A Simulation of the Catalytic Mechanism of Aspartylglucosaminidase Using ab Initio Quantum Mechanics and Molecular Dynamics

Abstract

Ab initio quantum mechanical (QM) and molecular dynamics (MD) methods have been used to study the catalytic mechanism of aspartylglucosaminidase (AGA)-catalyzed hydrolysis of an amide bond. QM active-site models were used to calculate the reaction sequences of the acylation and deacylation parts of the catalytic reaction at the MP2/6-31G*//HF/6-31G* level. MD simulations, in which the structures of the active sites were constrained to the geometries obtained from the QM model calculations, were carried out for all the species of the reaction sequence. Structural information from the MD simulations was used in the subsequent QM calculations in which the charge distribution of the protein environment and solvent was included as a set of atomic point charges. These QM calculations provided an estimate of the effects of the protein environment on the energetics of the catalytic reaction. The reaction mechanism was also simulated using a continuum model for the aqueous solvent, in order to differentiate genera...