Effect of Guanine Adduct Size, Shape, and Linker Type on the Conformation of Adducted DNA: A DFT and Molecular Dynamics Study.

DNA is damaged through various exogenous sources (e.g., automobile exhaust, tobacco smoke, and processed foods), which can yield diverse C8-dG bulky aryl adducts. Adducts are known to induce structural changes to DNA that can lead to various biological outcomes, ranging from cell death to diseases such as cancer. Unfortunately, the relationship between the chemical composition of the damaged product, the adducted DNA structure, and the biological consequences is not well understood, which limits the development of disease detection and prevention strategies. The present study uses density functional theory (DFT) calculations and quintuplicate 1 µs molecular dynamics (MD) simulations to characterize the structure of DNA containing 21 model C8-dG adducts that systematically differ in size (phenyl to pyrenyl), shape (α (2,3), ß (3,4) fusion, or ring substitution), and nucleobase-aryl group linkage (N, O, and C-linked). DFT calculations reveal that the inherent structural features of the G nucleobase adducts are impacted by linker type and bulky moiety shape, but not size, with the conformational flexibility reducing with α-ring fusion and linker composition as N > O > C. These structural properties are maintained in nucleoside models, which also reveal an increased propensity for anti-to-syn rotation about the glycosidic bond with N < O < C linker type. Although these diverse chemical features do not influence the global structure of adducted DNA, the adducts differentially impact the conformation local to the adducted site, including the relative populations of structures with the bulky moiety in the major groove (B conformer) and intercalated (stacked) into the helix (S conformer). Specifically, while the smallest phenyl adducts favor the B conformation and the largest pyrenyl-derived adducts stabilize the S conformation, the B/S ratio decreases with an increase in ring size and N > O > C linker composition. The shape and size (length) of the adduct can further finetune the B/S ratio, with ß-fused naphthyl or α-fused phenanthryl N-linked adducts and O or C-linked adducts containing ring substitution increasing the prevalence of the S adducted DNA conformation. Overall, this work uncovers the significant effect of bulky moiety size and linker type, as well as the lesser impact of aryl group shape, on adducted DNA structure, which suggests differential replication and repair outcomes, and thereby represents an important step toward rationalizing connections between the structure and biological consequences of diverse DNA adducts.

Multiscale computational investigations of the translesion synthesis bypass of tobacco-derived DNA adducts: critical insights that complement experimental biochemical studies.

Among the numerous agents that damage DNA, tobacco products remain one of the most lethal and result in the most diverse set of DNA lesions. This perspective aims to provide an overview of computational work conducted to complement experimental biochemical studies on the mutagenicity of adducts derived from the most potent tobacco carcinogen, namely 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (nicotine-derived nitrosaminoketone or NNK). Lesions ranging from the smallest methylated thymine derivatives to the larger, flexible pyridyloxobutyl (POB) guanine adducts are considered. Insights are obtained from density functional theory (DFT) calculations and molecular dynamics (MD) simulations into the damaged nucleobase and nucleoside structures, the accommodation of the lesions in the active site of key human polymerases, the intrinsic base pairing potentials of the adducts, and dNTP incorporation opposite the lesions. Overall, the computational data provide atomic level information that can rationalize the differential mutagenic properties of tobacco-derived lesions and uncover important insights into the impact of adduct size, nucleobase, position, and chemical composition of the bulky moiety.

DFT Study on the Deglycosylation of Methylated, Oxidized, and Canonical Pyrimidine Nucleosides in Water: Implications for Epigenetic Regulation and DNA Repair.

Density functional theory (B3LYP) was used to characterize the kinetics and thermodynamics of the (nonenzymatic) deglycosylation in water for a variety of 2'-deoxycytidine (dC) and 2'-deoxyuridine (dU) nucleoside derivatives that differ in methylation and subsequent oxidation of the C5 substituent. A range of computational models are considered that combine implicit and explicit solvation of the nucleophile and nucleobase. Regardless of the model implemented, our calculations reveal that the glycosidic bond in dC is inherently more stable than that in dU. Furthermore, C5 methylation of either pyrimidine and subsequent oxidation of the methyl group yield overall small changes to the Gibbs reaction energy profiles and thereby preserve lower deglycosylation barriers for the dC compared to those for the dU nucleoside derivatives. However, hydrolytic deglycosylation becomes significantly more energetically favorable when 5-methyl-dC (5m-dC) undergoes two or three rounds of oxidation, with the Gibbs energy barrier decreasing and the reaction becoming more exergonic by up to 40 kJ/mol. In fact, two or three oxidation reactions from 5m-dC result in a deglycosylation barrier similar to that for dU, as well as those for the associated C5-methylated (2'-deoxythymidine) and oxidized (5-hydroxymethyl-dU) derivatives. These predicted trends in the inherent deglycosylation energetics in water directly correlate with the previously reported activity of thymine DNA glycosylase (TDG), which cleaves the glycosidic bond in select dC nucleosides as part of epigenetic regulation and in dU variants as part of DNA repair. Thus, our data suggests that fundamental differences in the intrinsic reactivity of the pyrimidine nucleosides help regulate the function of human enzymes that maintain cellular integrity.