We first evaluated the quality of the predicted binding poses generated by Smina for the 4,277 ligands in the PDBbind Training Set (3,752) and PDBbind Test Set (525). For each ligand, up to 20 diverse poses were generated. Only 1,357 (≈ 32%) of the ligands re-docked by Smina had at least one pose with with an RMSD less than 2 Å with respect to the crystallographic coordinates. For 1,003 ligands (≈ 23%), every pose generated by Smina had an RMSD greater than 4 Å. The distribution of the lowest RMSD docked pose for each complex is shown in Supporting Information Figure . The AutoDock Vina scoring function used by Smina often failed to rank a near-native ("good") pose first even when one was generated by Smina: of the 1,357 complexes with at least one pose with an RMSD below 2 Å, about half (691) of the top-ranked poses returned for Smina had an RMSD greater than 2 Å, and about a quarter (371) of these had an RMSD of greater than 4 Å. This agrees with previous results that have shown that docking scoring functions are not always a reliable way of selecting the best pose from a set of putative binding poses. One well documented source of error in docking is the difficulty of sampling the conformational space of large, highly flexible molecules. However, we found little correlation between either the size or the flexibility of the ligand and the RMSD of the best docked pose (Supporting Information Figure ).