Influence of Mg²⁺ on the Guanine–Cytosine Tautomeric Equilibrium: Simulations of the Induced Intermolecular Proton Transfer

Abstract

Metallic ions are essential for stabilizing the nucleic acid structure, and are also involved in the majority of RNA and DNA biological functions. However, at large concentrations metals may play an opposite role by promoting alterations in the genetic code (mutagenicity). To contribute to the understanding of this effect, theoretical tools are used to investigate the influence of the magnesium dication on the guanine-cytosine (GC) base pair structure and stability. To this end, a fully hydrated Mg(2+) cation is inserted in two models: an isolated GC base pair, and a more realistic DNA model corresponding to a hydrated double-stranded trimer. Calculations performed with a hybrid ONIOM approach reveal that the Mg(2+) cation coordination to the GC base pair alters drastically the natural tautomeric equilibria in DNA by promoting single proton transfer. Nevertheless, the generated rare tautomer will have a limited impact on the total spontaneous mutation due to the low back-reaction barrier allowing a quick return to the canonical form. Additionally, it is demonstrated that the major effects of biological environment arise from the hydration and stacking influence, whereas the impact of phosphate groups is minor.

Cisplatin cytotoxicity: a theoretical study of induced mutations

“…Inspection of Fig. 51 It is notable that our results partially differ from those reported in the pioneering study by Hirao and co-workers, 36 who located the Pt-induced rare tautomers at ca. This dissimilarity can be analysed in terms of two variables, namely the different conformations adopted by the base pairs and the DNA sequence.…”

“…34 Besides global DNA changes, ONIOM calculations have also been used to model cisplatin local effects. 51 This is a key parameter because the adverse effects of metallation at N7(G) might be partially, if not completely, mitigated if the induced PT in the base pair has a low back-reaction barrier allowing a quick return to the canonical form. According to these previous investigations, cisplatin could promote the formation of so-called rare tautomers in DNA, that is, non-canonical structures arising from exchanging protons with respect to the original canonical structure.…”

“…In particular, Hirao and co-workers 36,37 and Sarmah and Deka 38 have investigated the stability and structure of base pairs covalently bonded to the platinum center. 51 To gain further insights into this possible cisplatin cytotoxicity mechanism, we address all these issues in the present contribution, which is divided as follows: in Section 2 we design the cisplatin-DNA models and detail our calculation protocol. Such proton transfer (PT) reactions are energetically unfavourable in natural DNA, [39][40][41][42][43][44] but metallation at N7(G) might activate the transfer of the H1 proton in the GC base pair [45][46][47][48] and may consequently lead to permanent genetic errors.…”

Elementary Molecular Mechanisms of the Spontaneous Point Mutations in DNA: A Novel Quantum-Chemical Insight into the Classical Understanding

“…that is adequate for proton transfer reactions (Brovarets' & Hovorun, 2010a, 2010bCerón-Carrasco & Jacquemin, 2011b) …”

“…Following the pioneering Löwdin's work the DNA base pairs have been extensively studied using a wide range of theoretical approaches, essentially in the gas phase (Cerón-Carrasco et al, 2011a;Cerón-Carrasco & Jacquemin, 2011b;Gorb et al, 2004;Florian et al, 1995;Florian & Leszczynski, 1996;Villani, 2005Villani, , 2006Villani, , 2010.…”