Cytosine tautomeric stabilities

Table VI collects the theoretical quantities appropriate to the description of the tautomeric stability of cytosine, computed by methods including both -n- and cr-electrons. We have added to it the results of a 77-SCF MO approach (including cr-polarization effects) on heats of atomization of different tautomeric forms of cytosine. Bodor et al.liB have related the heat of atomization to the stability of the tautomers, and found that the most stable structure of the molecule is the amine-lactam 2 having the greatest heat of atomization (59.707 eV). They predict on this basis the following order of stability 2 > 3 > 6 > 1.

For other CNDO/2 calculations on tautomeric stability of cytosine, see refs. 14, 152, 153. In all these calculations the same geometry of the ring has been used for different tautomers. 

The Mg+ complexes of cytosine, thymine and uracil are the most complex system studied via photodissociation spectroscopy to date . A complication for these systems is that these nucleobases can exist in various tautomeric forms and that complexation of a metal can change the stability order of the tautomers. DFT calculations located four tautomeric Mg(cytosine)+ complexes, and three of these (29, 30, and 31) were suggested to be responsible for the four reactive photofragment ions 32-35 observed at a wavelength of 360 nm (Scheme 4) . Related photofragmentation reactions were observed for the Mg(thymine)+" and Mg(uracil)+" complexes . ... 

Effect of Substituent on the Stability of Tautomeric Forms of Cytosine... 

In spite of the various difficulties and limitations, quantum-mechanical calculations may provide valuable information concerning the tautomeric equilibria of many molecules with similar structure, e.g., influence of substituents on tautomeric equilibria. It can be assumed that the errors in estimating the relative stabilities for a series of molecules with similar structures are of the same order. The results obtained for the amino and imino tautomers of cytosine (8a/8b) and 7V(4)-hydroxy cytosine (9a/9b) fall in this category. 

As concerns the fundamental biological question of the relative stabilities of the tautomers, for which very restricted experimental knowledge exists, it has been throughly treated theoretically. For the particular case of the constituents of the nucleic acids, the theoretical results indicate that it is guanine and cytosine which should have the greatest tendancy to exist in their respective (lactim and imine) rare forms. These are therefore the bases most likely to be involved in spontaneous mutations, in so far, of course, as tautomerization may be considered as a cause of such mutations. The transformation G — C — A — T should thus be more frequent than the reverse one. 

Owing to importance of cytosine in biochemistry and significant effects of tautomeric interconversions on DNA mutations, the tautomerism in cytosine was extensively studied by quantum-mechanical calculations on various levels. In contrast to uracil, the dioxo tautomer of which is significantly more stable than the other tautomers, three tautomers of cytosine (201a-c) are reasonably close in energy, so the order of stability is essentially determined by the level of calculations. 

The relative stability of the tautomers of purine and pyrimidine bases is of fundamental importance to the structure and functioning of nucleic acids. The occurrence of rare tautomers was considered a factor responsible for the formation of mismatches leading to spontaneous mutations in the genetic code fl,2]. Cytosine, in particular, has been the subject of several studies, both experimental [3-5] and theoretical [5-15] which have provided a reliable picture of the relative stability of its tautomers, both in the gas phase and in solution. Tautomerization is generally the result of proton transfer (PT) reactions whose activation barriers may exert a kinetic control over the formation of some tautomers. As far as cytosine is concerned, a large majority of the studies available in the literature focus on the thermodynamic aspects of tautomerization and quite a few [16-19] are devoted to the elucidation of the kinetic aspects. The tautomerization of cytosine in the gas phase, with a special attention to the activation energy of the proton transfer reactions, has been afforded by this group in a previous paper [19]. By comparison with experimental data [4,5] it was... 

Zeleny T, Hobza P, Kabelac M (2009) Microhydration of guanine center dot center dot cento dot cytosine base pairs, a theoretical study on the role of water in stability, structure and tautomeric equilibrium. PCCP 11 3430-3435... 

Fig. 28 (a) The five more stable species of cytosine enol-amino trans (EAt), enol-amino cis (EAc), keto-amino (KA), keto-imino trans (Kit), keto-imino cis (KIc) given in order of stability according to MP2/6-311++G(d,p) ab initio calculations, (b) LA-MB-FTMW spectra for the li i-Oo,o rotational transition of the five species, (c) Theoretical simulation of the nuclear quadrupole hyperfine structure for the Iri-Oo o rotational transition. The differences among the various patterns act as fingerprints for tautomeric/conformational assignment. (From [169])... 

Finally, the tautomerism of cytosine has been largely studied both theoretically [118,140-142] and experimentally [143,144 and references therein] owing to its possible impact in G->A mutations and in the stabilization of d(G.C.C) triple helices at neutral or basic pH [145]. In the gas phase cytosine exists as a mixture of keto-amino and enol-amino forms, the keto-imino and enol-imino species being minoritary. In fact, experimental data... 

A polar solvent like water introduces a dramatic shift in the tautomeric preferences of cytosine, leading to a stabilization of the keto-amino tautomer. Thus, experimental data precludes the existence of significant amount of imino or enol tautomers of cytosine in aqueous solution [144]. MC-FEP and SCRF calculations [118] indicate that the preferential solvation of the keto-amino tautomer in front of the keto-imino and enol-amino tautomers amounts to around 4 and 7 kcal/mol. Therefore, the enol and imino tautomers of cytosine are predicted to be 6-7 kcal/mol less stable than the canonical keto-amino tautomer [118]. 

---