A theoretical study for the hydrolysis mechanisms several selected substrates catalyzed by α/β-hydroylase superfamily were investigated by means of ONIOM method with a two-layered model.Three hydrolysis pathways were examined and the most favored one was determined,which result was consistent with the experimental data.The intermediate was less stable and the serine catalytic triad played an important key role.The interactions between the carboxyl groups of the substrates and NH2 groups of residues and other substrates were discussed in detail.