Finally, a spherical droplet with a radius of 33 Å from the COMT center of mass was extracted. It contained COMT with substrates, sodium ions and the corresponding water molecules and was used as starting structure for the QM/MM calculations. For QM/MM calculations starting from the vacuum structure, the water molecules and ions were deleted from the spherical droplet structure. For QM/MM calculations starting from the crystal with all MM solvent molecules and ions fixed to their initial coordinates. All charges evaluated for charge convergence tests are calculated from the Voronoi deformation density (VDD) of the reactant structures only.