Binding of General Anesthetics to Ion Channels

Abstract

The directsite hypothesis assumes general anesthetics bind ion channels to impact protein equilibrium and function, inducing anesthesia. Despite advancements in the field, a firstprinciple allatom demonstration of this structurefunction premise misses. We focus on the clinically used sevoflurane interaction to anestheticsensitive Kv1.2 mammalian channel to resolve if sevoflurane binds protein's wellcharacterized open and closed structures in a conformationdependent manner to shift channel equilibrium. We employ an innovative approach relying on extensive docking calculations and freeenergy perturbation and find sevoflurane binds open and closed structures at multiple sites under complex saturation and concentration effects. Results point to a nontrivial interplay of conformationdependent modes of action involving distinct binding sites that increase channel open probability at diluted ligand concentrations. Given the challenge in exploring more complex processes potentially impacting channel anesthetic interaction, the result is reassuring as demonstrates the process of multiple binding events alone may account for open probability shifts recorded in measurements.