Since these conformational shifts are largely governed by dihedral angle changes, accurately modeling the free energies of these angles is essential for reliable protein simulations. In our study, we explored the free energy surface corresponding to the Ramachandran angles of the alanine dipeptide in water (Figure , Panel D), comparing ML/MM and MM/MM results. We selected alanine dipeptide as it was one of the peptides used in parametrizing the Amber ff19SB force field, which was also applied here, and because its free energy surface at the ωB97X/6-31G* level of theory has been simulated for benchmarking other ML/MM implementations. Remarkably, the key secondary structure minima were consistent across both the ML/MM and the MM/MM surfaces. These minima include: right-handed α-helix, left-handed α-helix, polyproline II and β-strand, as showed on Figure . Furthermore, minima location and free energy barriers obtained for alanine dipeptide at the same QM/MM level show a very good agreement with our ML/MM profiles. simulations. The corresponding mean absolute errors (MAE) are 1.3 and 3.3 kcal/mol, respectively. Interestingly, employing MBIS charges without polarization or distortion corrections results in interaction energies that fall between the MM/MM and QM/MM distributions (Figure ).