{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T19:51:53Z","timestamp":1774122713254,"version":"3.50.1"},"reference-count":57,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T00:00:00Z","timestamp":1663027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u2013Cytosine hydrogen bond is replaced by the presence of two cation-\u03c0 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.<\/jats:p>","DOI":"10.3390\/ijms231810621","type":"journal-article","created":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T21:06:52Z","timestamp":1663103212000},"page":"10621","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Formation Mechanism of Inter-Crosslink in DNA by Nitrogen Oxides Pollutants through A Diazonium Intermediate"],"prefix":"10.3390","volume":"23","author":[{"given":"Noemi","family":"Hernandez-Haro","sequence":"first","affiliation":[{"name":"Departament de Qu\u00edmica, Universitat de les Illes Balears, 07122 Palma de Mallorca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Solis-Calero","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Biochemistry, Universidad Nacional Mayor de San Marcos, Lima 15001, Peru"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodrigo","family":"Casasnovas","sequence":"additional","affiliation":[{"name":"Departament de Qu\u00edmica, Universitat de les Illes Balears, 07122 Palma de Mallorca, Spain"},{"name":"Institut d\u2019Investigaci\u00f3 Sanit\u00e0ria Illes Balears (IdISBa), 07020 Palma de Mallorca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christophe","family":"Morell","sequence":"additional","affiliation":[{"name":"Institut des Sciences Analytiques, Universit\u00e9 de Lyon, Universit\u00e9 Claude Bernard Lyon 1, UMR CNRS 5280, CEDEX, 69622 Villeurbanne, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andre","family":"Grand","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Grenoble Alpes, CEA, CNRS, INAC-SyMMES, 38000 Grenoble, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2562-9975","authenticated-orcid":false,"given":"Juan","family":"Frau","sequence":"additional","affiliation":[{"name":"Departament de Qu\u00edmica, Universitat de les Illes Balears, 07122 Palma de Mallorca, Spain"},{"name":"Institut d\u2019Investigaci\u00f3 Sanit\u00e0ria Illes Balears (IdISBa), 07020 Palma de Mallorca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8131-0315","authenticated-orcid":false,"given":"Joaqu\u00edn","family":"Ortega-Castro","sequence":"additional","affiliation":[{"name":"Departament de Qu\u00edmica, Universitat de les Illes Balears, 07122 Palma de Mallorca, Spain"},{"name":"Institut d\u2019Investigaci\u00f3 Sanit\u00e0ria Illes Balears (IdISBa), 07020 Palma de Mallorca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3382","DOI":"10.1073\/pnas.0906548107","article-title":"Attribution of climate forcing to economic sectors","volume":"107","author":"Unger","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","unstructured":"Balakrishnan, K., Chen, G., Brauer, M., Chow, J., DeMarini, D.M., Knudsen, L.E., Forastiere, F., Laden, F., Heinrich, U., and Morgan, D.L. (2015). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Outdoor Air Pollution, International Agency for Research on Cancer."},{"key":"ref_3","unstructured":"(2021). Air Quality in Europe\u20132021 Report, European Environment Agency. EEA report No. 15\/2021."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S1383-5742(99)00009-5","article-title":"Oxygen and nitrogen are pro-carcinogens. Damage to DNA by reactive oxygen, chlorine and nitrogen species: Measurement, mechanism and the effects of nutrition","volume":"443","author":"Halliwell","year":"1999","journal-title":"Mutat. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.freeradbiomed.2012.04.008","article-title":"Formation of ring-opened and rearranged products of guanine: Mechanisms and biological significance","volume":"53","author":"Jena","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.ijbiomac.2017.01.140","article-title":"Formation mechanism of glyoxal-DNA adduct, a DNA cross-link precursor","volume":"98","author":"Vilanova","year":"2017","journal-title":"Int. J. Biol. Macro."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"14032","DOI":"10.1073\/pnas.0706044104","article-title":"Oxidation of the sugar moiety of DNA by ionizing radiation or bleomycin could induce the formation of a cluster DNA lesion","volume":"104","author":"Regulus","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1021\/tx700283c","article-title":"The chemical toxicology of 2-deoxyribose oxidation in DNA","volume":"21","author":"Dedon","year":"2008","journal-title":"Chem. Res. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1021\/cr960421s","article-title":"Oxidative nucleobase modifications leading to strand scission","volume":"98","author":"Burrows","year":"1998","journal-title":"Chem. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/nrc3088","article-title":"DNA interstrand crosslink repair and cancer","volume":"11","author":"Deans","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S0304-3835(00)00439-0","article-title":"Formation of abasic sites in DNA by t-butyl peroxyl radicals: Implication for potent genotoxicity of lipid peroxyl radicals","volume":"156","author":"Kanazawa","year":"2000","journal-title":"Cancer Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1038\/nrc749","article-title":"DNA and its associated processes as targets in cancer therapy","volume":"2","author":"Hurley","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mrrev.2003.11.001","article-title":"Oxidative DNA damage and disease: Induction, repair and significance","volume":"567","author":"Evans","year":"2004","journal-title":"Mutat. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.cell.2007.08.043","article-title":"Defective DNA repair and neurodegenerative disease","volume":"130","author":"Rass","year":"2007","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.clinbiochem.2006.10.006","article-title":"Increased DNA damage and oxidative stress in patients with rheumatoid arthritis","volume":"40","author":"Altindag","year":"2007","journal-title":"Clin. Biochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/S0891-5849(02)00878-X","article-title":"Oxidative DNA damage: Assessment of the role in carcinogenesis, atherosclerosis, and acquired immunodeficiency syndrome","volume":"33","author":"Olinski","year":"2002","journal-title":"Free Radic. Biol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1021\/cr960428+","article-title":"Photocleavage of nucleic acids","volume":"98","author":"Armitage","year":"1998","journal-title":"Chem. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"12950","DOI":"10.1021\/ja983092p","article-title":"Sequence dependent long range hole transport in DNA","volume":"120","author":"Meggers","year":"1998","journal-title":"J. Am. Chem. Soc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1021\/ar990040b","article-title":"Long-distance charge transport in DNA: The hopping mechanism","volume":"33","author":"Giese","year":"2000","journal-title":"Acc. Chem. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7063","DOI":"10.1021\/ja9609821","article-title":"Theoretical studies of GG-specific photocleavage of DNA via electron transfer: Significant lowering of ionization potential and 5\u2019-localization of HOMO of stacked GG bases in B-form DNA","volume":"118","author":"Sugiyama","year":"1996","journal-title":"J. Am. Chem. Soc."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"12686","DOI":"10.1021\/ja981888i","article-title":"Mapping of the Hot Spots for DNA Damage by One-Electron Oxidation: Efficacy of GG Doublets and GGG Triplets as a Trap in Long-Range Hole Migration","volume":"120","author":"Saito","year":"1998","journal-title":"J. Am. Chem. Soc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1021\/ja972331q","article-title":"Effect of Guanine Stacking on the Oxidation of 8-Oxoguanine in B-DNA","volume":"120","author":"Prat","year":"1998","journal-title":"J. Am. Chem. Soc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1080\/07391102.2013.783508","article-title":"Sequence and conformation effects on ionization potential and charge distribution of homo-nucleobase stacks using M06-2X hybrid density functional theory calculations","volume":"32","author":"Rooman","year":"2014","journal-title":"J. Biomolec. Struc. Dyn."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1021\/tx020117w","article-title":"Nitric oxide-induced interstrand cross-links in DNA","volume":"16","author":"Caulfield","year":"2003","journal-title":"Chem. Res. Toxicol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3030","DOI":"10.1073\/pnas.89.7.3030","article-title":"DNA damage and mutation in human cells exposed to nitric oxide in vitro","volume":"89","author":"Nguyen","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/0027-5107(96)00020-6","article-title":"DNA adducts from chemotherapeutic agents","volume":"355","author":"Lawley","year":"1996","journal-title":"Mutat. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.niox.2005.11.001","article-title":"Peroxynitrite-induced oxidation and nitration products of guanine and 8-oxoguanine: Structures and mechanisms of product formation","volume":"14","author":"Niles","year":"2006","journal-title":"Nitric Oxide"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1093\/nar\/gkh606","article-title":"Solution structure of a nitrous acid induced DNA interstrand cross-link","volume":"32","author":"Edfeldt","year":"2004","journal-title":"Nucl. Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2795","DOI":"10.1093\/nar\/gkh607","article-title":"Sequence context effect on the structure of nitrous acid induced DNA interstrand cross-links","volume":"32","author":"Edfeldt","year":"2004","journal-title":"Nucl. Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.abb.2003.12.017","article-title":"Reactive nitrogen species in the chemical biology of inflammation","volume":"423","author":"Dedon","year":"2004","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1038\/nchembio0706-348","article-title":"One-electron oxidation of DNA and inflammation processes","volume":"2","author":"Cadet","year":"2006","journal-title":"Nat. Chem. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1021\/ja00443a080","article-title":"Isolation and identification of cross-linked nucleosides from nitrous acid treated deoxyribonucleic acid","volume":"99","author":"Shapiro","year":"1977","journal-title":"J. Am. Chem. Soc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4681","DOI":"10.1021\/ja00012a047","article-title":"Nitrous Acid Cross-Links Duplex DNA Fragments through Deoxyguanosine Residues at the Sequence 5-CG","volume":"113","author":"Kirchner","year":"1991","journal-title":"J. Am. Chem. Soc."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1021\/cr0404646","article-title":"NMR structures of damaged DNA","volume":"106","author":"Lukin","year":"2006","journal-title":"Chem. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"102673","DOI":"10.1016\/j.dnarep.2019.102673","article-title":"Inflammation-induced DNA damage, mutations and cancer","volume":"83","author":"Kay","year":"2019","journal-title":"DNA Repair"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.9734\/JSRR\/2016\/26773","article-title":"Nitrate Metabolism: A Curse or Blessing to Humanity?","volume":"11","author":"Nnate","year":"2016","journal-title":"J. Sci. Res. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1093\/nar\/28.2.544","article-title":"Formation of 2\u2032-deoxyoxanosine from 2\u2032-deoxyguanosine and nitrous acid: Mechanism and intermediates","volume":"28","author":"Suzuki","year":"2000","journal-title":"Nucl. Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"10942","DOI":"10.1021\/ja961334k","article-title":"Pyrimidine Ring Opening in the Unimolecular Dediazoniation of Guanine Diazonium Ion. An Ab Initio Theoretical Study of the Mechanism of Nitrosative Guanosine Deamination","volume":"118","author":"Glaser","year":"1996","journal-title":"J. Am. Chem. Soc."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/cbic.200400287","article-title":"DNA Interstrand Crosslinks: Natural and Drug Induced DNA Adducts that Induce Unique Cellular Responses","volume":"6","year":"2005","journal-title":"ChemBioChem"},{"key":"ref_40","first-page":"W26","article-title":"Web 3DNA 2.0 for the analysis, visualization, and modeling of 3D nucleic acid structures","volume":"37","author":"Shuxiang","year":"2019","journal-title":"Nucl. Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5917","DOI":"10.1093\/nar\/gkp608","article-title":"CURVES+ web server for analyzing and visualizing the helical, backbone and groove parameters of nucleic acid structures","volume":"37","author":"Lavery","year":"2009","journal-title":"Nucl. Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev.biophys.30.1.1","article-title":"Hydrogen bonding, base stacking, and steric effects in dna replication","volume":"30","author":"Kool","year":"2001","journal-title":"Annu. Rev. Biophys. Biomol. Struct."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7346","DOI":"10.1021\/ja0501159","article-title":"Cytosine Catalysis of Nitrosative Guanine Deamination and Interstrand Cross-Link Formation","volume":"127","author":"Glaser","year":"2005","journal-title":"J. Am. Chem. Soc."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High Performance Molecular Simulations through Multi-Level Parallelism from Laptops to Supercomputers","volume":"1","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-3-319-15976-8_1","article-title":"Tackling Exascale Software Challenges in Molecular Dynamics Simulations with GROMACS","volume":"Volume 8759","author":"Markidis","year":"2015","journal-title":"Solving Software Challenges for Exascale"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1021\/ct700301q","article-title":"GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation","volume":"4","author":"Hess","year":"2008","journal-title":"J. Chem. Theory Comput."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1002\/jcc.20291","article-title":"GROMACS: Fast, Flexible and Free","volume":"26","author":"Lindahl","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1002\/jcc.20090","article-title":"The GROMOS force-field parameter sets 53A5 and 53A6","volume":"25","author":"Oostenbrink","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"14101","DOI":"10.1063\/1.2408420","article-title":"Canonical Sampling through Velocity Rescaling","volume":"126","author":"Bussi","year":"2007","journal-title":"J. Chem. Phys."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"7182","DOI":"10.1063\/1.328693","article-title":"Polymorphic Transitions in Single Crystals: A New Molecular Dynamics Method","volume":"52","author":"Parrinello","year":"1981","journal-title":"J. Appl. Phys."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"10089","DOI":"10.1063\/1.464397","article-title":"Particle Mesh Ewald: An N Log(N) Method for Ewald Sums in Large Systems","volume":"98","author":"Darden","year":"1993","journal-title":"J. Chem. Phys."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1063\/1.458452","article-title":"An all-electron numerical method for solving the local density functional for polyatomic molecules","volume":"92","author":"Delley","year":"1990","journal-title":"J. Chem. Phys."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"6107","DOI":"10.1021\/jp952713n","article-title":"Fast Calculation of Electrostatics in Crystals and Large Molecules","volume":"100","author":"Delley","year":"1996","journal-title":"J. Phys. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"7756","DOI":"10.1063\/1.1316015","article-title":"From molecules to solids with the DMOL3 approach","volume":"113","author":"Delley","year":"2000","journal-title":"J. Chem. Phys."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"8487","DOI":"10.1073\/pnas.1705670114","article-title":"Revised M06-L functional for improved accuracy on chemical reaction barrier heights, noncovalent interactions, and solid-state physics","volume":"114","author":"Wang","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/0009-2614(77)80574-5","article-title":"The synchronous-transit method for determining reaction pathways and locating molecular transition states","volume":"49","author":"Halgren","year":"1977","journal-title":"Chem. Phys. Lett."},{"key":"ref_57","unstructured":"Apol, E., Apostolov, R., Berendsen, H.J.C., Buuren, A.V., Bjelkmar, P., Drunen, R.V., Feenstra, A., Fritsch, S., Groenhof, G., and Junghans, C. (2016). Reference Manual, Gromacs."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/18\/10621\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:30:27Z","timestamp":1760142627000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/18\/10621"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,13]]},"references-count":57,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["ijms231810621"],"URL":"https:\/\/doi.org\/10.3390\/ijms231810621","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,13]]}}}