{
  "abstract": "The TREK two-pore domain potassium channels regulate membrane excitability and respond to diverse physiological stimuli. Single-site mutations of TREK are associated with neurodevelopmental disorders and can cause pathological channel hyperactivation. Here, using the OneOPES enhanced-sampling molecular dynamics framework, we characterize the energetics of conformational transition along a predefined pathway connecting the up and down states of TREK-2, together with initial conformational rearrangements of the selectivity filter under physiological stimuli and disease-mimicking conditions. The simulations reveal a shared energetic axis coupling the lower helices, proximal C-terminus, and selectivity filter to govern channel gating. Predicted conformational effects of a disease-mimicking mutation were validated electrophysiologically using a conformation-sensitive TREK-2 inhibitor. Together with our previous unbiased MD simulations, these results establish an energetic framework for TREK-2 regulation and dysfunction, complementing prior structural and mechanistic studies while highlighting the potential and methodological challenges of advanced enhanced-sampling approaches for resolving complex conformational landscapes of ion channels.",
  "abstract_shown": true,
  "affiliations": [
    "Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany.",
    "Insitute of Chemistry, Technical University of Berlin, Berlin, Germany.",
    "School of Pharmaceutical Sciences, University of Geneva, Rue Michel Servet 1, Genève, Switzerland. valerio.rizzi@unige.ch.",
    "Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, Genève, Switzerland. valerio.rizzi@unige.ch.",
    "Swiss Institute of Bioinformatics, University of Geneva, Genève, Switzerland. valerio.rizzi@unige.ch.",
    "Institute of Physiology, Kiel University, Kiel, Germany.",
    "School of Pharmaceutical Sciences, University of Geneva, Rue Michel Servet 1, Genève, Switzerland.",
    "Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, Genève, Switzerland.",
    "Swiss Institute of Bioinformatics, University of Geneva, Genève, Switzerland.",
    "Institute of Physiology, Kiel University, Kiel, Germany. m.schewe@physiologie.uni-kiel.de.",
    "School of Pharmaceutical Sciences, University of Geneva, Rue Michel Servet 1, Genève, Switzerland. francesco.gervasio@unige.ch.",
    "Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, Genève, Switzerland. francesco.gervasio@unige.ch.",
    "Swiss Institute of Bioinformatics, University of Geneva, Genève, Switzerland. francesco.gervasio@unige.ch.",
    "Department of Chemistry, University College London, London, United Kingdom. francesco.gervasio@unige.ch.",
    "Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany. hsun@fmp-berlin.de.",
    "Insitute of Chemistry, Technical University of Berlin, Berlin, Germany. hsun@fmp-berlin.de."
  ],
  "article_type": "research support, non u.s. gov't",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Berke Türkaydin",
      "orcid": "0000-0003-1699-0312"
    },
    {
      "affs": [
        2,
        3,
        4
      ],
      "name": "Valerio Rizzi",
      "orcid": "0000-0001-5126-8996"
    },
    {
      "affs": [
        5
      ],
      "name": "Chaimae Benkerdagh",
      "orcid": "0009-0009-5038-4448"
    },
    {
      "affs": [
        0
      ],
      "name": "Simon Ghysbrecht",
      "orcid": "0009-0003-7556-9592"
    },
    {
      "affs": [
        6,
        7,
        8
      ],
      "name": "Simone Aureli",
      "orcid": "0000-0002-4938-8603"
    },
    {
      "affs": [
        5
      ],
      "name": "Thomas Baukrowitz",
      "orcid": "0000-0003-4562-0505"
    },
    {
      "affs": [
        9
      ],
      "name": "Marcus Schewe",
      "orcid": "0000-0002-6192-5651"
    },
    {
      "affs": [
        10,
        11,
        12,
        13
      ],
      "name": "Francesco Luigi Gervasio",
      "orcid": "0000-0003-4831-5039"
    },
    {
      "affs": [
        14,
        15
      ],
      "name": "Han Sun",
      "orcid": "0000-0002-1655-0838"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/963a12qb8vzek.bib",
  "cited_by": 0,
  "doi": "10.1038/s41467-026-77935-w",
  "fulltext_url": "https://europepmc.org/articles/PMC13687069",
  "id": "963a12qb8vzek",
  "issns": [
    "2041-1723"
  ],
  "landing_url": "https://europepmc.org/article/MED/42907444",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Ion channel regulation and function"
    ]
  ],
  "openalex": "W7214045356",
  "pdf_url": "https://europepmc.org/articles/PMC13687069?pdf=render",
  "pmcid": "PMC13687069",
  "pmid": "42907444",
  "published": "2026-09-22",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/963a12qb8vzek.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:57Z",
      "native_id": "MED:42907444",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42907444"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Ion channel regulation and function",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Cross-talk of filter gate and lower helices drives polymodal regulation and disease in TREK channels.",
  "title_text": "Cross-talk of filter gate and lower helices drives polymodal regulation and disease in TREK channels.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:57Z",
  "url": "https://research.draconitic.com/paper/963a12qb8vzek",
  "venue": "Nature communications",
  "versions": []
}