Determination of productive conformations of acetylcholinesterase substrates using theoretical conformational analysis.

All equilibrium conformations of twenty-three acetylcholinesterase effectors were calculated by the molecular mechanics method, nonbonded interactions, torsion energy and energy of bond angles deformation being taken into account. In a series of conformationally flexible derivatives of acetylcholine the correlation was found between hydrolysis rate and population of the completely extended tt-conformation. In a series of cyclic analogues of acetylcholine the high hydrolysis rate occurs only for substrates sterically corresponding to tt-conformation of acetylcholine with regard to disposition of ammonium group, carbonyl oxygen and carbonyl carbon. The hydrolysis rate of acetylcholine derivatives with elongated chain between acetyl and cationic groups is directly proportional to the population of the conformations similar to tt-conformation of acetylcholine. It is concluded that tt-conformation of acetylcholine is productive for acetylcholinesterase hydrolysis.