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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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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. |
format | Online Article Text |
id | pubmed-8635979 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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