Multi scale computational approaches to understand a structure, dynamics and activity of thehuman dipeptidyl-peptidase III

Tomić, Antonija (2015) Multi scale computational approaches to understand a structure, dynamics and activity of thehuman dipeptidyl-peptidase III. Doctoral thesis, Faculty of Science > Department of Chemistry.

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Abstract

The dipeptidyl-peptidase III (DPP III) is a zinc-exopeptidase that hydrolyzes dipeptide from the N-terminus of its substrates. In this thesis a structure and dynamics of ligand-free enzyme and its complexes is investigated in detail by multi scale computational approaches. Modeling study was based on the three-dimensional enzymes structures obtained by X-ray diffraction analysis. Molecular dynamics (MD) simulations of the ligand-free enzyme revealed large flexibility of the protein, while the simulations of DPP III in the complexes with synthetic and peptide substrates enabled understanding of its broad substrate specificity, and, in combination with the free energy calculations, helped in determination of the most probable and chemically active ligand binding mode. The active enzyme conformation was confirmed by different MD approaches as well as by the hybrid quantum mechanicsmolecular mechanics (QM/MM) calculation of the different zinc ion coordinations. The reaction mechanism was determined using the model system consisting of substrate, amino acids participating in catalysis and the residues that coordinate the zinc ion.

Item Type: Thesis (Doctoral thesis)
Keywords: free energy calculations, human dipeptidyle peptidase III, metaloenzymes,molecular dynamics, molecular mechanics, quantum mechanics, substrate specificity
Supervisor: Tomić, Sanja
Date: 2015
Number of Pages: 233
Subjects: NATURAL SCIENCES > Chemistry
Divisions: Faculty of Science > Department of Chemistry
Depositing User: Branka Maravic
Date Deposited: 30 Apr 2015 10:49
Last Modified: 30 Apr 2015 10:49
URI: http://digre.pmf.unizg.hr/id/eprint/3919

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