Modulation of the Gloeobacter violaceus Ion Channel by Fentanyl: A Molecular Dynamics Study.

David F. Plant,Christopher Faulkner,Nora H. de Leeuw

doi:10.1021/acs.biochem.9b00881

David F. Plant, Christopher Faulkner + Show 1 more

Open Access

https://doi.org/10.1021/acs.biochem.9b00881

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Journal: Biochemistry	Publication Date: Nov 13, 2019
Citations: 7	License type: cc-by

Affiliation: Atomic Weapons Establishment, Cardiff University

Abstract

Fentanyl is an opioid analgesic, which is routinely used in general surgery to suppress the sensation of pain and as the analgesic component in the induction and maintenance of anesthesia. Fentanyl is also used as the main component to induce anesthesia and as a potentiator to the general anesthetic propofol. The mechanism by which fentanyl induces its anesthetic action is still unclear, and we have therefore employed fully atomistic molecular dynamics simulations to probe this process by simulating the interactions of fentanyl with the Gloeobacter violaceus ligand-gated ion channel (GLIC). In this paper, we identify multiple extracellular fentanyl binding sites, which are different from the transmembrane general anesthetic binding sites observed for propofol and other general anesthetics. Our simulations identify a novel fentanyl binding site within the GLIC that results in conformational changes that inhibit conduction through the channel.

Highlights

GLIC structure[9] in a different, extracellular binding site compared to that of general anesthetics
The GLIC open state structure at atomic resolution (2.4 Å) published by Sauguet et al.[6] and the previous simulation studies of anesthetics interacting with ion channels[13−15] provide us with the opportunity to compare the effect of fentanyl on a GLIC structure with the binding and modulation of the channel by general anesthetics
Our analysis clearly shows the formation of a hydrophobic gate within the pore that is consistent with that observed for general anesthetics

Summary

Introduction

GLIC structure[9] in a different, extracellular binding site compared to that of general anesthetics. The GLIC open state structure at atomic resolution (2.4 Å) published by Sauguet et al.[6] and the previous simulation studies of anesthetics interacting with ion channels[13−15] provide us with the opportunity to compare the effect of fentanyl on a GLIC structure with the binding and modulation of the channel by general anesthetics.

Results

Conclusion