Andrea L. Millen

Glycosidic bond cleavage in deoxynucleotides ― A density functional study

Density functional theory was used to study the glycosidic bond cleavage in deoxynucleotides with the main goal to determine the effects of the nucleobase, hydrogen bonding with the nucleobase, and the (bulk) environment on the reaction energetics. Since direct glycosidic bond cleavage is a high-energy process, two nucleophile models were considered (HCOO–···H2O and HO–), which represent different stages of activation of a water nucleophile. The glycosidic bond cleavage barriers were found to decrease, while the reaction exothermicity increases, with an increase in the nucleobase acidity. The gas-phase barriers and reaction energies for bond cleavage in all deoxynucleotides were found to be significantly affected by hydrogen-bonding interactions with the nucleobase (by up to 30 kJ mol–1 depending on the nucleophile). Although the barriers increase and reaction energies become less exothermic in enzymatic and aqueous environments, the effects of the bulk environment are similar in the presence and absence ...

yDNA versus xDNA Pyrimidine Nucleobases: Computational Evidence for Dependence of Duplex Stability on Spacer Location

The structural and binding properties of the natural and x- and y-pyrimidines were compared using computational methods. Our calculations show that although the x-pyrimidines favor different orientations about the glycosidic bond compared to the natural pyrimidines, which could have implications for the formation and resulting stability of xDNA duplexes and jeopardize the selectivity of expanded nucleobases, y-pyrimidines have rotational profiles more similar to the natural bases. Increasing the pyrimidine size using a benzene spacer leads to relatively minor changes in the hydrogen-bond strength of isolated Watson-Crick base pairs. However, differences in the anomeric carbon distances in pairs composed of x- or y-pyrimidines suggest yDNA may yield a more optimal expanded structure. By stacking two monomers via their centers of mass, we find that the expanded nucleobases stack much stronger than the natural bases. Additionally, although replacing xT by yT changes the stacking energy by less than 5 kJ mol (-1), replacing xC by yC significantly strengthens complexes with the natural nucleobases (by up to 30%). Calculations on larger duplex models composed of four nucleobases reveal that x- and y-pyrimidines can increase duplex stability of natural helices by strengthening both the intra and interstrand stacking interactions. Furthermore, when the total stability (sum of all hydrogen-bonding and (intrastrand and interstrand) stacking interactions) of the larger models is considered, y-pyrimidines lead to more stable complexes than x-pyrimidines for all but three duplex sequences. Thus, through analysis of a variety of properties, our calculations suggest that the location of the benzene spacer affects the properties of expanded nucleobases and the stability of expanded duplexes, and therefore should be carefully considered when designing future expanded analogues.

C8-linked bulky guanosine DNA adducts: experimental and computational insights into adduct conformational preferences and resulting mutagenicity

Bulky DNA adducts are formed through the covalent attachment of aryl groups to the DNA nucleobases. Many of these adducts are known to possess conformational heterogeneity, which is responsible for the variety of mutagenic outcomes associated with these lesions. The present contribution reviews several conformational and mutagenic themes that are prevalent among the DNA adducts formed at the C8-site of the guanine nucleobase. The most important conclusions obtained (to date) from experiments are summarized including the anti/syn conformational preference of the adducts, their potential to inflict DNA mutations and mismatch stabilization, and their interactions with DNA polymerases and repair enzymes. Additionally, the unique role that computer calculations can play in understanding the structural properties of these adducts are highlighted.

An indole-linked C8-deoxyguanosine nucleoside acts as a fluorescent reporter of Watson–Crick versus Hoogsteen base pairing

Pyrrole- and indole-linked C(8)-deoxyguanosine nucleosides act as fluorescent reporters of H-bonding specificity. Their fluorescence is quenched upon Watson-Crick H-bonding to dC, while Hoogsteen H-bonding to G enhances emission intensity. The indole-linked probe is ∼ 10-fold brighter and shows promise as a fluorescent reporter of Hoogsteen base pairing.