These results demonstrate that advanced force fields with improved electrostatics can stabilize the active site structure reconstructed from the low-resolution cryo-EM structure of the complex and X-ray structure of the isolated protein, after a small displacement of the reactive phosphate. To complement these observations, it would be interesting in future work to assess the stability of this active structure when using explicitly polarizable force fields, that, in principle, should provide an even finer electrostatic description. The structure of the active site is then very similar to that of previously described nucleases, even if it lacks the typical aspartate residue bridging the two ions, previously thought to be essential for reactivity. 11