Comparison of the Mechanisms of Hydrolysis of Organophosphates with Good and Poor Leaving Group by Phosphotriesterase from Pseudomonas diminuta

Combined quantum mechanics/molecular mechanics approaches are used to determine the mechanisms of organophosphate hydrolysis in an active site of Pseudomonas diminuta phosphotriesterase. For a substrate with a good leaving group, the reaction proceeds through two elementary stages with low energy barriers, and a gain in energy is observed. With a poor leaving group, only the formation of an unstable reaction intermediate is possible, and hydrolysis is incomplete. A comparison of the resulting reaction mechanisms explains the experimental kinetic data, according to which the enzyme hydrolyzes only substrates with good leaving groups.