In addition, to address any potential low agreement between force field and QM energies due to change in conformation after MM energy minimization, we performed a conformer matching process (match-minima) for each MM structure which considered the final optimized geometries and energy differences. In this case, the ddE takes into account the energy difference between each MM optimized conformer and the MM conformer with lowest RMSD with respect to the QM minimum, relative to (dE QM ). The equations used in compareforcefields and match-minima to compute the ddE between the MM and QM energy for the ith conformer of a specific molecule are reported in the SI (Eq S1 and Eq S2, respectively).