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QM/MM study of the zinc coordination in the active site of the human DPP III

In the crystal structure of the ligand-free human DPP III (PDB ID: 3FVY), the central zinc ion is coordinated by two histidines (His450, His455), one glutamate (Glu508) and one water molecule. Our previous results [1, 2] showed that during the early stage of the molecular dynamics (MD) simulations of the free protein one additional water molecules and one of the Glu451 carboxy oxygens entered the Zn2+ coordination sphere, resulting with octahedral coordination of the zinc cation. In these simulations we used the non- bonding parameters for Zn2+, derived in our previous work [3] (r=1.22Å, ε=0.25kcal/mol and charge +2e). In order to further examine reliability of the zinc coordination geometry obtained after the MD simulations the ONIOM (Our own N-layered Integrated molecular Orbital and molecular Mechanics) QM/MM calculations were performed for the initial and final protein structure. For this purpose the protein was divided into two layers which were handled at different levels of theory. The quantum mechanical (QM) layer was treated by the DFT method using B3LYP functional [4] and the 6-311++g(d, p) basis set. The molecular mechanic (MM) calculations were performed using the AMBER force field (param96) [5]. In all structures the QM layer consisted of, His450, Glu451, His455 and Glu508 side chains (as well as the hydrogen link atoms used to link QM part with the MM part and placed between Cα and Cβ atoms of the mentioned residues), the zinc ion and two water molecules. These two water molecules corresponded either to crystallographic water molecules, or to those found in the zinc coordination sphere after 101 ns of MD simulations. [1] Tomić A., Abramić M., Špoljarić J., Agić D., Smith M. D., Tomić S., J. Mol. Recogn. 24 (2011), 804-814 ; [2] Tomić A., Tomić S., paper in preparation [3] Bertoša B., Kojić- Prodić B., Wade R. C., Tomić S., Biophys. J. 94 (2008), 27-37 [4] Becke, A. D. Phys. Rev. A, 38 (1988), 3098 ; Becke, A. D. J. Chem. Phys., 98 (1993), 1372-1377 ; Becke, A. D. J. Chem. Phys., 98 (1993), 5648

qm/mm; zinc coordination; dipeptidyle-peptidase III

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