[Conformational differences in the sorption of choline ligands at the active site of acetylcholinesterase]

All the relatively stable conformers of acetylcholine, acetylthiocholine, and Rp- and Sp-enantiomers of the thiocholine-containing inhibitor of acetylcholine esterase, (CH3)2CHO(CH3)P(O)SCH2CH2N+(CH3)3, were calculated by the method of molecular mechanics. The population and the distances between functional atoms were determined for the relatively stable conformers. For the inhibitors, the accessibility of the phosphorus atom for interaction with the hydroxyl group of the Ser200 residue was determined. A computer model is proposed for the productive sorption of acetylcholine. The model assumes the contact of acetylcholine in the active center the hydroxyl group of the Ser200 residue, with the group behaving as a donor of H-bond, and also with the trimethylammonium sorptive segment. Among the organophosphorus inhibitors studied there are no relatively stable conformers that would be complementary to the sorptive site of the substrate, the choline head of the inhibitor cannot be sorbed at the trimethylammonium segment of the active center. An explanation was given for the stereospecificity of the studied enantiomers of an organophosphorus inhibitor within the limits of the proposed model.