All QM/MM calculations used the minimized and equilibrated initial structures (see above) obtained in our previous work 20, , from which geometry optimizations were performed for both reactants and products. All QM/MM calculations were performed using the Amsterdam Modeling Suite (AMS Version 2020.203) , using PBE and a DZ and a TZP Slater-type orbital basis set for geometry optimizations and single point calculations, respectively. For the MM region the ForceField engine of AMS was used with the AMBER95 force field , which was extended by parameters for the substrates. All charges are calculated from the Voronoi deformation density (VDD) of the reactant structures only. Further details are given in the Supporting Information (see Section S1).