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

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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.

In: eLife, Vol. 10, 68369, 2021.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Bergh, C, Heusser, SA, Howard, R & Lindahl, E 2021, 'Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel', eLife, vol. 10, 68369. https://doi.org/10.7554/eLife.68369

APA

Bergh, C., Heusser, S. A., Howard, R., & Lindahl, E. (2021). Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel. eLife, 10, [68369]. https://doi.org/10.7554/eLife.68369

Vancouver

Bergh C, Heusser SA, Howard R, Lindahl E. Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel. eLife. 2021;10. 68369. https://doi.org/10.7554/eLife.68369

Author

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. In: eLife. 2021 ; Vol. 10.

Bibtex

@article{8c68da1384b84137b1c704f56cb4a397,
title = "Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel",
abstract = "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.",
keywords = "ligand-gated ion channel, gating, allosteric modulation, molecular dynamics, electrophysiology, markov state model, Xenopus, ACETYLCHOLINE-RECEPTOR, MOLECULAR-DYNAMICS, OPEN PROBABILITY, CONFORMATIONAL TRANSITIONS, GLOEOBACTER-VIOLACEUS, NICOTINIC RECEPTOR, KINETIC-PROPERTIES, STRUCTURAL BASIS, MECHANISM, DESENSITIZATION",
author = "Cathrine Bergh and Heusser, {Stephanie A.} and Rebecca Howard and Erik Lindahl",
year = "2021",
doi = "10.7554/eLife.68369",
language = "English",
volume = "10",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications Ltd.",

}

RIS

TY - JOUR

T1 - Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel

AU - Bergh, Cathrine

AU - Heusser, Stephanie A.

AU - Howard, Rebecca

AU - Lindahl, Erik

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - ligand-gated ion channel

KW - gating

KW - allosteric modulation

KW - molecular dynamics

KW - electrophysiology

KW - markov state model

KW - Xenopus

KW - ACETYLCHOLINE-RECEPTOR

KW - MOLECULAR-DYNAMICS

KW - OPEN PROBABILITY

KW - CONFORMATIONAL TRANSITIONS

KW - GLOEOBACTER-VIOLACEUS

KW - NICOTINIC RECEPTOR

KW - KINETIC-PROPERTIES

KW - STRUCTURAL BASIS

KW - MECHANISM

KW - DESENSITIZATION

U2 - 10.7554/eLife.68369

DO - 10.7554/eLife.68369

M3 - Journal article

C2 - 34652272

VL - 10

JO - eLife

JF - eLife

SN - 2050-084X

M1 - 68369

ER -

ID: 288270343