Preorganized Electric Fields in Voltage-Gated Sodium Channels.

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 Na1.5, Na1.6, and Na1.7 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.