The conformational landscape of ADP results form a delicate balance between intra-and intermolecular interactions that depend on the environment. In vacuo, the most populated ADP conformer is C7eq ( -80°,  75°) due to the formation of an intramolecular hydrogen bond interaction between the consecutive peptide groups. In aqueous solution, the preferred conformer is PII (j -70°, y 150°), with other states (C5 (j -150°, y 155°) and αR (j -75°, y -20°)) being also populated due to the solute-solvent interactions favoured by the larger accessibility of the polar groups. Figure shows the ADP model and the 2D DFT/MM Free Energy Surface (FES) obtained in aqueous solution. This FES qualitatively agrees with the experimental observations, showing that the preferred conformations in aqueous solution are αR and PII. A more quantitative comparison would require longer simulations (the statistical error is estimated to be 0.3 kcal•mol -1 ; see section 3.2) and integration over the surface to get the correct population of each conformer. The deviations of all the four ML/MM FESs from the reference DFT surface are shown in Figure . The FESs are provided as Supplementary Information (Figure ). The error  for each FES is calculated as the RMSE over the FES bins. In all cases, only the bins with free energies below 20 kcal•mol -1 were considered, to exclude bins that contain very few samples and therefore have a high statistical error. The six ML/MM models each reproduce the main features of the DFT/MM surface (Figure , Figure ), at a significantly reduced computational cost (see below). The RMSE values are, in all cases, smaller than 2 kcal•mol -1 . The in vacuo potential has a significant impact on the total error. The ANI-2X generic ML potential results in a RMSE errors between 1.9 and 1.2 kcal•mol -1 , depending on the embedding model. In contrast, using a system-specific Δ-ML potential reduces the RMSE almost by a half (between 1.5 and 0.7 kcal•mol -1 ). This is not unexpected, because the Δ-ML potential was tailored to the studied system. A comparison of the distribution of the potential energy errors of the two ML in vacuo potentials with respect to the ωB97X/6-31G* energies indicates that the Δ-ML potential reproduces the ωB97X/6-31G* energies better (Figure ), which thus translates into a better description of the FES.