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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Autores principales:	Cathrine Bergh, Stephanie A Heusser, Rebecca Howard, Erik Lindahl
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	ligand-gated ion channel gating allosteric modulation molecular dynamics electrophysiology markov state model Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/8d7ef17dfa724cc3afa78e5417a615be
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spelling	oai:doaj.org-article:8d7ef17dfa724cc3afa78e5417a615be2021-12-01T15:18:33ZMarkov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel10.7554/eLife.683692050-084Xe68369https://doaj.org/article/8d7ef17dfa724cc3afa78e5417a615be2021-10-01T00:00:00Zhttps://elifesciences.org/articles/68369https://doaj.org/toc/2050-084XLigand-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.Cathrine BerghStephanie A HeusserRebecca HowardErik LindahleLife Sciences Publications Ltdarticleligand-gated ion channelgatingallosteric modulationmolecular dynamicselectrophysiologymarkov state modelMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ligand-gated ion channel gating allosteric modulation molecular dynamics electrophysiology markov state model Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	ligand-gated ion channel gating allosteric modulation molecular dynamics electrophysiology markov state model Medicine R Science Q Biology (General) QH301-705.5 Cathrine Bergh Stephanie A Heusser Rebecca Howard Erik Lindahl Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel
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	article
author	Cathrine Bergh Stephanie A Heusser Rebecca Howard Erik Lindahl
author_facet	Cathrine Bergh Stephanie A Heusser Rebecca Howard Erik Lindahl
author_sort	Cathrine Bergh
title	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_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_sort	markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/8d7ef17dfa724cc3afa78e5417a615be
work_keys_str_mv	AT cathrinebergh markovstatemodelsofprotonandporedependentactivationinapentamericligandgatedionchannel AT stephanieaheusser markovstatemodelsofprotonandporedependentactivationinapentamericligandgatedionchannel AT rebeccahoward markovstatemodelsofprotonandporedependentactivationinapentamericligandgatedionchannel AT eriklindahl markovstatemodelsofprotonandporedependentactivationinapentamericligandgatedionchannel
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Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel

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