Modeliranje reakcije kvercetina s hidroksil radikalom

master's thesis

• Title (english): Modeling the reaction of quercetin with hydroxyl radical
• Author: David Vuzem
• Mentor: Viktor Pilepić (mentor)
• Committee member: Viktor Pilepić (predsjednik povjerenstva)
• Committee member: Domagoj Kifer (član povjerenstva)
• Committee member: Cvijeta Jakobušić Brala (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of physical chemistry); Zagreb
• Defense date and country: 2024-12-18, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

U brojnim biološkim pokusima utvrđeno povoljno djelovanje polifenola kvercetina na organizam tumači se između
ostalog i mogućim reakcijama kvercetina s vrlo reaktivnim kisikovim radikalskim spojevima (ROS). U tim
antioksidativnim reakcijama kvercetin može predati vodikov atom vrlo reaktivnom radikalu i tako ga prevesti u slabo
reaktivan i neopasan spoj. U takvim reakcijama nastaje i slabo reaktivni kvercetin radikal anion koji ne predstavlja
opasnost i može se ukloniti.
U ovom radu cilj je bio metodama računske kemije na modelnom sustavu ispitati mogući reakcijski mehanizam za
antioksidativno djelovanje polifenola kvercetina u fiziološkim uvjetima. U tu svrhu koristile su se DFT metode i analiza
„intrinzičnih veznih orbitala“ (IBO). Modelni sustav sastojao se od aniona kvercetina deprotoniranog na 4'-OH ili 7-OH
skupini, hidroksil radikala (OH• ) i 405 molekula vode. Provedeni su izračuni molekulske dinamike te se pokazalo da se
za niz trajektorija koje su dobivene može utvrditi da je došlo do reakcije prijenosa vodikovog atoma s molekule
kvercetina na hidroksil radikal. Također je utvrđeno da hidroksil radikal propagira kroz otapalo uglavnom
reorganizacijom vodikovih veza odnosno Grotthuss-ovim mehanizmom. Za niz trajektorija kod kojih je došlo do
prijenosa vodikovog atoma, provedena je IBO analiza. IBO analiza omogućuje identifikaciju molekulskih orbitala na
kemijski intuitivni način kao i praćenje preraspodjele molekulskih orbitala tijekom reakcije te je stoga uspješno korištena
za istraživanje reakcijskih mehanizama. Za sve provedene simulacije gdje je došlo do prijenosa vodikovog atoma,
provedena IBO analiza je pokazala da β spin elektron koji se uparuje s nesparenim α spin elektronom OH• dolazi iz π
IBO aromatskog sustava kvercetin aniona, dok oba elektrona vezne σ IBO OH skupine kvercetina nakon otpuštanja
protona ostaju na kvercetinu, a oba elektrona slobodnog elektronskog para OH• radikala stvore s prenesenim protonom σ veznu IBO nastale molekule vode.
U svim analiziranim slučajevima, IBO analiza trajektorija pokazala je da se prijelaz vodikovog atoma s neke od OH
skupine aniona kvercetina na OH•radikal odvija tako da su u proces prijelaza elektrona i protona uključene različite IBO
te se može pretpostaviti da se ova reakcija odvija reakcijskim mehanizmom spregnutog prijelaza elektrona i protona
(PCET).

Abstract (english)

The beneficial effects of the polyphenol quercetin on the body, which have been determined in numerous biological
experiments, are explained, among other things, by the possible reactions of quercetin with highly reactive oxygen
species (ROS). In these antioxidative reactions, quercetin can quench the reactive radical by transferring a hydrogen
atom and turning it into a less reactive and harmless form. The less reactive quercetin radical anion formed in these
reactions does not pose any further danger and can be eliminated.
The goal of this thesis is to propose a possible reaction mechanism for the antioxidative effect of quercetin under
physiological conditions based on computational chemistry methods in a model system. DFT methods and 'intrinsic
bond orbital' (IBO) analysis were used for this purpose. The model system is composed of quercetin anion deprotonated
on either the 4'-OH or 7-OH group, hydroxyl radical (OH• ) and 405 molecules of water. Molecular dynamics simulations
are run on the system, and a number of trajectories, in which the reaction of hydrogen transfer from quercetin to hydroxyl
radical was successful, were identified. It has also been identified that the main method of hydroxyl radical propagation
through the medium is through reorganization of hydrogen bonds, also known as the Grotthuss reaction mechanism. On
the trajectories in which the hydrogen transfer reaction was confirmed, IBO analysis was performed. IBO analysis
enables the identification of molecular orbitals in a chemically intuitive way by means of which it is possible to monitor
the redistribution of molecular orbitals during the reaction and is therefore successfully used for the investigation of
reaction mechanisms. For all performed simulations where hydrogen atom transfer occured, the performed IBO analysis
showed that the β spin electron that pairs with the unpaired α spin electron of OH• comes from the IBO of the π aromatic
system of the quercetin anion, while both electrons of the σ bonding IBO of the OH group of quercetin after the release
of the proton remain on quercetin, and both electrons of the free electron pair of the OH• radical create the σ bonding
IBO of the resulting water molecule with the transferred proton.
In all analyzed cases, the IBO analysis of the trajectories has revealed that the hydrogen atom transfer from one of the
OH groups of the quercetin anion to the OH• radical utilizes different sets of IBOs for proton and for electron transfer,
and thus in this case, a proton coupled electron transfer (PCET) reaction mechanism can be proposed.

• Keywords: kvercetin; hidroksil radikal; intrinzične vezne orbitale; spregnuti prijelaz elektrona i protona
• Keywords (english): quercetin; hydroxyl radical; intrinsic bond orbitals; proton coupled electron transfer
• Language: croatian
• URN:NBN: urn:nbn:hr:163:198673
• Study programme: Title: Pharmacy - integrated undergraduate and graduate - university study; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: sveučilišni magistar farmacije (sveučilišni magistar farmacije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2025-01-31 13:37:55