All the parameter files, as well as typical input files for classical and QM/MM-MD simulations and selected trajectories are provided in an online repository. 36 MD Simulation protocol. All classical molecular dynamics simulations were performed using Gromacs2022 software. Visualization of the trajectories and evolution of key collective variables was performed in VMD augmented by the Colvars dashboard. The system was first minimized for 2000 steps, using flat-bottom harmonic restraints (k = 20000 kJ/mol/nm 2 ) that act when the distance between the Mg 2+ ions and all the oxygen atoms initially present in their first hydration shells (4 water molecules, the bound oxygen atom of Asp56, Glu10 and Glu96) exceed 2.2 Å. In addition-and after initial tests that all immediately resulted in the active site falling apart-the scissile phosphate group of A117 was moved to adopt a bridge localization in between the two Mg 2+ ions, thus replacing the water molecule that bridges the two ions in the X-ray structure (see Figure . This was done using flat-bottom harmonic restraints on both Mg 2+ -O2P(pro-Sp)(A117) distances, with a harmonic wall at 2.2 Å. In addition, position restraints were applied to all heavy atoms of the complex.