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Markov modeling reveals novel intracellular modulation of the human TREK-2 selectivity filter
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Abstract
Two-pore domain potassium (K2P) channel ion conductance is regulated by diverse stimuli that directly or indirectly gate the channel selectivity filter (SF). Recent crystal structures for the TREK-2 member of the K2P family reveal distinct “up” and “down” states assumed during activation via mechanical stretch. We performed 195 μs of all-atom, unbiased molecular dynamics simulations of the TREK-2 channel to probe how membrane stretch regulates the SF gate. Markov modeling reveals a novel “pinched” SF configuration that stretch activation rapidly destabilizes. Free-energy barrier heights calculated for critical steps in the conduction pathway indicate that this pinched state impairs ion conduction. Our simulations predict that this low-conductance state is accessed exclusively in the compressed, “down” conformation in which the intracellular helix arrangement allosterically pinches the SF. By explicitly relating structure to function, we contribute a critical piece of understanding to the evolving K2P puzzle.
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Markov state models of biomolecular conformational dynamics
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Metadata
- Authors
- Harrigan, M. P., McKiernan, K. A., Shanmugasundaram, V., Denny, R. A., & Pande, V. S.
- Affiliations
- Stanford University (US)
- Pfizer (United States) (US)
- Corresponding author
- Denny, Rajiah Aldrin
- Pande, Vijay S.
- ORCID
- Venue
- Scientific Reports
- Published
- 2017-04-04
- Volume
- 7
- Issue
- 1
- Pages
- 632-632
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5428000
- OpenAlex
- W2951044253
- Cited by
- 19
- References
- 1
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 4 · 2020: 3 · 2019: 2 · 2018: 2
- FWCI
- 0.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Science Foundation (1439982)
- Pfizer
- National Institutes of Health (5u19ai109662-05, U19 AI109662, AI109662)
- National Institute of General Medical Sciences (R01GM062868)
- National Institute of Allergy and Infectious Diseases (U19-AI109662)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Engineering › Biomedical Engineering › Nanopore and Nanochannel Transport Studies
- Keywords
- TREK-2, two-pore domain potassium channels, selectivity filter, ionic conduction, allosteric modulation, activation barrier, Markov state models, channel gating, conformational states
- MeSH terms
- Humans, Ions, Markov Chains, Models, Molecular, Protein Conformation, Structure-Activity Relationship, Ion Channel Gating, Potassium Channels, Tandem Pore Domain, Intracellular Space
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