Quantum mechanical study on the activation mechanism of human carbonic anhydrase VII cluster model with bis-histamine schiff bases and bis-spinaceamine derivatives.

The activation mechanism of human carbonic anhydrase (hCA) isoform VII, hCA VII, with histamine, histamine bis-Schiff bases and bis-spinaceamine derivatives has been investigated using quantum mechanical calculations. The DFT-D3 method has been employed to calculate in detail the electronic structure and electronic energy of different compounds and complexes throughout the reaction pathway. The model system of hCA VII included the core catalytic center, the Zn2+ ion, its three histidine ligands and a hydroxide ion or water molecule coordinated to it. Furthermore, Thr199, Glu106 and the deep water molecule were considered in the model. Five activators of this enzyme, including histamine as standard, in complex with the cluster model of hCA VII were investigated. Thermodynamic functions for the overall reaction and for the complexation between activators and hCA VII were evaluated. Our results demonstrate that the protonatable moiety of these activators participates in proton transfer reactions from the zinc-bound water molecule to the reaction medium, promoting the formation of the catalytically active zinc hydroxide species of the enzyme. The QM analysis revealed that the electrostatic interactions between activators and hCA VII are the driving force of the enzyme-activator complex formation.