CatGeoBench: Mechanism-Guided Catalytic Geometry for Enzyme–Ligand Co-Folding

Existing benchmarks for protein–ligand structure prediction and docking rely on crystal structures and evaluate binding geometry and physical plausibility, but do not assess whether predicted enzyme complexes satisfy the geometric prerequisites of catalysis. We present CatGeoBench, a benchmark for catalytic geometric compatibility based on mechanisms from M-CSA. It includes a core set built directly from M-CSA and an extended set that covers related enzymes with alternative substrates. For each mechanism we build electron-flow chains and extract reacting atom pairs as the intermolecular bond-forming atom pairs collected up to the first intermolecular structure-changing electron-flow event. CatGeoBench scores predictions with mechanism-derived distance criteria based on scaled van der Waals radii of these pairs, rather than by comparison to crystal ligand poses. The core set comprises 239 entries with 320 reacting atom pairs, and the extended set comprises 123 entries with 161 pairs. Each entry provides a curated enzyme functional unit, validated substrate and cofactor inputs, explicit atom mappings for downstream structure evaluation, and the associated distance thresholds. We evaluate representative co-folding models under a unified protocol. Models achieve high success under the distance-only criterion on the core set but degrade on the extended set, where core performance does not reliably indicate success on related enzymes with alternative substrates.