Correlation between the substrate structure and the rate of acetylcholinesterase hydrolysis modeled with the combined quantum mechanical/molecular mechanical studies

The combined quantum mechanical–molecular mechanical (QM/MM) based computational scheme for modeling the structure–reaction rate correlations was elaborated for the hydrolysis of the set of neutral esters in the active site of acetylcholinesterase (AChE). The energy barriers of hydrolysis were estimated on the basis of the equilibrium geometry configurations of the enzyme–substrate (ES) complexes. The obtained correlation between the rate of hydrolysis and the hydrophobicity of the substrate leaving group is consistent with experimental data. The developed method can be used to predict the substrate reactivity and to interpret the specific nature of the enzyme catalysis.