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. 2022 Sep 13;23(18):10621.
doi: 10.3390/ijms231810621.

Formation Mechanism of Inter-Crosslink in DNA by Nitrogen Oxides Pollutants through A Diazonium Intermediate

Noemi Hernandez-Haro  1 , Christian Solis-Calero  2 , Rodrigo Casasnovas  1   3 , Christophe Morell  4 , Andre Grand  5 , Juan Frau  1   3 , Joaquín Ortega-Castro  1   3
Affiliations

Formation Mechanism of Inter-Crosslink in DNA by Nitrogen Oxides Pollutants through A Diazonium Intermediate

Noemi Hernandez-Haro et al. Int J Mol Sci. .

Abstract

Outdoor air pollution is a mixture of multiple atmospheric pollutants, among which nitrogen oxide (NOx) stands out due to its association with several diseases. NOx reactivity can conduct to DNA damage as severe as interstrand crosslinks (ICL) formation, that in turn is able to block DNA replication and transcription. Experimental studies have suggested that the ICL formation due to NOx is realized through a diazonium intermediate (DI). In this work, we have modeled the DI structure, including a DNA double-strand composed of two base pairs GC/CG, being diazotized as one of the guanine nucleotides. The structural stability of DNA with DI lesion was essayed through 500 ns molecular dynamics simulations. It was found that the DNA structure of the oligonucleotide is stable when the DI is present since the loss of a Guanine-Cytosine hydrogen bond is replaced by the presence of two cation-π interactions. Additionally, we have studied the mechanism of formation of a crosslink between the two guanine nucleobases from the modeled DI by carrying out DFT calculations at the M06-L/DNP+ level of theory. Our results show that the mechanism is thermodynamically favored by a strong stabilization of the ICL product, and the process is kinetically viable since its limiting stage is accessible.

Keywords: DFT; DNA; MD; inter-crosslink; nitrogen oxide; pollutant.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Histograms of distances during the MD simulations (Left Panel) and a representation of principal interaction schemes in the dodecamer DNA models for the DI (Central and Right Panel). The solid blue and green lines represent the histogram of hydrogen bonding for the G–D pairs in the diazonium DNA model and the dashed gray and yellow lines are the major histograms for the cation-π interactions during the MD simulations. A representative figures of the base in the oligonucleotide model (Right Panel) and its place in the dodecamer (yellow square) are also shown. Pink lines are pi–pi stacked interactions; orange lines are cation–π interactions.
Figure 2
Figure 2
Root mean square deviation (RMSD) of the residues of the native (green), diazonium models (yellow), ICL-A model (brown), and ICL-B model (blue) during 500 ns of MD simulation.
Scheme 1
Scheme 1
Mechanism of formation of Guanine-Guanine ICL (S5) from the diazonium adduct (S1).
Figure 3
Figure 3
Free energy (ΔG) profile for the formation of Guanine–Guanine intercross link.
Figure 4
Figure 4
Histograms of distances between the C1’ of the attached sugars for each base pair of the central GGCC sequence (yellow square) of the native structure and the G-ICL-G sequences of the ICL-A and ICL-B models presented during the MD simulations.
Figure 5
Figure 5
Propeller twist angle between Guanine analogs of the ICL-A (orange) and ICL-B (blue) models and the propeller twist angle of the G-G base pair of the native (green) model during 500 ns of MD simulation. The solid line represents the moving average of each simulation.
Figure 6
Figure 6
Representative structures of the ICL interactions (Å) with the base pair stacking in the oligonucleotide models are shown. The pink lines are pi–pi stacked interactions, and the green lines are hydrogen bonds.
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This research received no external funding.