Binding of the general anesthetic sevoflurane to ion channels

Letícia Stock, Juliana Hosoume, Leonardo Cirqueira and Werner Treptow

PLOS Computational Biology, 2018, vol. 14, issue 11, 1-23

Abstract: The direct-site hypothesis assumes general anesthetics bind ion channels to impact protein equilibrium and function, inducing anesthesia. Despite advancements in the field, a first principle all-atom demonstration of this structure-function premise is still missing. We focus on the clinically used sevoflurane interaction to anesthetic-sensitive Kv1.2 mammalian channel to resolve if sevoflurane binds protein’s well-characterized open and closed structures in a conformation-dependent manner to shift channel equilibrium. We employ an innovative approach relying on extensive docking calculations and free-energy perturbation of all potential binding sites revealed by the latter, and find sevoflurane binds open and closed structures at multiple sites under complex saturation and concentration effects. Results point to a non-trivial interplay of site and conformation-dependent 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 revealing as it demonstrates the process of multiple anesthetic binding events alone may account for open-probability shifts recorded in measurements.Author summary: General anesthetics are central to modern medicine, yet their microscopic mechanism of action is still unknown. Here, we demonstrate that a clinically used anesthetic, sevoflurane, binds the mammalian voltage-gated potassium channel Kv1.2 effecting a shift in its open probability, even at low concentrations. The results, supported by recent experimental measurements, are promising as they demonstrate that the molecular process of direct binding of anesthetic to ion channels play a relevant role in anesthesia.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1006605

DOI: 10.1371/journal.pcbi.1006605

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