Quantum Chemical Studies of the Structure and Stability of N-Methylated DNA Nucleobase Dimers: Insights into the Mutagenic Base Pairing of Damaged DNA

Abstract

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.

Computational Probing of Watson–Crick/Hoogsteen Breathing in a DNA Duplex Containing N1-Methylated Adenine

“…The occurrence of these two distorted WC pairs appears reminiscent of the wobble bps of T·T mismatches . Moreover, the current WC* bp mode is similar to a distorted WC bp state of m1G·C predicted in an earlier quantum-mechanical study . The WC* bp was marginally stable as compared to the WC** bp (Δ G WC*→WC** = 1.7 kcal/mol), and the free energy barrier from WC* to WC** was only 2.3 kcal/mol.…”

“…41 Moreover, the current WC* bp mode is similar to a distorted WC bp state of m1G•C predicted in an earlier quantum-mechanical study. 42 The WC* bp was marginally stable as compared to the WC** bp (ΔG WC*→WC** = 1.7 kcal/mol), and the free energy barrier from WC* to WC** was only 2.3 kcal/mol. Hence, we expected that interconversions between WC* and WC** would possibly be realized with a normal MD simulation.…”

Nanoscale Properties of the Methylation in GpC Dinucleotide Systems

“…There are numerical studies of DNA focusing not only on a mesoscopic or microscopic scale, via classical molecular dynamics simulations, [9][10][11][12][13][14] but also at a nanoscopic scale by interpreting first-principles calculations. [15][16][17][18][19][20][21][22] The information obtained with these numerical studies, at length and time scales that are prohibitively small from the experimental point of view, complement experimental structural data. [23] For instance, quantum chemical calculations provide information about potential hydrogenbonding interactions in nucleobase dimers, [24] DNA damage recognition and repair, [25] the electronic charge and the equilibrium spatial distribution of a molecule could confirm that steric effects are relevant in particular reactions, and a quantitative description of the energy difference between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), could be used in the design of new DNA sequencing methods or DNA/RNA methylation detection, [26,27] only to name a few.…”

Non-dissociative structural transitions of the Watson-Crick and reverse Watson-Crick А·Т DNA base pairs into the Hoogsteen and reverse Hoogsteen forms

“…In this study we have provided investigations at the basic, but sufficient level of the isolated H-bonded pairs of nucleotide bases, that adequately simulates the processes in real biological systems 93 – 95 , in particular in the base-pair recognition pocket of the high-fidelity DNA-polymerase 42 – 46 . At this, we have relied on the experience received in the previous works 11 , 96 – 98 on the related topic and systems, in which the negligibly small impact of the stacking and sugar-phosphate backbone on the tautomerisation processes has been shown.…”