Naslov
Najnovija saznanja o koordinaciji cinka i o vezanju liganda u aktivno mjesto humane DPP III – implikacije na mehanizam kemijske reakcije
(The recent findings on the zinc ion coordination and ligand binding in the human DPP III active site – implication on the chemical reaction mechanism)

Autori
Tomić, Antonija ; Tomić, Sanja

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
XXIII. hrvatski skup kemičara i kemijskih inženjera, knjiga sažetaka / Hadžiev, Andrea ; Blažeković, Zdenko - Zagreb : Hrvatsko društvo kemijskih inženjera i tehnologa (HDKI), 2013, 177-177

ISBN
978-953-6894-50-5

Skup
XXIII. hrvatski skup kemičara i kemijskih inženjera

Mjesto i datum
Osijek, Hrvatska, 21.04.2013. - 24.04.2013

Vrsta sudjelovanja
Poster

Vrsta recenzije
Domaća recenzija

Ključne riječi
QM/MM; ONIOM calculations; dipeptidyle peptidase III

Sažetak
The recently performed long molecular dynamic (MD) simulations of the unbound human dipeptidyle peptidase III (DPP III, pdb code: 3FVY) and newly obtained experimental data of the DPP III − opioid peptide tynorphyn complex (X-ray structure of the E451A mutant, missing the central zinc ion, pdb code: 3T6B) revealed large scale conformational change of the protein as a result of interdomain movement, described as a “protein closure” [1, 2]. Although results of the MD simulations indicated that the substrate Arg−Arg−2−naphthylamide (RRNA) makes stronger and persistent interactions in the enzyme binding site when the protein is in its more compact form than in the “open” one [1], the active conformation of the enzyme is still unknown. However, in order to understand the reaction mechanism in the DPP III active site, the knowledge of the central zinc ion coordination is required. Discrepancy between the experimental data (tetrahedral zinc coordination in the “open” DPP III structure (3FVY), where the zinc ion is coordinated by two histidines (H450 and H455), one glutamate (E508) and one water molecule) and the results of MD simulations (octahedral coordination, contributed by one additional Glu451 carboxyl oxygen and water molecule), prompted new, quantum mechanical researches. To determine the energetically most favourable substrate binding mode and zinc coordination geometry, high level QM/MM ONIOM (Our own N- layered Integrated molecular Orbital and molecular Mechanics) minimizations of a few different bound and unbound protein structures were performed. Initial structures were obtained from classical MD simulations and QM/MM MD simulations using the self-consistent-charge density functional tight- binding method (SCC-DFTB) implemented in AMBER12 program suite, and third order integral parameters obtained from www.dftb.org website. [1] A. Tomić, S. Tomić, J. Chem. Inf. Model. 52 (2012) 1583-1594. [2] G. A. Bezerra, E. Dobrovetsky, R. Viertlmayr, A. Dong, A. Binter, M. Abramić, P. Macheroux. S. Dhe-Paganon, K. Gruber, PNAS 109 (2012) 6525-6530.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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