{
  "abstract": "AI-enabled computational drug discovery is advancing rapidly in predicting molecular structures, binding poses and affinities, but ligand dissociation kinetics remain harder to access. Bound-state residence time, important for biological response and kinetic selectivity, is not fixed by equilibrium affinity but depends on the dissociation free-energy landscape and dissipative friction effects. Here, we show that restrained umbrella-sampling trajectories can be used to calculate residence times on the minutes timescale. Time-resolved coordinate fluctuations yield friction profiles that incorporate non-Markovian effects on dissociation kinetics. Combining them with the free-energy profile, we predict a residence time of $τ_{\\rm res}$ = 275 s for the adenosine A$_{2A}$ receptor with ZM241385 (comparable to the experimental value of 125 s) and reproduce the experimental ranking of wild type and two receptor mutants. For HSP90 with compound 18 and RNase S with the S15 peptide, we predict $τ_{\\rm res}$ = 2,169 s and 2,259 s (experimental values are 833 s and 2,439 s). Neglecting memory effects on residence kinetics overestimates $τ_{\\rm res}$ by factors of 2.6 to 29.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": "2610.20271",
  "author_total": 3,
  "authors": [
    {
      "name": "Hossein Batebi"
    },
    {
      "name": "Lucas Tepper"
    },
    {
      "name": "Roland R. Netz"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/azt2cs33yph26.bib",
  "cited_by": 0,
  "doi": "10.48550/arxiv.2610.20271",
  "fulltext_url": null,
  "id": "azt2cs33yph26",
  "issns": [],
  "landing_url": "https://arxiv.org/abs/2610.20271",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "http://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": "CC0-1.0",
  "native_subjects": [
    [
      "arxiv",
      "cond-mat.stat-mech"
    ],
    [
      "arxiv",
      "physics.bio-ph"
    ],
    [
      "openalex",
      "1703|Computational Drug Discovery Methods"
    ]
  ],
  "openalex": "W7221875660",
  "pdf_url": "https://arxiv.org/pdf/2610.20271",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-14",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/azt2cs33yph26.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:29:31Z",
      "native_id": "2610.20271",
      "source": "arxiv",
      "url": "https://arxiv.org/abs/2610.20271"
    }
  ],
  "subjects": [
    {
      "field": "physics",
      "origin": "arxiv:physics.bio-ph",
      "subfield": "biological-medical"
    },
    {
      "field": "physics",
      "origin": "arxiv:cond-mat.stat-mech",
      "subfield": "statistical-nonlinear"
    }
  ],
  "title": "Memory-resolved prediction of ligand residence times on the minutes timescale",
  "title_text": "Memory-resolved prediction of ligand residence times on the minutes timescale",
  "type": "preprint",
  "updated_at": "2026-10-30T12:29:31Z",
  "url": "https://research.draconitic.com/paper/azt2cs33yph26",
  "venue": "arXiv",
  "versions": []
}