KEY ACTIVE-SITE RESIDUES IN THE INHIBITION OF ACETYLCHOLINESTERASES BY SOMAN

Molecular modeling (GEMM 7.3) and molecular mechanics calculations (YETI V 5.3) using the X-ray coordinates for acetylcholinesterase (AChE) from Torpedo californica indicate electrostatic stabilization by the active site, Glu-199, of the developing positive charge on the incipient carbonium ion in the dealkylation in the adducts of AChE with P(S)C(R) and P(S)C(S) diastereomers of 2-(3,3-dimethylbutyl) methylphosphonofluoridate (soman). His-440 is indispensable as a general acid catalyst of C-0 bond breaking in the dealkylation reaction and that of bond breaking to the Ser gamma-O in reactivation. This demand for catalysis seems to be satisfied for the reactivation of enzyme from the P(S)C(S) diastereomer of soman, but not from the P(S)C(R) diastereomer.