We chose to use distance RMSD values (dRMSDs) over position RMSDs due to much higher sensitivity and since we previously defined extended active sites as predominantly h-bonding networks. dRMSD values were calculated for sets of 12-16 distances (see detailed lists in the Supplementary Information section). For hBChE systems, distributions of dRMSD values were computed for the last 5 ns of unrestrained MD run. Reference values on graphs correspond to mean values from the first NPT step.