preorganized Electric Fields in Voltage‐Gated Sodium Channels

## TL;DR

This study shows that electric fields in sodium channels help ions move through the channel, highlighting the role of charge-dipole interactions.

## Contribution

The paper introduces the concept of preorganized electric fields in voltage-gated sodium channels using polarizable simulations.

## Key findings

- Charged and uncharged residues generate strong electric fields that assist Na+ motion in the pore.
- Charge–dipole interactions significantly modulate Na+ dynamics alongside charge–charge interactions.
- Residues share mutual information through electric fields, enabling optimization of allosteric pathways.

## 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 Na+ motion in the pore. This work emphasizes the importance of charge–dipole interactions in modulating Na+ 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.

Charged and uncharged polar residues in ion channels are preorganized to generate electric fields that align water molecules in the pore and facilitate ion dynamics. These electric fields emanate primarily from charge–dipole and charge–charge interactions.© 2025 WILEY‐VCH GmbH