Binding of the general anesthetic sevoflurane to ion channels

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.

Open‐channel blocking action of volatile anaesthetics desflurane and sevoflurane on human voltage‐gated Kv1.5 channel

“…While mutagenesis experiments are associated with allosteric effects, computational docking simulations cannot completely reproduce the physiological cellular milieu involved in drug–channel interaction. Furthermore, although previous workers have adopted an innovative approach of ionic flux simulations under applied transmembrane voltages to investigate channel‐anaesthetic interaction (Stock et al, 2018), our simulation study did not reproduce K + efflux through the fully flexible channel protein embedded in cell membranes. Because our site‐directed mutagenesis and docking simulation experiments were conducted by focusing on the channel pore region, our studies do not necessarily rule out other molecular mechanisms underlying the open‐channel blocking action of desflurane and sevoflurane on hK v 1.5 channels.…”

“…To evaluate possible docking sites, the number of docking solutions per site was counted in top 100 poses of desflurane or sevoflurane docked to the hKv1.5 homology model, determined by docking scores composed of electrostatic, van der Waals, solvation, and strain energy (Goto et al, 2008; Mori et al, 2012). The hK v 1.5 channel protein was divided into seven possible regions, namely, inner cavity of the channel pore, S6‐pore helix interface, extracellular face, S4‐S5 linker, voltage‐sensor domain, S4‐pore interface (Stock, Hosoume, Cirqueira, & Treptow, 2018; Stock, Hosoume, & Treptow, 2017), and other locations.…”

Hydrophobic Drug/Toxin Binding Sites in Voltage-Dependent K+ and Na+ Channels

“…The inhalation anaesthetic, sevoflurane, seems to bind within the central cavity and to a similar hydrophobic pocket as psora-4 (Stock et al, 2018). Apart from these binding regions, the polar lipophilic molecule has been shown to interact with the S4-S5 linker, pore helix, segment S6, and even the VSD, likewise to the many binding regions of sevoflurane on the Na v channel (Barber et al, 2011;Barber et al, 2014).…”

“…Apart from these binding regions, the polar lipophilic molecule has been shown to interact with the S4-S5 linker, pore helix, segment S6, and even the VSD, likewise to the many binding regions of sevoflurane on the Na v channel (Barber et al, 2011;Barber et al, 2014). These sites are primarily dehydrated and lipid accessible, which is highly favourable for the polar lipophilic sevoflurane molecule (Stock et al, 2018). The specific residues involved in sevoflurane binding are not known, but one residue within the S4-S5 linker (G329 according to K v 1.2 numbering) has been identified to play an important role (Liang et al, 2015).…”

“…Zinc pyrithione, on the other hand, seems to solely bind to the back side of the PD, implying that the front and back side of the PD could serve as distinct binding sites ( Figures 5 and 7) (Xiong et al, 2007). Psora-4 and sevoflurane are less specific regarding their binding site, as they both bind to the front and back side of the PD, among others (Marzian et al, 2013;Liang et al, 2015;Stock et al, 2018). Although certain compounds solely bind to the front or back side of the PD it seems that all residues point toward a similar lipophilic region, leading to the speculation that these seemingly distinct binding sites may converge to just one conserved lipophilic binding region in K v channels.…”