Focusing on the embedding, for both the ANI-2x and the Δ-ML in vacuo potentials we observe a reduction in the errors when moving from a simple MM embedding (fixed charges) to the EMLE embedding with only charges (EMLE static) or to the EMLE embedding with charges and polarizabilities (EMLE total). The RMSE error () is reduced for the two in vacuo potentials when the MM embedding is changed to the EMLE static one: from 1.9 to 1.3 kcal•mol -1 in the ANI-2x calculations and from 1.5 to 1.3 kcal•mol -1 when using the specific Δ-ML potential for ADP. Both these embedding models consider only the interaction through partial charges, but while the MM embedding works with fixed point charges, in the EMLE static model the atomic charges are spread into Slater functions and their magnitudes respond to geometrical changes in ADP. Figure compares the distribution of MBIS charges calculated at the DFT level and with EMLE for ADP configurations sampled during the MD simulations, with hydrogen atom charges summed into their bonded heavy atoms. (The ff19SB charges are also shown for comparison.) The EMLE model is able to capture not only the average values of the DFT charges but also their fluctuations. An interesting observation is that the EMLE model differentiates between the two carbonyl carbon atoms, in agreement with DFT calculations, while these atoms are identical from a MM perspective. As demonstrated by the RMSE errors given in Figure , the charge model implemented in EMLE provides a better description of the electrostatic interaction than the simpler fixed point charge model used in the MM force fields. This means that a unique set of non-polarizable point charges is not enough to accurately reproduce the solute-solvent interaction energies for the whole set of structures that are being sampled during the conformational exploration. There are some ADP structures, far from the minimum energy regions (see regions of the FES with the largest errors in Figure ), whose interaction energy with the solvent cannot be correctly represented with the single set of point charges. The conclusion is that even when only small changes are expected in the charge distribution of the solute (as for conformational change in the neutral ADP system), ML/MM embedding with fixed charges may fail to reproduce results from more accurate QM/MM simulations. The MM embedding becomes too rigid to describe solute-solvent interactions for conformations significantly different from those observed in or near the most populated minima. Instead, the flexible charges provided by the EMLE model improve the treatment of solute-solvent interactions significantly, even for ADP structures far from the most populated conformations (Figure ). The use of a flexible embedding model thus appears to be a requisite for correct treatment of solute-solvent interactions when a variety of configurations, with different charge distributions, are considered. This is a key observation for the development of ML/MM strategies for simulating chemical processes, in particular when the charge distribution of the solute or reacting species can show significant variations, e.g. in a chemical reaction.