Combined quantum mechanical–molecular mechanical study of catalysis by the enzyme phospholipase A 2 : an investigation of the potential energy surface for amide hydrolysis

A combined ab initio molecular orbital–molecular mechanical computational model has been applied to the investigation of the potential energy surface of catalysis by the enzyme phosphoiipase A2. By the integration of molecular mechanical and quantum mechanical gradients, the model allows the geometry optimisation of a substrate within the environment of the active site. The method has been applied to a comparison of the mechanisms of ester and amide hydrolysis by phospholipase A2. An estimation of the transition state for amide hydrolysis is described.