DNA is constantly under attack from exogenous and endogenous sources that modify the chemical structure of the nucleobases. A common type of nucleobase damage is N-methylation, which can result in mutagenesis. Nevertheless, these lesions are often repaired by the DNA repair enzyme AlkB, albeit at varying rates. Herein we use density functional theory (B3LYP-D3(BJ)/6-311++G(2df,2p)//B3LYP/6-31G(d,p)) to comprehensively examine the structural and energetic properties of base pairs between seven nucleobase lesions resulting from N-methylation on the Watson-Crick (WC) binding face and each canonical nucleobase. By characterizing 105 stable nucleobase dimers, we provide fundamental details regarding the preferred lesion base pairings. Specifically, we reveal that the flexibility of the methylamino group resulting from methylation of an exocyclic amino substituent allows the 2MeG, 4MeC, and 6MeA lesions to maintain a preference for canonical WC base pairing, which correlates with the experimentally reported lack of mutagenicity for these damage products. In contrast, calculated distortions in key structural parameters and altered binding energies for base pairs involving adducts formed upon methylation of a ring nitrogen (namely, 1MeG, 3MeT, 1MeA, and 3MeC) help rationalize the associated mutagenicity and repair efficiencies. Most importantly, our work provides molecular-level information about the interactions between N-methylated and canonical nucleobases that is critical for future large-scale modeling of damaged DNA and enzyme-DNA complexes that strive to further uncover the mutagenicity and repair propensities of these detrimental lesions.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone is a potent nicotine-based carcinogen that generates many DNA lesions, including the HOCH 2 −C, HOCH 2 −G, and HOCH 2 -A hydroxymethyl adducts. Despite all lesions containing an altered exocyclic amino group, which allows the hydroxymethyl group to be directed away from the Watson−Crick binding face, only the most persistent adenine adduct is mutagenic. As a first step toward understanding this differential mutagenicity, density functional theory (DFT) and molecular dynamics (MD) simulations were used to gain atomic-level structural details of these DNA damage products. DFT calculations reveal that all three lesions exhibit conformational diversity. However, regardless of the hydroxymethyl−nucleobase orientation, both DFT and MD simulations highlight that HOCH 2 −C and HOCH 2 −G form pairs with the canonical complementary base (G and C, respectively) that are structural and energetically preferred over mispairs. In contrast, depending on the hydroxymethyl−nucleobase orientation, the Watson−Crick HOCH 2 -A:T pair can become significantly destabilized relative to undamaged A:T. As a result, HOCH 2 -A mispairs with G, C, and A are energetically accessible and maintain key geometrical features of canonical DNA. Overall, our data directly correlate with the reported differential mutagenicity of the hydroxylmethyl lesions and will encourage future studies to further uncover the cellular impact of the most persistent adenine lesion.

Background While maternal sexually transmitted infections (STIs) during pregnancy have been extensively studied, fewer studies have directly compared the associations of different infections and co‐infections or investigated the association between STIs in pregnancy and maternal outcomes. Objectives We examine associations between STIs and co‐infections in pregnancy on risks of adverse neonatal and maternal outcomes. Methods Data from the 2019 US natality files (n = 3,747,882) were used to assess the associations between STIs in pregnancy on adverse pregnancy outcomes. Five mutually exclusive STI groups were examined: a single chlamydia, syphilis, or gonorrhoeal infection, chlamydia and gonorrhoea co‐infection, and syphilis co‐infection (with chlamydia, gonorrhoea, or both). Demographic and obstetric characteristics among each STI group were compared to those of an uninfected comparison group. Prevalence ratios (PR) of adverse neonatal outcomes (preterm birth, small for gestational age [SGA] births, and 5‐min APGAR (Appearance, Pulse, Grimace, Activity, and Respiration) score < 7) and maternal outcomes (gestational hypertension) by STI status were examined using log‐binomial regression. Results Increased prevalence of preterm birth was apparent, especially among those with a syphilis infection (PR 1.19, 95% confidence intreval [CI] 1.10, 1.30 for single infections and PR 1.31, 95% CI 1.10, 1.57 for co‐infections). All STI groups, except gonorrhoea and chlamydia co‐infections, were associated with an increased prevalence of gestational hypertension, with the strongest association among those with syphilis co‐infections (PR 1.41, 95% CI 1.13, 1.76). Conclusions An increased prevalence was of preterm birth and low APGAR scores were associated with syphilis infection. Increased prevalence of GH among those with STIs warrants further investigation into the relationships and corresponding mechanisms of STIs in pregnancy on adverse maternal outcomes.