ML/MM simulations were performed employing different embedding schemes: the polarizable mechanical embedding using the ANI-MBIS model (equation ( )), a mechanical embedding scheme using the ANI-MBIS model without polarization and distortion correction (but MBIS charges predicted on-the-fly), and the actual mechanical embedding with ANI-2x, using fixed charges for the ML region, obtained from the corresponding force field (as specified below). QM/MM reference simulations were performed using the ωB97X/6-31G* level of theory to match the level of theory that the ANI models were trained on.