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PreprintCC BY-NC-NDChemRxiv

Decoding Residue-level Energetic Rewiring in PROTAC Ternary Cooperativity

  • Wenjing Zhou1,2
  • Xiaohui Wang3,4
  • Lizhen Huo3,4,5,6
  • Yucheng Han3,4,7,8
  • Lingjie Kong3,4,5,6
  • Baochuan Hu1,2
  • Piero Procacci9
  • Xiao He1,2,10,11,12
  • Zhaoxi Sun3,4
12 affiliations
  1. 1School of Chemistry and Molecular Engineering
  2. 2East China Normal University
  3. 3Faculty of Synthetic Biology
  4. 4Shenzhen University of Advanced Technology
  5. 5Department of Biomedical Engineering
  6. 6Southern University of Science and Technology
  7. 7School of Pharmaceutical Sciences (Shenzhen
  8. 8Sun Yat-sen University
  9. 9Dipartimento di Chimica “Ugo Schiff, Università degli Studi di Firenze, Via della Lastruccia 3, Sesto Fiorentino, Italy, 50019
  10. 10Anhui Provincial Key Laboratory of Advanced Catalysis and Energy Materials
  11. 11Anhui Ultra High Molecular Weight Polyethylene Fiber Engineering Research Center, School of Chemistry and Chemical Engineering, Anqing Normal University
  12. 12New York University Shanghai
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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.

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Cite

BibTeXRIS
BibTeX
@misc{zhou2026decoding,
  title = {{Decoding Residue-level Energetic Rewiring in PROTAC Ternary Cooperativity}},
  author = {Wenjing Zhou and Xiaohui Wang and Lizhen Huo and Yucheng Han and Lingjie Kong and Baochuan Hu and Piero Procacci and Xiao He and Zhaoxi Sun},
  howpublished = {ChemRxiv},
  year = {2026},
  month = sep,
  doi = {10.26434/chemrxiv.15009534/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009534/v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - Decoding Residue-level Energetic Rewiring in PROTAC Ternary Cooperativity
AU  - Wenjing Zhou
AU  - Xiaohui Wang
AU  - Lizhen Huo
AU  - Yucheng Han
AU  - Lingjie Kong
AU  - Baochuan Hu
AU  - Piero Procacci
AU  - Xiao He
AU  - Zhaoxi Sun
PY  - 2026
DA  - 2026/09/28
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15009534/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009534/v1
AB  - 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.
ER  -