Naslov
Natural vs. synthetic peptides binding to human dipeptidyl-peptidases (DPP III), computational insight

Autori
Tomić, Antonija ; Tomić, Sanja

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

Izvornik
Book of Abstracts of the "Australia-Croatia Workshop on Antimicrobial Peptides and Summer School in Biophysics PhD Programme: AMP 2010" / Juretić, Davor ; Separovic, Frances - Split : Faculty of Science, University of Split, 2010, 49.-49.

ISBN
978-953-7155-15-5

Skup
Australia-Croatia Workshop on Antimicrobial Peptides and Summer School in Biophysics PhD Programme: AMP 2010

Mjesto i datum
Split, Hrvatska, 09.08.2010. - 13.08.2010

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
dipeptidyl-peptidases III; molecular dynamics simulations

Sažetak
Human dipeptidyl-peptidases (h.DPP III) hydrolyzes dipeptides from the N-terminal of its substrates. It has implied role in intracellular protein catabolism, as well in pain-modulatory system and endogenous defense against oxidative stress.1, 2, 3 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, respectively. We accomplished 30 ns of MD simulations for the complexes between WT and the H568N mutated DPP III with synthetic ligands. For their complexes with endomorphine-1 we performed 4 ns and for the free W300L mutant of DPP III and its complex with RRNA 3 ns of MD simulations. Systems simulated 30 ns show octahedral coordination of the central zinc ion, while for others the zinc coordination sphere is still no 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 DPPIII active site in a similar manner. Ligand binding induced reorganization of the binding site as well as its partial closure, involving a small flexible loop at the narrow end of the cleft. The binding free energies were evaluated using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA). Further MD simulations are required to elucidate: a) effects of the tryptophan to leucine mutation on the complex stability and b) to thoroughly investigate the endomorphine-1 binding into the active site. Also, using the QM/MM methodology we plan to shed some light on the hydrolysis that takes place in the DPP III active site.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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