{
  "abstract": "Protein-small molecule association involves multiple recognition stages governed by distinct physical interactions, yet resolving their kinetic contributions remains computationally challenging. Here, we develop a multiscale Monte Carlo framework that combines an atomistic, conformationally flexible ligand with a coarse-grained protein binding pocket and an atomistic steric envelope. Association is decomposed into three stages: molecular encounter, pocket entry, and productive binding. We evaluate the framework using ten protein-ligand complexes representing nine distinct targets, with experimentally derived association rates spanning nearly four orders of magnitude. Simulated pocket-entry rates exhibit the strongest correspondence with experimental kinetics (Pearson r = 0.617; Spearman {rho} = 0.758), whereas productive-binding rates show closer agreement in absolute magnitude. Systematic perturbations of electrostatic interactions, hydrophobic attraction, hydrogen bonding, and ligand torsional flexibility reveal stage-dependent sensitivities. Initial encounter is comparatively insensitive to these perturbations, while hydrophobic attraction and conformational flexibility influence pocket entry. Productive binding exhibits additional sensitivity to local interactions, with excessive hydrogen-bond strengthening potentially hindering native-pose formation. Probability-derived kinetic-stage barriers and normalized mechanism descriptors further reveal heterogeneous recognition behavior across protein targets. Together, this framework provides a computationally efficient and interpretable approach for investigating protein-ligand association pathways and their physical determinants across diverse molecular systems.",
  "abstract_shown": true,
  "affiliations": [
    "Albert Einstein College of Medicine"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 2,
  "authors": [
    {
      "name": "Z. Su"
    },
    {
      "affs": [
        0
      ],
      "name": "Y. Wu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bkn3h29w5pt7v.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.23.761358",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.23.761358v1.full",
  "id": "bkn3h29w5pt7v",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.23.761358v1",
  "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|Protein Structure and Dynamics"
    ]
  ],
  "openalex": "W7223563177",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.23.761358v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-23",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/bkn3h29w5pt7v.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:29:38Z",
      "native_id": "10.64898/2026.10.23.761358",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.23.761358v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "biorxiv:biophysics",
      "subfield": "biophysics"
    }
  ],
  "title": "Decoding the Physical Mechanisms of Protein-Small Molecule Association by Multiscale Kinetic Monte-Carlo Simulations",
  "title_text": "Decoding the Physical Mechanisms of Protein-Small Molecule Association by Multiscale Kinetic Monte-Carlo Simulations",
  "type": "preprint",
  "updated_at": "2026-10-30T12:29:38Z",
  "url": "https://research.draconitic.com/paper/bkn3h29w5pt7v",
  "venue": "bioRxiv",
  "versions": []
}