zPoseScore model for accurate and robust protein–ligand docking pose scoring in CASP15

Abstract We introduce a deep learning‐based ligand pose scoring model called zPoseScore for predicting protein–ligand complexes in the 15th Critical Assessment of Protein Structure Prediction (CASP15). Our contributions are threefold: first, we generate six training and evaluation data sets by employing advanced data augmentation and sampling methods. Second, we redesign the “zFormer” module, inspired by AlphaFold2's Evoformer, to efficiently describe protein–ligand interactions. This module enables the extraction of protein–ligand paired features that lead to accurate predictions. Finally, we develop the zPoseScore framework with zFormer for scoring and ranking ligand poses, allowing for atomic‐level protein–ligand feature encoding and fusion to output refined ligand poses and ligand per‐atom deviations. Our results demonstrate excellent performance on various testing data sets, achieving Pearson's correlation = 0.783 and 0.659 for ranking docking decoys generated based on experimental and predicted protein structures of CASF‐2016 protein–ligand complexes. Additionally, we obtain an averaged local distance difference test (lDDT pli = 0.558) of AIchemy LIG2 in CASP15 for de novo protein–ligand complex structure predictions. Detailed analysis shows that accurate ligand binding site prediction and side‐chain orientation are crucial for achieving better prediction performance. Our proposed model is one of the most accurate protein–ligand pose prediction models and could serve as a valuable tool in small molecule drug discovery.