The reaction mechanism was investigated by use of the QM/MM calculations for the representative snapshots from the MD trajectories for each system. QM regions included R90, E78 and entire substrate molecule, the coordinates for the QM region can be found in SI. All protein residues and water molecules within 8Å of the substrate were included in the 'active region' of the QM/MM calculations. The atoms in the 'active region' interact with the QM atoms through electrostatic and van der Waals interactions and the corresponding polarization effects were considered in the subsequent QM/MM calculations. All QM/MM calculations were performed with ChemShell, by combining Turbomole for the QM part, and DL_POLY for the MM part . The MM region was described using the Amber ff14SB force field, and the electronic embedding scheme was used to account for the polarizing effect of the enzyme environment on the QM region . The QM/MM boundary was treated using hydrogen link atoms with the charge-shift model .