Modeling Protein–Protein and Protein–Ligand Interactions by the <scp>ClusPro</scp> Team in <scp>CASP16</scp>
In the CASP16 experiment, our team employed hybrid computational strategies to predict both protein-protein and protein-ligand complex structures. For protein-protein docking, we combined physics-based sampling-using ClusPro FFT docking and molecular dynamics-with AlphaFold (AF)-based sampling, followed by AF-based refinement. Our method produced numerous high-accuracy complex models, including cases where AF alone failed, underscoring the critical role of physics-based sampling alongside deep learning-based refinement. For protein-ligand docking, we integrated the ClusPro LigTBM template-based approach with a machine learning-based confidence model for rescoring. The method preserves conserved interaction fragments derived from homologous complexes, followed by local resampling using physics-based sampling and a diffusion model. Our template-based strategy achieved a mean lDDT-PLI of 0.69 across 233 targets, which was highly competitive. These results demonstrate that combining physics-based modeling with AI-driven refinement can significantly enhance the accuracy of both protein-protein and protein-ligand structure predictions.
Authors
- Dmitri Beglov
- Ken A. Dill (ORCID: https://orcid.org/0000-0002-2390-2002)
- Xin Cao (ORCID: https://orcid.org/0000-0001-8787-594X)
- Omeir Khan (ORCID: https://orcid.org/0000-0002-5822-1549)
- Dzmitry Padhorny (ORCID: https://orcid.org/0000-0002-7840-8677)
- Y. Zhu (ORCID: https://orcid.org/0009-0003-8771-5665)
- Ryota Ashizawa (ORCID: https://orcid.org/0000-0002-5082-9058)
- Sándor Vajda (ORCID: https://orcid.org/0000-0003-1540-8220)
- Stan Xiaogang Li
- Kushal Koirala (ORCID: https://orcid.org/0009-0009-7935-4533)
- George Jones (ORCID: https://orcid.org/0000-0002-5028-2072)
- Carlos L. Simmerling (ORCID: https://orcid.org/0000-0002-7252-4730)
- Sergei Kotelnikov (ORCID: https://orcid.org/0000-0001-9400-101X)
- Dima Kozakov (ORCID: https://orcid.org/0000-0003-0464-4500)
- Diane Joseph‐McCarthy (ORCID: https://orcid.org/0000-0001-9685-6177)
- Evangelos A. Coutsias (ORCID: https://orcid.org/0000-0003-2910-9125)
- Darya Stepanenko (ORCID: https://orcid.org/0000-0002-8745-734X)
- Alexander Tropsha (ORCID: https://orcid.org/0000-0003-3802-8896)
- Ernest Glukhov (ORCID: https://orcid.org/0009-0009-0056-0423)
- Dmytro Kalitin
- Ayse A. Bekar-Cesaretli (ORCID: https://orcid.org/0000-0001-9122-4955)
- Veranika Averkava
- Maria Lazou (ORCID: https://orcid.org/0009-0003-6443-8060)
- Yu Hao
- Mark Lukin
- T. Patsahan
- Derara Hailegeorgis
Institutions
- Boston University (US)
- University of North Carolina at Chapel Hill (US)
- University of Massachusetts Boston (US)
- Simons Foundation (US)
- Yukhnovskii Institute for Condensed Matter Physics of the National Academy of Sciences of Ukraine (UA)
- New York University (US)
- Stony Brook University (US)
- The University of Texas at Austin (US)
- Lviv Polytechnic National University (UA)
Publication Details
- Journal
- Proteins Structure Function and Bioinformatics
- Published
- 2025-10-20
- DOI
- https://doi.org/10.1002/prot.70066
- Citations
- 7
- Primary Topic
- Protein Structure and Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 5.64
Funders
- National Science Foundation
- U.S. Department of Energy
- Office of Science
- National Institute of General Medical Sciences
- Oak Ridge National Laboratory