Računalniške simulacije direktne alkilacije DNK z akrilonitrilom

magistrsko delo študijskega programa II. stopnje

Eva Brglez Mojzer (Author), Urban Bren (Mentor)

Abstract

V današnjem času smo povsod obdani s kancerogenimi snovmi, zato je naša naloga, da spoznamo, kako te snovi vplivajo na naše telo oz. kakšne spremembe povzročijo na dednem materialu DNK. Ena izmed teh snovi je akrilonitril, za katerega se je do sedaj predvidevalo, da se v telesu presnavlja predvsem po oksidativnem mehanizmu, saj se mehanizem direktne alkilacije oz. Michaelove adicije akrilonitrila na DNK še ni dovolj preučil. Preučevanja mehanizma direktne alkilacije akrilonitrila na DNK smo se posledično lotili v tem magistrskem delu. Mehanizem Michaelove adicije smo preučevali preko računalniških kvantnomehanskih simulacij na podlagi več različnih ab initio metod s programskim paketom Gaussian 09. Za realnejši izračun smo uporabili tudi implicitne modele vode, ki deluje kot topilo za reakcije v bioloških sistemih. Solvatacijske metode, ki smo jih uporabili, predstavljajo model polarizabilnega kontinuuma, ki spada v skupino metod samouglašenega reakcijskega polja, metoda Langevinovih dipolov in model AMSOL za semiempirične metode. Na podlagi aktivacijskih prostih energij smo ugotovili, da je reakcija direktne alkilacije z vidika energijske pregrade povsem mogoča. Rezultati so pokazali, da ima najnižjo aktivacijsko prosto energijo gvanin in je zatorej najbolj podvržen direktni alkilaciji s strani akrilonitrila, kar je tudi eksperimentalo potrjeno. Vendar pa so energijsko ugodne tudi reakcije adenina in citozina. Primerjava naših rezultatov z rezultati adicije cianoetilen oksida na DNK so razkrili, da je alkilacija akrilonitrila na DNK lahko celo energijsko ugodnejša, kar pomeni, da je mehanizem direktne alkilacije morda celo verjetnejši od oksidativnega mehanizma presnove akrilonitrila. Na podlagi dobljenih izsledkov smo torej pokazali, da je ključnega pomena nadaljevati z raziskavami mehanizma Michaelove adicije akrilonitrila na DNK, saj lahko le-ta predstavlja enega od ključnih mehanizmov kancerogeneze.

Keywords

akrilonitril;DNK;kvantna mehanika;računalniška kemija;Michaelova adicija;

Data

Language:	Slovenian
Year of publishing:	2015
Typology:	2.09 - Master's Thesis
Organization:	UM FKKT - Faculty of Chemistry and Chemical Engineering
Publisher:	[E. Brglez Mojzer]
UDC:	66.093:577.21(043.2)
COBISS:	18969110
Views:	1496
Downloads:	207
Average score:	0 (0 votes)
Metadata:

Other data

Secondary language:	English
Secondary title:	Computer simulations of direct DNA alkylation with acrylonitrile
Secondary abstract:	Nowadays carcinogenic substances surround us at every step, so our goal should become to get acquainted with the effects they have on our bodies and with what kind of modifications they can cause to our DNA. Acrylonitrile is a known carcinogenic substances which can be metabolised in the body via two different pathways, and until now it was believed that the oxidative pathway represents the major one, mainly because direct alkylation - the Michael addition pathway - had not been studiedin sufficient detail. Studying the direct alkylation mechanism was therefore the objective of this master thesis. We have studied this mechanism through quantum mechanical simulations using several ab initio methods incorporated in the Gaussian 09 series of programs. To compare the theoretical results to real systems and thus incorporate the solvent effects we have used implicit water models: the polarisable continuum model that belongs to the group of self-consistent reaction field methods, the Langevine dipoles method, and the AMSOL model for semiempirical calculations. On the basis of activation free energy we have come to conclusion that direct alkylation of DNA by acrylonitrile is perfectly plausable. The results have in complience with experiment shown that among DNA bases guanine has the lowest activation free energy and is therefore the most reactive with acrylonitrile. However, the energy bariers for adenine and cytozine are very similar to those of guanine and are low enough to cause direct alkylation by acrylonitrile as well. The comparison of our results with the results of cyanoethylene oxide addition to DNA have shown that investigated mechanism might even be more energetically favorable than the oxidative mechanism, thus possibly making direct Michael addition more the plausable mechanism for the metabolism of acrylonitrile. With these results we have shown that further studies of the Michael addition of acrylonitrile to DNA are needed, as it may represent one of the carcinogenic mechanisms.
Secondary keywords:	DNA;acrylonitrile;quantum mechanics;computational chemistry;Michael addition;
URN:	URN:SI:UM:
Type (COBISS):	Master's thesis/paper
Thesis comment:	Univ. v Mariboru, Fak. za kemijo in kemijsko tehnologijo
Pages:	XI, 64 str.
ID:	8888736