Naslov
Computational and experimental approach to the study of ligands binding into the active site of the human dipeptidyl-peptidases (DPPIII)

Autori
Tomić, Antonija ; Abramić, Marija ; Smith, David ; Tomić, Sanja

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

Izvornik
Book of Abstracts of the "The 3rd Adriatic Meeting On Computational Solutions in the Life Sciences" / Babić, Darko ; Došlić, Nađa ; Smith, David ; Tomić, Sanja ; Vlahoviček, Kristian - Zagreb : Centre for Computational Solutions in the Life Sciences, Ruđer Bošković Institute, 2009, 77-77

ISBN
978-953-6690-80-0

Skup
The 3rd Adriatic Meeting On Computational Solutions in the Life Sciences

Mjesto i datum
Primošten, Hrvatska, 01.09.2009. - 05.09.2009

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
dipeptidyl-peptidases III; molecular dynamics simulations; ligands binding

Sažetak
Dipeptidyl-peptidases III (peptidase family M49) are zinc-dependent enzymes that specifically cleave the first two amino acids from the N terminus of peptides. However, the molecular mechanism of their action is still unknown. Recently determined crystal structure of human DPPIII (PDB code 3FVY) enabled detailed molecular modelling study. In order to better understand the mechanism of the substrates, Arg-Arg-2naphthylamide (RRNA) and Ala-Ala-2naphthylamide (AANA), as well as the inhibitor (Tyr-Phe-hydroxamate) binding into the active site of H-DPPIII we performed molecular modelling study using the Amber10 program suite. The initial structures of the complexes were built in the program Insight II (http://accelrys.com/products/insight/) and to determine possible orientations of the ligands (inhibitor and substrates) in the enzyme binding site the steered molecular dynamics (MD) simulations were performed. According to the results, all the ligands studied bind into the DPPIII active site in a similar manner. Specifically, in each case, the Zn2+ cation is coordinated by the carbonyl oxygen and the hydrophobic rings are accommodated into a similar part of the binding cleft. In the native enzyme the zinc ion is coordinated by His-450, Glu-451 and His-455 from the first conserved (450HELLGH455) signature motif, Glu-508 which is part of the second conserved motif (507EECRAE512), and a water molecule. In the complexes, additional coordination is established by the carbonyl group belonging to the second peptide bond from the N terminus of the ligand. Besides the complexes with the WT protein we studied complexes with several mutants: N403Q, N403S, L402Q and H565N. To study their relative stability as well as to better sample possible orientations of the ligands in the enzyme binding site, we performed 2 ns of molecular dynamics simulations in explicit water for each complex (altogether 14 ns of MD simulation). According to the oscillations of the radius of gyration and Root Mean Square Deviations (RMSD) the stabilization is achieved after about 1.2 ns of the simulations. The RRNA-L402Q complex is found to be the most compact and most stable.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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