Preorganized electric fields facilitate ion binding and permeation in voltage-gated sodium channel Nav1.7

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 the language of electric fields can be generalized to other biological macromolecules. Here, we calculate the electric fields generated by the residues of human voltage-gated sodium channel Nav1.7. We show that in the inactivated state, and in the absence of an external bias (transmembrane potential), residues in the selectivity filter and outer-ring of carboxylates, as well as a few others, generate strong electric fields that assist in Na+ binding and permeation. We validated these results by characterizing water alignment in the channel pore and computing the free energy profile of pore Na+s. We found that areas with stronger electric fields (stronger water alignment) correlates with Na+ minimum-energy sites. Additionally, we show that Nav1.7’s residues exert an electric field aligned along the S4 helix in each domain, assisting channel state transitions. Interestingly, we observe that the four domains of Nav1.7 do not contribute equally to these fields, revealing a functional difference in the homologous domains. Overall, our results show that the residues in Nav1.7 generate preorganized electric fields that facilitate gating, ion binding and permeation, thereby expanding electrostatic preorganization theory to ion channels.