ArticlePLoS computational biology2012
General anesthetics predicted to block the GLIC pore with micromolar affinity.
Article in PLoS computational biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 63 citations in OpenAlex.
- General anesthetic modulation of a pentameric ligand-gated ion channel explored with simulations.Biophysical journal · 2026Article
- Structural and functional characterization of Caenorhabditis elegans cyclic GMP-activated channel TAX-4 via molecular dynamics simulations.European biophysics journal : EBJ · 2026Article
- Propofol binds and inhibits skeletal muscle ryanodine receptor 1.British journal of anaesthesia · 2024Article
- Alchemical Free Energy Calculations on Membrane-Associated Proteins.Journal of chemical theory and computation · 2023Review
- Simulation and Machine Learning Methods for Ion-Channel Structure Determination, Mechanistic Studies and Drug Design.Frontiers in pharmacology · 2022Review
- Binding Sites and the Mechanism of Action of Propofol and a Photoreactive Analogue in Prokaryotic Voltage-Gated Sodium Channels.ACS chemical neuroscience · 2021Article
- Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel.eLife · 2021Article
- Menthol Binding to the Human α4β2 Nicotinic Acetylcholine Receptor Facilitated by Its Strong Partitioning in the Membrane.The journal of physical chemistry. B · 2020Article
- A Refined Open State of the Glycine Receptor Obtained via Molecular Dynamics Simulations.Structure (London, England : 1993) · 2020Article
- A Streamlined, General Approach for Computing Ligand Binding Free Energies and Its Application to GPCR-Bound Cholesterol.Journal of chemical theory and computation · 2018Article
- Ion channels can be allosterically regulated by membrane domains near a de-mixing critical point.The Journal of general physiology · 2018Article
- Binding of the general anesthetic sevoflurane to ion channels.PLoS computational biology · 2018Article
- Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Propofol inhibits the voltage-gated sodium channel NaChBac at multiple sites.The Journal of general physiology · 2018Article
- Propofol inhibits prokaryotic voltage-gated NaThe Journal of general physiology · 2018Article
- Permeating disciplines: Overcoming barriers between molecular simulations and classical structure-function approaches in biological ion transport.Biochimica et biophysica acta. Biomembranes · 2018Review
- Molecular Mechanics Parameterization of Anesthetic Molecules.Methods in enzymology · 2018Article
- Ketamine Inhibition of the Pentameric Ligand-Gated Ion Channel GLIC.Biophysical journal · 2017Article
- Concentration-Dependent Binding of Small Ligands to Multiple Saturable Sites in Membrane Proteins.Scientific reports · 2017Article
- A membrane-embedded pathway delivers general anesthetics to two interacting binding sites in theThe Journal of biological chemistry · 2017Article
Corrections and comments
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Authors and funding
5 authors at 4 institutions in 2 countries.
Funding
Abstract
Although general anesthetics are known to modulate the activity of ligand-gated ion channels in the Cys-loop superfamily, there is at present neither consensus on the underlying mechanisms, nor predictive models of this modulation. Viable models need to offer quantitative assessment of the relative importance of several identified anesthetic binding sites. However, to date, precise affinity data for individual sites has been challenging to obtain by biophysical means. Here, the likely role of pore block inhibition by the general anesthetics isoflurane and propofol of the prokaryotic pentameric channel GLIC is investigated by molecular simulations. Microscopic affinities are calculated for both single and double occupancy binding of isoflurane and propofol to the GLIC pore. Computations are carried out for an open-pore conformation in which the pore is restrained to crystallographic radius, and a closed-pore conformation that results from unrestrained molecular dynamics equilibration of the structure. The GLIC pore is predicted to be blocked at the micromolar concentrations for which inhibition by isofluorane and propofol is observed experimentally. Calculated affinities suggest that pore block by propofol occurs at signifcantly lower concentrations than those for which inhibition is observed: we argue that this discrepancy may result from binding of propofol to an allosteric site recently identified by X-ray crystallography, which may cause a competing gain-of-function effect. Affinities of isoflurane and propofol to the allosteric site are also calculated, and shown to be 3 mM for isoflurane and 10 μM for propofol; both anesthetics have a lower affinity for the allosteric site than for the unoccupied pore.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.