{
  "abstract": "The atomic structure of the human Ether-a-go-go-Related Gene (hERG) K+ channel has recently been resolved by cryo-electron microscopy (cryo-EM) under both high- and low-K+ conditions, in order to obtain information on the mechanism of the K+-sensitive, very rapid C-type inactivation typical of this channel. Although the currently available high-K+ structures have been widely interpreted as representing the conductive, active state, whether they correspond to a dynamically stable conductive conformation remains unresolved. Here, we used extensive all-atom molecular dynamics (MD) simulations, with and without Electronic Continuum Correction (ECC), to investigate selectivity filter (SF) dynamics and ion permeation in wild-type (WT) hERG and the non-inactivating N629D mutant. Across all membrane potentials tested, WT hERG failed to support K+ permeation and instead spontaneously evolved towards a non-conductive SF conformation characterized by extracellular dilation, localized inner constriction, depletion of the outer ion-binding sites, and persistent trapping of K+ ions within the central binding sites of the filter, closely resembling the inactivated SF of Shaker channels recently resolved by cryo-EM. By contrast, N629D maintained a stable conductive SF architecture, analogous to the conductive filters of canonical K+ channels such as KcsA, while exhibiting robust voltage-dependent K+ permeation. ECC enhanced ion permeation in N629D mutant, but failed to support conduction in WT hERG, which remained structurally and functionally non-conductive. Together, these findings challenge the prevailing interpretation of the high-K+ WT cryo-EM structure as a stable conductive state and identify SF remodeling as the structural mechanism underlying hERG C-type inactivation.",
  "abstract_shown": true,
  "affiliations": [
    "University of Bologna"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "name": "M. V. Leonardi"
    },
    {
      "name": "A. Michelucci"
    },
    {
      "name": "Y. Aldakul"
    },
    {
      "name": "H. Sun"
    },
    {
      "name": "L. Catacuzzeno"
    },
    {
      "affs": [
        0
      ],
      "name": "S. Furini"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/f5srbw7x71bha.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.02.748792",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.02.748792v1.full",
  "id": "f5srbw7x71bha",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.02.748792v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "biophysics"
    ],
    [
      "openalex",
      "1312|Ion channel regulation and function"
    ]
  ],
  "openalex": "W7210289163",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.02.748792v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-02",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/f5srbw7x71bha.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:47Z",
      "native_id": "10.64898/2026.09.02.748792",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.02.748792v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "biorxiv:biophysics",
      "subfield": "biophysics"
    }
  ],
  "title": "The wild-type hERG cryo-EM structure fails to support conduction and evolve toward an inactivated-like selectivity filter conformation in molecular dynamics simulations",
  "title_text": "The wild-type hERG cryo-EM structure fails to support conduction and evolve toward an inactivated-like selectivity filter conformation in molecular dynamics simulations",
  "type": "preprint",
  "updated_at": "2026-10-30T12:19:47Z",
  "url": "https://research.draconitic.com/paper/f5srbw7x71bha",
  "venue": "bioRxiv",
  "versions": []
}