The aging mechanism of acetylcholinesterase (AChE) inhibited by dichlorvos has been studied by using a combined quantum mechanics/molecular mechanics (QM/MM) computation. The doubt whether His447 should be protonated or not during the aging process was investigated. The results show that the exponential average barrier of the aging reaction with His447 in unprotonated state is 8.4 kcal/mol lower than that in protonated state, suggesting that His447 should be unprotonated during the aging process of dichlorvos-inhibited AChE. The further analysis reveals that residues Glyl 22 and A1a204 can facilitate the reaction through dispersing the charge and stabilizing the transition state. Crown Copyright (C) 2015 Published by Elsevier B.V. All rights reserved.