By analyzing the resulting free energy profiles for each group, we extract one or more candidate states for further all-vs-all comparison (Figure ). We did not take any minima that was more than 5 kcal/mol higher than the global one. In total, 15 unique protonation states were shortlisted for the next step (Figures ). We then lifted position restraints from the whole extended active site and monitored the conservation of the geometry in dynamics (Figure ). Two states, 9 and 10, displayed the best similarity to the x-ray reference (Fig ). Both feature the protonated catalytic His438, with an additional proton on Glu197 or Glu441 for states 9 and 10 respectively. These are exactly the systems that we modeled classically in the beginning of this study and that were shortlisted by Luschchekina and Masson before. Intriguingly, we observed rapid interconversion between these two states in the absence of any biasing potential, with a preference for state 10. We studied this behavior quantitatively and reconstructed the free energy profile (Fig 4C ). We found that two protons switch their bonding partners in an almost concerted manner (Fig ).