This result is consistent with a lack of training data in the region of conformational space close to φ 1 = 270 • , φ 2 = 270 • (Figure MC simulations of the second iteration of the GAP (GAP-v2) were run in the three environments and the errors are summarized in Table . Now, the errors are close to 1 kcal mol -1 in all three environments. Figure further reveals a very good correlation between GAP and QM intramolecular energies, although there is one significant outlier whose phenyl and pyridine rings approach too close (Figure , inset). Removal of this configuration from the ensemble of 3BPA in water reduces the error in the GAP still further from 1.42 kcal mol -1 to 0.93 kcal mol -1 . Further iterative training of the GAP would prevent sampling of this configuration during the MC simulations. The structures of the protein-ligand complexes sampled during MC simulations are in good agreement with the crystal structures of 3BPA bound to p38 kinase and leukotriene A4 hydrolase. Figure shows representative structures from the MC simulations overlaid on the original crystal structures (Supporting Information). Both GAP and MM retain the binding mode indicated by the crystal structure of p38 MAP kinase. As discussed, we have identified a binding mode of 3BPA to leukotriene A4 hydrolase that appears to be consistent with both QM dynamics and the observed electron density map. We emphasize that the crystallographically-assigned structure of 3BPA is not physically reasonable due to severe steric clashes (Figure ), although alternative (and multiple) binding modes are possible.