Eksperimentalno utemeljeno modeliranje interakcija nukleinskih kiselina i malih molekula

doctoral thesis

• Author: Marina Grabar Branilović
• Mentor: Sanja Tomić (mentor)
• Committee member: Ivo Piantanida (predsjednik povjerenstva)
• Committee member: Sanja Tomić (član povjerenstva)
• Committee member: Matko Glunčić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Physics); Zagreb
• Defense date and country: 2014-06-17, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Physics
• Universal decimal classification (UDC): 53 - Physics

Abstract

U okviru ove doktorske disertacije metodama molekulskog modeliranja proučavane su interakcije nukleinskih kiselina s nekoliko skupina organskih spojeva: derivatima bisfenantridina, guanidiniokarbonil-pirol-arilnim konjugatima, cijaninskimspojevima, te translacijskim(benzimidazolnimi diaminopiperidinskim) inhibitorimahepatitis C virusa. Istraženi su procesi njihovog kompleksiranja, interkaliranja, vezanja u utor te elektrostatskog međudjelovanja s polinukleotidima. Prve tri skupine spojeva imaju svojstvo molekulskog prepoznavanja nukleobaza,pa mogu poslužiti za razvojnovih specifičnih obilježivača pri istraživanju nukleinskih kiselina, te kao predložak za razvoj antitumorskih i antivirusnih lijekova sa svojstvom selektivnog blokiranja određenih sljedova DNA ili RNA. Kao polazišne točke za modeliranje korišteni su rezultati spektroskopskih mjerenja (UV-Vis i CD spektri, fluorimetrijske titracije) te difrakcijske i NMR analize. Istraživanja su provedena metodama molekulskog modeliranja različitih stupnjeva složenosti. U svrhu određivanja novih parametara korišteni su kvantno mehanički računi. Proučavanje strukture i fleksibilnosti nukleinskih kiselina i njihovih kompleksa s organskim molekulama provedeno je metodama polja sila (molekulska mehanika i molekulska dinamika). Kombinirane kvantno mehaničke –molekulsko mehaničke metode primijenjene su u svrhu ispitivanja utjecaja okoline, preciznije polinukleotidnog lanca i metalnih iona, na raspodjelu naboja na ligandima. Dobiveni rezultati u skladu su s eksperimentalnim saznanjima.

Abstract (english)

Scope of this thesis is the computational, molecular modeling study of interactions between nucleic acids and organic compounds like bis-phenanthridinium derivatives, guanidiniocarbonyl-pyrrole-aryl conjugates, phosphonium dyes and translation (benzimidazole and diaminopiperidine) inhibitors of hepatitis C virus. They bind to polynucleotide in specific way, either as intercalators orgroovebindersandin addition establishstrong electrostatic interactions with polynucleotides. The first three groups of compounds have ability of molecular recognition of nucleobases so they can be used eitheras a template for development of thenew,highly specific nucleic acids markersor antiviral drugs with the ability to selectively block transcription of specific DNA/RNA sequences. Starting points for modeling were results of spectroscopic measurements(UV-Vis and CD spectra, fluorimetric titrations) and X-ray and NMR analysis. Study wasperformed using molecular modeling methods of various degrees of complexity.In order to determinate new parameters quantum mechanics calculations were used. The study of the structure and flexibility of nucleic acids and their complexes with small organic molecules was performed using the force field methods (molecular mechanics and molecular dynamics), while influence of the nucleic acid environment, precisely polynucleotide strand and metal ions, on the ligand charge distribution was investigated by the combined quantum mechanics –molecular mechanics approach. The results obtained within the research arein accordance with the experimental findings.

• Keywords: nukleinske kiseline; polje sila; molekulska mehanika; molekulska dinamika; kvantno mehanički računi; interkalatori; mali utor –vežući spojevi; inhibitori HCV-a
• Keywords (english): nucleic acids; force field; molecular mechanics; molecular dynamics quantum; mechanical calculations; intercalators; minor groove binders; HCV inhibitors
• Language: croatian
• URN:NBN: urn:nbn:hr:217:485930
• Study programme: Title: Physics; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje fizika (doktor/doktorica znanosti, područje prirodnih znanosti, polje fizika)
• Type of resource: Text
• Extent: 108 str.
• File origin: Born digital
• Access conditions: Open access
• Created on: 2017-08-22 10:25:07