Determination of Productive Conformation of Acetylcholinesterase Substrates Using Molecular Mechanics

Abstract All equilibrium conformations (conformers) of 23 acetylcholinesterase substrates, conformationally flexible or semirigid derivatives of acetylcholine, were calculated using molecular mechanics. In a series of α‐alkyl‐β‐alkyl derivatives of acetylcholine, a correlation was found between the rate of hydrolysis of substrates and population of their completely extended tt‐conformers. Among cyclic analogs of acetylcholine, only those substrates which are compatible with the tt‐conformer of acetylcholine by the spatial disposition of the ammonium group, carbonyl oxygen and carbonyl carbon, are hydrolyzed at a high rate. In acetylcholine derivatives with elongated chain between acetyl and cationic groups, the hydrolysis rate varies directly with the population of conformers compatible with the tt‐conformer of acetylcholine. It is concluded that the tt‐conformer of acetylcholine is productive for the hydrolysis by acetylcholinesterase.