Flowchart illustrating data processing pipeline. Beginning from the PDBbind v2019 proteinligand dataset, we clustered ligands for all structures of the same Uniprot into distinct binding sites to define cross-docking groups. We used Rosetta (version) to prepare the structures for docking, including filling in missing sidechain atoms and adding protons. We prepared 3D conformations for each ligand using RDKit and used these conformations to dock to the crystal structures within each binding site cluster. We additionally prepared conformational ensembles using the Rosetta hybridization protocol and docked ligands within each binding site cluster.