where ∆G A and ∆G B are the free energy differences between the GAP (λ = 0) and MM (λ = 1) models computed in water and protein environments respectively. The implementation of GAP is fully compatible with the replica exchange with solute tempering method, which allows us to perform enhanced sampling of the ligand degrees of freedom, and with the JAWS algorithm, which aids hydration of the binding site in the bound simulations. Full details of the set-up and parameters used in the MC/FEP calculations are provided in the Supporting Information. . The use of high temperatures allows a thorough sampling of conformational space in this case. The white circles show the positions of the corresponding dihedral angles in the two crystal structures studied here. The compound bound to p38 MAP kinase adopts a conformation that is well sampled by our training data (φ 1 = 334 • , φ 2 = 204 • ). Interestingly, on the other hand, the pose in the leukotriene A4 hydrolase crystal structure is in a seemingly disallowed region of conformational space (φ 1 = 168 • , φ 2 = 116 • ). Closer inspection reveals that, in this conformation, the -NH 2 group on the aminopyridine is in unphysical close contact with the -CH 2 -linker (Figure (c) and Figure ). This is, therefore, likely an artefact of the crystal structure refinement. By visual inspection, we were able to orient 3BPA within the leukotriene A4 hydrolase binding site with a conformation that is more consistent with the QM dynamics (φ 1 ∼ 270 • , φ 2 ∼ 270 • ). We therefore used this bound conformation as the starting point for our MC simulations. Next, we ran MC simulations of 3BPA in three different environments, using GAP-v1 to describe its intramolecular energetics, and the OPLS/CM1A force field to describe its interactions with the proteins and water. As discussed in the Introduction, 3BPA is capable of occupying a range of potentially environment-dependent conformations, and so it is important not only to validate the gas phase potential energy surface, but also those conformations adopted in the condensed phase. Hence, 300 configurations of 3BPA were saved from each trajectory, and its energetics recomputed at the MP2/6-311G(2d,p) level of theory in vacuum. Table shows the RMS error in the GAP for 3BPA in water, and bound to the two proteins. The errors are less than 1 kcal mol -1 in water and bound to p38 MAP kinase, which is consistent with the reported accuracy of the GAP on the test set described in the Methods section. However, despite the reorientation of 3BPA in the binding pocket of leukotriene A4 hydrolase, the RMS errors in the GAP are extremely high (19 kcal mol -1 ).