The computational studies provided valuable insight into the steric constraints and also tentatively identified the problematic, bulky carbamate warheads that could not reach and carbamoylate the catalytic Ser198. Additionally, the determined carbamoylation rate and Gibbs free energy of activation for inhibitor 6 agreed nicely with the quantum-mechanically predicted reaction barrier for a reaction with a model nucleophile in solution. Therefore, the steric effects appear to be the crucial factors in determining the covalent binding behaviour of these carbamate ChEIs. These results bring together the missing (and in our opinion, final) pieces to the puzzle on carbamate ChEI and when translated across different scaffolds, they could aid other researchers in the selection of the correct carbamate structure to achieve the desired, prolonged duration of action.