We have chosen to demonstrate the application of the GAP to the computation of corrections to the MM binding free energy of 3BPA to two proteins. The GAP is used to describe the intramolecular energetics of the ligand only. It should be emphasized that there are still inaccuracies in protein dynamics and protein-ligand interactions due to the use of standard MM force fields for these components of the total energy. However, a wide range of parallel work is being devoted to deriving these components from QM data, either within the confines of the MM functional form or using expanded machine learning data sets. By making use of free energy perturbation theory, we estimate the corrections to MM binding free energies to be close to 1 and 2 kcal mol -1 for p38 kinase and leukotriene A4 hydrolase, respectively. For comparison, a recent study of 138 experimentally-verified FEP predictions of relative free energies of binding found that the accuracy of the computed results is close to 1 kcal mol -1 . The computation of absolute binding free energies is expected to be less accurate than relative free energies, nevertheless it appears that substantial accuracy gains are achievable by improving the description of intramolecular energetics. Of course, in computer-aided drug design one is typically interested in the relative binding free energies of a congeneric series of ligands, and similar free energy cycles could be employed also in these applications. We note in this regard that a full evaluation of the accuracy of GAP for correcting protein-ligand binding free energies will require evaluation of a significantly larger validation set for which accurate experimental data are available (only approximate binding affinities of the 3BPA fragment are available 1,2 ). Our goal is first to optimize the balance between accuracy and the size of the training dataset (which affects the computational time required to evaluate the potential). This is expected to be even more crucial as we move to drug-like compounds that are typically even larger and more flexible than 3BPA