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Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel

Ligand-gated ion channels conduct currents in response to chemical stimuli, mediating electrochemical signaling in neurons and other excitable cells. For many channels, the details of gating remain unclear, partly due to limited structural data and simulation timescales. Here, we used enhanced sampl...

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Detalles Bibliográficos
Autores principales: Bergh, Cathrine, Heusser, Stephanie A, Howard, Rebecca, Lindahl, Erik
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8635979/
https://www.ncbi.nlm.nih.gov/pubmed/34652272
http://dx.doi.org/10.7554/eLife.68369
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author Bergh, Cathrine
Heusser, Stephanie A
Howard, Rebecca
Lindahl, Erik
author_facet Bergh, Cathrine
Heusser, Stephanie A
Howard, Rebecca
Lindahl, Erik
author_sort Bergh, Cathrine
collection PubMed
description Ligand-gated ion channels conduct currents in response to chemical stimuli, mediating electrochemical signaling in neurons and other excitable cells. For many channels, the details of gating remain unclear, partly due to limited structural data and simulation timescales. Here, we used enhanced sampling to simulate the pH-gated channel GLIC, and construct Markov state models (MSMs) of gating. Consistent with new functional recordings, we report in oocytes, our analysis revealed differential effects of protonation and mutation on free-energy wells. Clustering of closed- versus open-like states enabled estimation of open probabilities and transition rates, while higher-order clustering affirmed conformational trends in gating. Furthermore, our models uncovered state- and protonation-dependent symmetrization. This demonstrates the applicability of MSMs to map energetic and conformational transitions between ion-channel functional states, and how they reproduce shifts upon activation or mutation, with implications for modeling neuronal function and developing state-selective drugs.
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spelling pubmed-86359792021-12-03 Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel Bergh, Cathrine Heusser, Stephanie A Howard, Rebecca Lindahl, Erik eLife Computational and Systems Biology Ligand-gated ion channels conduct currents in response to chemical stimuli, mediating electrochemical signaling in neurons and other excitable cells. For many channels, the details of gating remain unclear, partly due to limited structural data and simulation timescales. Here, we used enhanced sampling to simulate the pH-gated channel GLIC, and construct Markov state models (MSMs) of gating. Consistent with new functional recordings, we report in oocytes, our analysis revealed differential effects of protonation and mutation on free-energy wells. Clustering of closed- versus open-like states enabled estimation of open probabilities and transition rates, while higher-order clustering affirmed conformational trends in gating. Furthermore, our models uncovered state- and protonation-dependent symmetrization. This demonstrates the applicability of MSMs to map energetic and conformational transitions between ion-channel functional states, and how they reproduce shifts upon activation or mutation, with implications for modeling neuronal function and developing state-selective drugs. eLife Sciences Publications, Ltd 2021-10-15 /pmc/articles/PMC8635979/ /pubmed/34652272 http://dx.doi.org/10.7554/eLife.68369 Text en © 2021, Bergh et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Computational and Systems Biology
Bergh, Cathrine
Heusser, Stephanie A
Howard, Rebecca
Lindahl, Erik
Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel
title Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel
title_full Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel
title_fullStr Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel
title_full_unstemmed Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel
title_short Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel
title_sort markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel
topic Computational and Systems Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8635979/
https://www.ncbi.nlm.nih.gov/pubmed/34652272
http://dx.doi.org/10.7554/eLife.68369
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