The wild-type hERG cryo-EM structure fails to support conduction and evolve toward an inactivated-like selectivity filter conformation in molecular dynamics simulations

The recent determination of the human Ether-a-go-go-Related Gene (hERG) K+ channel structure using cryo-electron microscopy (cryo-EM) under both high- and low-K+ conditions has sparked debate about the channel's conductive state. Many researchers have assumed the high-K+ structures represent a stable conductive conformation, but this study challenges that notion.

Utilizing extensive all-atom molecular dynamics (MD) simulations, both with and without Electronic Continuum Correction (ECC), the researchers investigated selectivity filter (SF) dynamics and ion permeation in wild-type (WT) hERG and a non-inactivating N629D mutant. The findings reveal that the WT hERG structure does not support K+ permeation and instead naturally evolves towards a non-conductive SF conformation.

This conformation is marked by extracellular dilation, localized inner constriction, depletion of outer ion-binding sites, and persistent trapping of K+ ions within the central binding sites, much like the inactivated SF seen in Shaker channels. In contrast, the N629D mutant maintains a stable conductive SF architecture, similar to that of canonical K+ channels like KcsA, while displaying robust voltage-dependent K+ permeation.

However, the study notes that electrostatic correction (ECC) helped increase ion permeation in the N629D mutant but did not support conduction in the WT hERG structure. This remained structurally and functionally non-conductive. These results question the widely held belief that the high-K+ WT hERG cryo-EM structure signifies a stable conductive state.

Instead, the study suggests that SF remodeling is the structural mechanism driving hERG C-type inactivation.