engleski

Development of new parameters for the Zn2+ ion for the specific environment of the DPP III enzyme catalytic site

The dipeptidyl peptidase III (DPP III) is a two-domain metallopeptidase that requires the zinc cation for its activity. Computational studies performed so far used the non-bonding parameters for the zinc ion. These parameters describe the metal-ligand interactions only through electrostatic and van der Waals potentials. Treating zinc metal in a non-bonded fashion resulted in a strong preference for octahedral zinc coordination that was not observed in the DPP III structures determined by the X-ray diffraction. In the experimentally determined DPP III structure the zinc ion is mostly tetrahedrally coordinated by two histidines, glutamate and one water or the substrate/inhibitor molecule. The quantum mechanics - molecular mechanics (QMMM) calculations showed an exchange of the four- and five-coordinated zinc ion during the reaction. In order to generate zinc ion parameters that will show better agreement with experimental findings and the results of QMMM calculations, several different strategies for metal ion modeling were tested. So far the hybrid model1, 2 that combines bonded and non- bonded approaches in a way that new bonds between the metal ion and protein residues are defined while leaving all other ligands unrestrained has shown the most promising results. The existing dummy atom model3 where the metal center is described by a set of cationic dummy atoms (CaDA) connected to the central atom in the tetrahedral coordination geometry to mimic the electron orbitals has not proved suitable for simulating the DPP III active site zinc ion. However, we are working on a modification and improvement of the available CaDA parameters. More accurate description of the Zn-protein interactions should aid to understand the factors governing specificity and coordination geometry around the metal center crucial for the novel DPP III ligands development.

dipeptidyl peptidase III, zinc parametrization, hybrid bonded/non-bonded model, cationic dummy atom model

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