Reviewer #3 (Public review): Distinct mechanisms of inhibition of Kv2 potassium channels by tetraethylammonium and RY785

This study represents an important advance in our understanding of how certain inhibitors affect the behavior of voltage gated potassium channels.Robust molecular dynamics simulation and analysis methods lead to a new proposed inhibition mechanism with convincing strength of support.This study has considerable significance for the fields of ion channel physiology and pharmacology and could aid in development of selective inhibitors for protein targets.