Title: PoseX: AI Defeats Physics-based Methods on Protein Ligand Cross-Docking
Primary area: datasets and benchmarks
Keywords: AI docking, AI co-folding, protein-ligand interaction, cross docking

Abstract: Recently, significant progress has been made in protein-ligand docking, especially in deep learning methods, and some benchmarks were proposed, such as PoseBench and PLINDER. However, these studies typically focus on the self-docking scenario, which is less practical in real-world applications. Moreover, some studies involve heavy frameworks requiring extensive training, posing challenges to convenient and efficient assessment of docking methods. To fill these gaps, we design PoseX, an open-source benchmark to evaluate both self-docking and cross-docking, enabling a practical and comprehensive assessment of algorithmic advances. Specifically, we curated a novel dataset comprising 718 entries for self-docking and 1,312 entries for cross-docking; secondly, we incorporated 23 docking methods in three methodological categories, including physics-based methods (e.g., Schrödinger Glide), AI docking methods (e.g., DiffDock) and AI co-folding methods (e.g., AlphaFold3); thirdly, we developed a relaxation method for post-processing to minimize conformational energy and refine binding poses; fourthly, we established a public leaderboard to rank submitted models in real-time. We derived some key insights and conclusions through extensive experiments: (1) AI-based approaches consistently outperform physics-based methods in overall docking success rate. (2) Most intra- and intermolecular clashes of AI-based approaches can be greatly alleviated with relaxation, which means combining AI modeling with physics-based post-processing could achieve excellent performance. (3) AI co-folding methods exhibit ligand chirality issues, except for Boltz-1x, which introduced physics-inspired potentials to fix hallucinations, suggesting that stereochemical modeling greatly improves the structural plausibility of the predicted protein-ligand complexes. (4) Specifying binding pockets significantly promotes docking performance, indicating that pocket information can be leveraged adequately, particularly for AI co-folding methods, in future modeling efforts.

TL;DR: a comprehensive benchmarking of various docking methods on a new curated dataset for self-docking and cross-docking