Modeling Protein–Protein and Protein–Ligand Interactions by the ClusPro Team in CASP16

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Abstract

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.