Theoretical analysis of DNA intrastrand cross linking by formation of 8,5′-cyclodeoxyadenosine

Abstract

Formation of intramolecular cross links by addition of C(5') deoxyribose radicals to the C(8)-N(7) double bond of an attached adenine base was analyzed by ab initio quantum-chemical methods. Conformational preferences that influence the stereospecificity of the reaction were investigated. A good correlation was found between the ratio of experimental yields of R and S stereoisomers of 8,5'-cyclodeoxyadenosine and the relative energy of conformations of the C(5) radical that are precursors to these isomers. Molecular mechanics based on the AMBER force field was used to model the effect of 8,5'-cyclodeoxyadenosine on the conformation of the DNA dodecamer d(CGCGAATTCGCG)2 with the lesion at the A6 position. The R and S stereoisomers of the intrastrand cross link cause comparable levels of DNA distortion with the major conformational changes occurring in backbone torsional angles at the site of the lesion.

Consequence of hydrogen atom abstraction from 5’-hydroxyl group of 2’-deoxyadenosine. Theoretical quantum mechanics study

“…Thermodynamic studies have shown the highest stability for compound 3 [10]. For this reason the alkoxy radical (O5') of dA can become a precursor of compounds 12 and 13.…”

“…However, the appearance of 12 and 13 will terminate the DNA elongation process, and from this point of view will be highly toxic for cells. Comparison of selected geometry properties of 3 calculated by B3LYP/DZP++ [10] and B3LYP/6-31G** in gas phase.…”

“…However, its participation in the cyclisation process leading to the cdA formation is negligible, due to the less favourable transfer of the radical from oxygen O5' to C5'. At this point two things should be mentioned: first, the 3 is by 0.243188 Hartrees more stable than 2; second, when the 3 radical is formed the bond C4'-C5' is longer than in neutral 2'-dA (1.54 Å → 1.60 Å) and the bond O5'-C5' becomes shorter (1.42 Å → 1.35 Å) [10]. Due to these facts, it is much more probable that reaction with a hydrogen atom donor will lead to the reconstitution of dA.…”

“…Brought to you by | MIT Libraries Authenticated Download Date | 5/12/18 8:27 AM compounds 12/13, with the oxygen bridge, I have adopted mechanism proposed by Miaśkiewicz [10] for cdA formation.…”

Ionisation potential and electron affinity of free 5′,8-cyclopurine-2′-deoxynucleosides. DFT study in gaseous and aqueous phase

“…Their frequency and level in a living cell is still an open question, even though some data covering this field exists in literature [8]. Cyclopurines disturb the spatial geometry of DNA, weakening the hydrogen bonds between complementary bases in the double helix [9,10]. Moreover, they are more exposed to the influence of free radicals, therefore, their level in DNA can be upset due to forward reactions.…”