A molecular orbital study on the zinc-water-Glu 270 system in carboxypeptidase A.

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Abstract
Many investigations on the reaction mechanism of carboxypeptidase A(CPA) have shown that the Zn2+ and Glu 270 in the active site are important in the catalytic reaction with a peptide substrate. X-Ray crystallographic studies of native CPA showed that the Zn2+ is coordinated to His 69, Glu 72, His 196 and 1 water molecule and that the Zn-coordinated water molecule forms a hydrogen bond with Glu 270. The zinc-water-Glu 270 system of native CPA was analyzed by the ab initio SCF-LCAO-MO [self-consistent field-linear combination of atomic orbitals-molecular orbital] method. Some ligands of Zn are included in the MO calculations as point fractional charges. The results show that the Zn-coordinated water molecule acts as a proton donor to Glu 270 and that the electrostatic effect of Zn2+ and its ligands and the electron delocalization between Zn2+ and the water play a significant role in lowering the barrier height of proton transfer. The carbonyl group of the substrate, without breaking the hydrogen bond between Glu 270 and the Zn-coordinated water molecule, may point towards a 5th coordination site slightly away from Zn2+ and the water molecule itself is possibly modified by its connection to Glu 270 in a way that favors the reaction.