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

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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.

Data availability

Additional data including simulation parameters and sampled conformations from the MSMs can be accessed at doi:10.5281/zenodo.4594193.

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Cathrine Bergh

Applied Physics, KTH Royal Institute of Technology, Stockholm, Sweden

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7540-5887
Stephanie A Heusser

Drug Design & Pharmacology, University of Copenhagen, Copehagen, Denmark

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3224-4547
Rebecca Howard

Drug Design & Pharmacology, University of Copenhagen, Copehagen, Denmark

Competing interests
The authors declare that no competing interests exist.
Erik Lindahl

Stockholm University, Stockholm, Sweden

For correspondence
erik.lindahl@dbb.su.se

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-2734-2794

Funding

Knut och Alice Wallenbergs Stiftelse

Erik Lindahl

Vetenskapsrådet (2017-04641)

Erik Lindahl

Vetenskapsrådet (2018-06479)

Erik Lindahl

Vetenskapsrådet (2019-02433)

Erik Lindahl

Swedish e-Science Research Centre

Rebecca Howard
Erik Lindahl

European Union Horizon 2020 (BioExcel (823830))

Erik Lindahl

Swedish National Infrastructure for Computing

Erik Lindahl

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.