In the beginning of this work, we showed that we are unable to correctly model hBChE, both free and DEP-inhibited, via classical MD. This notion corresponds well with our results on the delocalized nature of the proton in both these states. On the other hand, free hAChE is exclusively in Glh202 state. We modeled the dynamics of hAChE and 9 other structurally related enzymes with the external Glu protonated. No inter-replica convergence was observed for any of these enzymes (Figure ). However, the best replica for hAChE demonstrated a conformation quite close to the reference (Figure ). It seems likely that systems with less pronounced proton delocalization are easier to model correctly with classical MD. For other systems, ad hoc restraints may be needed to prevent the incorrect modeling of the active site. While concrete realization of such is to be devised, for hBChE we suggest that targeting non-bonded interactions between the water molecule and Glu197, Glu441 and Ser224 may be crucial (Figure ).