{
  "abstract": "Binding cooperativity is a defining determinant of the stability, selectivity, and degradation efficiency of PROTAC-mediated ternary complexes, yet its molecular origin remains poorly understood because existing computational approaches largely provide only global affinity estimates. Here we present MASIC (Multimeric Alanine Scanning with Interaction Convolution), a thermodynamically grounded end-point free energy framework that enables quantitative residue-level analysis of cooperativity in multimeric protein-protein-PROTAC systems. MASIC establishes a unified formulation linking end-point free energy theory, alanine-scanning interaction entropy, and multimeric cooperativity, while introducing a statistically robust interaction-convolution strategy that overcomes the finite-sampling instability of conventional interaction-entropy estimators. Beyond quantifying overall cooperativity, MASIC provides, to our knowledge, the first residue-resolved cooperativity landscapes of PROTAC ternary complexes and introduces the concept of cooperativity hotspots, identifying residues that govern cooperative stabilization rather than binding affinity alone. Extensive validation across diverse experimentally characterized PROTAC systems, including BRD9-VHL, BRD4-CRBN and FKBP12-CRBN, demonstrates accurate prediction of experimental cooperativity and consistently outperforms established structure-based approaches. Residue-level analyses reveal previously inaccessible many-body interaction networks underlying synergistic and antagonistic cooperativity, providing mechanistic insight into ternary-complex formation. Together, MASIC establishes a general framework for dissecting cooperative molecular recognition in multimeric biomolecular assemblies and provides a foundation for the rational design of next-generation targeted protein degraders.",
  "abstract_shown": true,
  "affiliations": [
    "School of Chemistry and Molecular Engineering",
    "East China Normal University",
    "Faculty of Synthetic Biology",
    "Shenzhen University of Advanced Technology",
    "Department of Biomedical Engineering",
    "Southern University of Science and Technology",
    "School of Pharmaceutical Sciences (Shenzhen",
    "Sun Yat-sen University",
    "Dipartimento di Chimica “Ugo Schiff, Università degli Studi di Firenze, Via della Lastruccia 3, Sesto Fiorentino, Italy, 50019",
    "Anhui Provincial Key Laboratory of Advanced Catalysis and Energy Materials",
    "Anhui Ultra High Molecular Weight Polyethylene Fiber Engineering Research Center, School of Chemistry and Chemical Engineering, Anqing Normal University",
    "New York University Shanghai"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Wenjing Zhou"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Xiaohui Wang"
    },
    {
      "affs": [
        2,
        3,
        4,
        5
      ],
      "name": "Lizhen Huo",
      "orcid": "0009-0001-5089-5493"
    },
    {
      "affs": [
        2,
        3,
        6,
        7
      ],
      "name": "Yucheng Han"
    },
    {
      "affs": [
        2,
        3,
        4,
        5
      ],
      "name": "Lingjie Kong"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Baochuan Hu"
    },
    {
      "affs": [
        8
      ],
      "name": "Piero Procacci"
    },
    {
      "affs": [
        0,
        1,
        9,
        10,
        11
      ],
      "name": "Xiao He"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Zhaoxi Sun"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1d0bkf67wapmc.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15009534/v1",
  "fulltext_url": null,
  "id": "1d0bkf67wapmc",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009534/v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Protein Degradation and Inhibitors"
    ]
  ],
  "openalex": "W7214664343",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15009534/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-28",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/1d0bkf67wapmc.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:21Z",
      "native_id": "10.26434/chemrxiv.15009534",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009534/v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Protein Degradation and Inhibitors",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Decoding Residue-level Energetic Rewiring in PROTAC Ternary Cooperativity",
  "title_text": "Decoding Residue-level Energetic Rewiring in PROTAC Ternary Cooperativity",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:21Z",
  "url": "https://research.draconitic.com/paper/1d0bkf67wapmc",
  "venue": "ChemRxiv",
  "versions": []
}