It should be emphasized that reproduction of the total QM energy for a flexible molecule of this size (15 heavy atoms) to an accuracy of 1 kcal mol -1 is a significant task. For comparison, we have computed the MM energies of the configurations of 3BPA extracted from the GAP-v2 MC simulations in the three different environments. Table and Figure summarize the accuracy of OPLS/CM1A, which is expected to be typical of standard small molecule force fields, in comparison with QM data. As expected, the MM force field is significantly less accurate than the machine learning potential. These improvements in intramolecular energetics are expected to carry over into improved thermodynamic quantities, such as binding free energies. As discussed in the Methods section, our implementation of GAP in the MCPRO software allows us to estimate corrections to protein-ligand binding free energies using free energy perturbation theory. In particular, the intramolecular energetics of the ligand were smoothly altered from GAP to OPLS/CM1A and the free energy cycle shown in Figure was employed to compute the correction to the binding free energy, ∆G A -∆G B (eq 8). Note that we have not computed the absolute binding free energies here. Focussing first on the binding of 3BPA to p38 MAP kinase, both GAP-v1 and GAP-v2 give a correction to the MM binding free energy of close to 1 kcal mol -1 . That is, we expect the standard MM force field to over-estimate binding, in this case, due to inaccuracies in the treatment of intramolecular energetics of the ligand in water and in the protein binding site. It is reassuring that the two versions of GAP agree on the magnitude of the correction; one would not expect the addition of extra training configurations to substantially affect the energetics of the molecule in either water or the p38 kinase binding site. The correction to the binding of 3BPA to leukotriene A4 hydrolase is larger, which is consistent with the inability of the MM force field to produce a binding mode that is consistent with the experimental electron density map (Figure ).