Journal
ELIFE
Volume 10, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.68369
Keywords
ligand-gated ion channel; gating; allosteric modulation; molecular dynamics; electrophysiology; markov state model; Xenopus
Categories
Funding
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsradet [2018-06479, 2019-02433, 2017-04641]
- Swedish Research Council
- Horizon 2020 BioExcel [823830]
- Swedish National Infrastructure for Computing [2020/3-37]
- Swedish Research Council [2019-02433, 2018-06479, 2017-04641] Funding Source: Swedish Research Council
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The study utilized enhanced sampling to simulate the pH-gated channel GLIC and construct Markov state models of gating, revealing differential effects of protonation and mutation on channel states, estimation of open probabilities and transition rates, as well as state- and protonation-dependent symmetrization.
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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