Računalne simulacije kompleksa ljudske dipeptidil-peptidaze III s angiotenzinom-(1-7) i njegovim stabilnim analogom

master's thesis

• Title (english): Computational Study of Complexes of Human Dipeptidyl Peptidase III with Angiotensin-(1-7) and its stabile analogue
• Author: Ivana Čavka
• Mentor: Sanja Tomić (mentor)
• Mentor: Biljana Balen (mentor)
• Committee member: Biljana Balen (predsjednik povjerenstva)
• Committee member: Vesna Benković (član povjerenstva)
• Committee member: Dijana Škorić (član povjerenstva)
• Committee member: Inga Marijanović (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2018-09-28, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology

Abstract

Dipeptidil-petidaza III (DPP III) je metalopeptidaza ovisna o cinku, koja ima široku supstratnu specifičnost. Uključena je u procese razgradnje kratkih peptida sastavljenih od tri do deset aminokiselina. Poznato je kako ljudska DPP III (hDPP III) posjeduje visok afinitet prema opioidnim peptidima i peptidima iz sustava renin-angiotenzin-aldosteron, pa se sukladno tome povezuje s različitim fiziološkim procesima kao što su regulacija krvnog tlaka, mehanizam modulacije boli i obrana od oksidacijskog stresa. Osim toga, aktivnost enzima DPP III se povezuje i s nekim patološkim stanjima kao što su pojava mrene i rast tumora. Ova otkrića razlog su tome što se DPP III razmatra kao potencijalna meta lijekova. Rad donosi rezultate molekulsko-dinamičkih (MD) simulacija enzima hDPP III u kompleksima s dva različita peptida. Prvi peptid je eksperimentalno potvrđen supstrat – angiotenzin-(1-7), a drugi peptid je njegov stabilizirani analog ACCA3, u kojem je valin zamijenjen neprirodnom cikličkom δ aminokiselinom (ACCA). Supstitucija valina onemogućuje degradaciju angiotenzina-(1-7) enzimom hDPP III. Rezultati rada otkrivaju moguće uzroke stabilnosti peptida ACCA3, a upućuju i na veću stabilnost kompleksa hDPP III s ACCA3 u odnosu na kompleks s angiotenzinom-(1-7).

Abstract (english)

Dipeptidyl peptidase III (DPP III) is a zinc-dependant metallopeptidase with a broad substrate specificity. It is involved in degradation of peptides with three to ten amino acid residues. It is known that human DPP III (hDPP III) exhibits high affinity to opioid peptides and peptides from renin-angiotensin-aldosteron system. In the view of this, hDPP III has been associated with different physiological processes, such as, pain-modulation, blood pressure regulation and, defence against oxidative stress. Furthermore, there have been some implications of hDPP III enzyme’s involvement in pathophysiological states like cataractogenesis and malignant growth. These findings have characterized DPP III as a potential drug target. This thesis brings results of molecular dynamics (MD) simulations of complexes of hDPP III with two different peptides. First one is angiotensin-(1-7), which has been experimentally confirmed as a substrate, and the other one is its stabile analogue ACCA3, in which valin has been substituted with a non-natural cyclic δ amino acid (ACCA). Valin substitution prevents angiotensin-(1-7) degradation by hDPP III. The results hold possible causes of ACCA3’s apparent stability and indicate the greater stability of the complex of hDPP III with ACCA3, than that of the complex of hDPP III with the angiotensin-(1-7).

• Keywords: metalopeptidaza; ljudska dipeptidil-peptidaza III; angiotenzin-(1-7); molekulsko modeliranje; molekulska dinamika; račun slobodne energije; MM-PBSA
• Keywords (english): metallopeptidase; human dipeptidyl peptidase III; angiotensin-(1-7); molecular dynamics; molecular mechanics; free energy calculation; MM-PBSA
• Language: croatian
• URN:NBN: urn:nbn:hr:217:300560
• Study programme: Title: Molecular Biology; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra molekularne biologije (magistar/magistra molekularne biologije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access; Embargo expiration date: 2020-09-28
• Created on: 2018-10-29 11:55:20