Molecular modeling studies of AChE inhibition by sarin

In the present study molecular modeling and molecular mechanics methods using the crystal structure coordinates for acetylcholinesterase (AChE) from Torpedo Californica were employed to demonstrate the behavior of key residues of the enzyme upon inhibition by both the P_R and P_S diastereomers of isopropylmethylphosphonofluoridate (sarin). Comparative studies between both the adducts of AChE with P_S and P_R sarin and with the native enzyme indicate the important role of the aromatic residues in the vicinity of the active site as well as that of His-440 which catalyzes both the C-O bond breaking in the dealkylation reaction and the reaction of bond breaking to the Ser γ-O in reactivation. In contrast to previous studies, the role of Glu-199 in stabilizing the developing positive charge on the incipient carbonium ion in the dealkylation reaction was not verified in this study