The QM/MM input files were generated using the PDB2ADF tool provided by AMS for protein systems and using a Python script (included in the data set at Ref. ) inspired by the functionality of PDB2ADF for the DNA system. Electrostatic embedding as implemented in AMS was applied for the interaction between the QM and MM regions. Link atoms in the protein systems were placed on the C α -C and C α -N bonds only including the α-carbon atom in the QM region for single QM amino acids, while also including the remaining backbone atoms between two subsequent QM amino acids to reduce the number of link atoms. In the DNA system link atoms were placed on the N-glycosidic bond only including the bases to the QM region and let the negatively charged backbone remaining in the MM region. Over-polarization at the boundary region is handled in AMS by setting the point charge of the MM boundary atom to zero and redistributing it over the remaining MM atoms conserving the total charge . Residues included in the different-sized QM regions for each system are listed in the Supporting Information in S1 and S2 (COMT), S4 and S5 (TIM), and S7 (DNA), which also list the corresponding QM region charges and the numbers of atoms and link atoms.