QM/MM calculations at the (point-charge) electrostatic embedding level were performed with the ASH software , using its interface to OpenMM (version 8.1.1) for the MM routines and to PySCF (version 2.6.2) for the QM routines. The ligand alone was defined as the QM region; thus, there were no covalent bonds crossing the QM/MM interface, and no link atoms were required.