Cross-docking. We superimposed receptors of the same uniprot ID using the chain identifiers present in the 'pocket' pdb file from PDBbind, keeping receptors that superimposed to within 5Å. We identified different binding sites within the same uniprot ID by clustering the center of mass of the superimposed ligands with DBSCAN 48 (parameters eps=5., min_samples=1). A small number of uniprot IDs ('targets') are represented by hundreds of receptor-compound pairs in PDBbind. To avoid those from dominating the cross-docked data set, we randomly selected five representatives from among the receptor-compound pairs to be included in the cross-docking procedure. Cross docking was performed on all members of each binding site cluster. The final training set consisted of targets that sampled at least one low-RMSD pose. This procedure gave a total of 27,166 target-compound pairs. Ensemble docking. We generated five diverse receptor conformations using the rosetta hybridize protocol (Supplemental Material) with the score3 and score4_smooth_cart scoring functions in stage 1 and 2 of the centroid stage, and the ref2015_cart scoring function with metalbinding_constraint in the full atom stage. Ligand parameterization relied on rosetta's templates whenever available or was generated with rosetta's molfile_to_params.py script using default settings. We used default weights for intra-ligand hetatm_cst_weight=1.0 and receptor-ligand hetatm_to_protein_cst_weight=1.0 constraints. Fragment insertions were disabled in stage 2: fragprob_stage2=0.0. We adjusted the stage 2 Monte Carlo temperature to 0.5: stage2_temperature=0.5. Next, we subjected each hybridized receptor conformation and the crystal structure to six rounds of energy relaxation with Rosetta's FastRelax protocol, retaining metal coordination with the SetupMetalsMover protocol combined with a metalbinding_constraint = 1.0. We observed that protein side-chain metal coordination was not preserved consistently throughout the hybridize protocol. In some cases that led to final models with unsatisfied coordinate-covalent bonds. We created a final ensemble of six receptor conformations by selecting the conformation with the lowest Rosetta energy from each of the six relaxed conformations starting from the hybridized models or crystal structure.