{
  "abstract": "The backbone Cα–Cα distance widely used to report kinase molecular-brake status gives a false negative under a clinically relevant FGFR1 resistance mutation: the brake's side-chain contact is destabilized in every replicate, yet the criterion reports it intact. Acquired FGFR1 kinase-domain mutations limit the clinical durability of erdafitinib, the first approved pan-FGFR inhibitor; loss of binding affinity is the assumed mechanism. We tested two questions in a single design: nine all-atom MD trajectories of the erdafitinib-bound kinase domain (wild type, V561M and molecular-brake mutant N546K; three replicates each; 4.491 μs). First, what a fully replicated comparison can resolve: neither MM/GBSA nor MM/PBSA detected a mutation-associated change in binding free energy; the observed mutant-versus-WT ΔΔG values lie below the detection limit of the present replicate set and within the intrinsic uncertainty of the end-point methods (GB ANOVA p = 0.27; PB p = 0.054). A large, E3810-like penalty (≈5 kcal·mol-1) is excluded. Second, the brake itself—N546K destabilizes the persistent engaged state of the residue-546–Glu562 contact: occupancy falls to 16–55% across replicates, entirely below the 95–100% of WT and V561M, at unchanged Cα–Cα geometry, dwell times fall from tens of nanoseconds to sub-nanosecond flickers, and broken periods reach 19 ns. V561M leaves the brake contact intact and instead loosens the gatekeeper-flanking hydrophobic network (Leu484/Val492/Lys514), dispersing its conformational ensemble across replicates. Side-chain proximity occupancy thus emerges as an operational order parameter for the molecular brake; the kinetic corollary, altered rates at unchanged affinity, is testable by SPR/BLI and unbinding calculations.",
  "abstract_shown": true,
  "affiliations": [
    "School of Computer Information",
    "Inner Mongolia Medical University"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 1,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Jia He",
      "orcid": "0009-0003-3522-1794"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2we370hpse9b7.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15011002/v1",
  "fulltext_url": null,
  "id": "2we370hpse9b7",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15011002/v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1703|Computational Drug Discovery Methods"
    ]
  ],
  "openalex": "W7223667437",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15011002/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-25",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/2we370hpse9b7.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:26Z",
      "native_id": "10.26434/chemrxiv.15011002",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15011002/v1"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "source:chemrxiv",
      "subfield": "general"
    }
  ],
  "title": "Resistance without a detectable bindingenergy penalty: distinct dynamic defects of gatekeeper and molecular-brake mutations in FGFR1–erdafitinib recognition",
  "title_text": "Resistance without a detectable bindingenergy penalty: distinct dynamic defects of gatekeeper and molecular-brake mutations in FGFR1–erdafitinib recognition",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:26Z",
  "url": "https://research.draconitic.com/paper/2we370hpse9b7",
  "venue": "ChemRxiv",
  "versions": []
}