Structural and energetic heterogeneities of canonical and oxidized central guanine triad of B-DNA telomeric fragments

Abstract

The intermolecular interaction energies in central guanine triad of telomeric B-DNA were estimated based on ab initio quantum chemistry calculations on the MP2/aDZ level of theory. The source of structural information was molecular dynamics simulation of both canonical (AGGGTT) and oxidized (AG8oxoGGTT) telomere units. Our calculations demonstrate that significant stiffness of central triad occurs if 8oxoG is present. The origin of such feature is mainly due to the increase of stacking interactions of 8oxoG with neighbouring guanine molecules and stronger hydrogen bonding formation of 8oxoG with cytosine if compared with canonical guanine. Another interesting observation is the context independence of stacking interactions of 8oxoG. Unlike to 5'-G2/G3-3' and 5'-G3/G4-3' sequences which are energetically different, 5'-G2/8oxoG3-3' and 5'-8oxoG3/G4-3' sequences are almost iso-energetic.

Non-additive interactions of nucleobases in model dinucleotide steps occurring in B-DNA crystals

“…Model d(XpY) steps were prepared according to procedure applied in our previous investigations [28][29][30][31][32] [35], in which fragments library was modified by replacement of native geometries (without hydrogen atoms) with monomers pre-optimized on MP2/aug-cc-pvDZ (aDZ) level (imposing C s symmetry). These monomers along with sets of 18 parameters (six for either hydrogen bonded pair and additional six for stacked two-bases pairs) were used for preparation of tetramers in which orientations of nucleobases exactly correspond to ones found in the original B-DNA structures.…”

“…It is reasonable to expect that presence of 8-oxoguanine in B-DNA can significantly alter intermolecular interactions [40]. For example intra-strand stacking interactions of 8-oxoG with guanine as well as hydrogen bonding with cytosine are stronger compared to canonical guanine at least in telomere repeat units [28,29]. It is interesting to see if modification of guanine leads also to any non-additivities in base-base interactions occurring in oxidized dinucleotide steps.…”

Molecular Perspective Review of Biochemical Role of Nucleobases Modified by Oxidative Stress

“…Such characteristics are only the first qualitative step and should be extended by detailed quantification of affinities of hydrogen bonded pairs including B-DNA environment. This important aspect is still unknown and deserve further attention although some initial studies were already published [69].…”

Structural and energetic properties of canonical and oxidized telomeric complexes studied by molecular dynamics simulations

“…Moreover, since GG and GGG stacked guanine sequences have lower IPs than single guanines [24, 27], such sequences are even more probable sites for undergoing oxidation. Also, formation of complexes by telomeric sequences with telomeric repeat binding factor (TRF) protein ligands is affected greatly by the presence of oxidative damage in the guanine triad [28, 29]. The appearance of a single 8-oxoguanine molecule decreases binding affinity between DNA and protein by about 50 %, while the presence of multiple 8-oxoguanine molecules in the telomeric sequence completely disrupts binding [30–32].…”

“…The appearance of a single 8-oxoguanine molecule decreases binding affinity between DNA and protein by about 50 %, while the presence of multiple 8-oxoguanine molecules in the telomeric sequence completely disrupts binding [30–32]. The most important changes related to the presence of the 8-oxoguanine molecule in telomeric sequences are observed in the space of the major groove [28, 29, 33], which plays the role of an active site responsible for binding of protein ligands. Figure 1 presents the structure of single subunit formed by one telomeric sequence and TRF1 protein ligand.…”