Naslov
Human dipeptidyl-peptidases (h.DPP III), sampling the substrate binding site - computational analysis

Autori
Tomić, Antonija ; Tomić, Sanja

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

Izvornik
Book of Abstracts of the "Fourth Humboldt Conference on Computational Chemistry" / Petrova, P. Galina ; Vayssilov, N. Georgie - Sofija, 2010, 63.-63.

Skup
Fourth Humboldt Conference on Computational Chemistry

Mjesto i datum
Varna, Bugarska, 12.07.2010. - 15.07.2010

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Human dipeptidyl-peptidases; molecular dynamics simulations

Sažetak
Human dipeptidyl-peptidases plays a significant role in the protein catabolism, pain regulation and defense against oxidative stress.1, 2, 3 It hydrolyzes dipeptides from the N-terminal of its substrates. We performed series of molecular dynamics (MD) simulations for the complexes between the enzyme, wild type (WT) and its H568N and W300L mutants, and both synthetic and natural ligands, Arg-Arg-2-naphthylamide (RRNA), Tyr-Phe-hydroxamate and endomorphine-1 (EM-1), respectively. We accomplished 30 ns of MD simulations for the complexes between WT and the H568N mutated h.DPP III with synthetic ligands. For the complexes with EM-1 we performed 4 ns and for the free W300L mutant of h.DPP III and its complex with RRNA 3 ns of MD simulations. Systems simulated 30 ns show octahedral coordination of the central zinc ion. In the other systems the zinc coordination sphere is still not stable mainly due to fluctuations of the active site Glu508 and His450. MD simulations revealed the enzyme subsites S1, S2, S1' and S2' as well as the substrate N-terminus recognition site pointing out that both, synthetic and natural ligands bind into the h.DPPIII active site in a similar manner. Ligand binding induced reorganization of the binding site and its partial closure. Further MD simulations are required to: a) thoroughly investigate the EM-1 binding into the active site, and b) to elucidate effects of the Trp to Leu mutation on the complex stability. Also, using the QM/MM methodology we plan to shed some light on the hydrolysis that takes place in the DPP III active site. [1] Ellis S, Nuenke JM (1967) J Biol Chem 242, 4623 [2] Abramić M, Zubanović M, Vitale Lj (1988) Biol Chem Hoppe-Seyler 369, 29 [3] Chen JM, Barrett AJ (2004) In: Barret AJ, Rawlings ND, Woessner JF (eds) Handbook of Proteolytic Enzymes, vol 1. Elsevier, Academic Press, London, pp 809-812

Izvorni jezik
Engleski

Znanstvena područja
Kemija

POVEZANOST RADA