Tautomers, cytosine stabilities

A -Methylation of cytosine stabilizes the amino-oxo tautomer, which is predicted to be the most stable form of 1-methylcytosine in the gas phase independent of the level of calculations. The stabilization of the amino-oxo tautomer of 1-methylcyto-sine on hydration is even more pronounced than that of the parent cytosine, so the population of the imino tautomer in aqueous solution is insignificant (86JST(148)45, 00JST(532)157, 01JPC(A)6575). For 3-methylcytosine, the imino-keto form 203a was predicted to be predominant in the gas phase (86JST(148)45). 

In the present paper the thermodynamic and kinetic aspects of the proton transfer reactions among cytosine tautomers assisted by specific solvent molecules was theoretically investigated. For the time being, bulk solvent effects were not considered and attention was only focused on the influence of hydrogen bonding on both (i) tautomers relative stability and (ii) the catalytic process occurring between adjacent positions of cytosine. The computational results on point (i) are compared with those of PCM calculations [15]. The results on point (ii) are discussed with reference to the conclusions of other theoretical studies available in the literature [16,17]. 

The proton transfer in these clusters via the water bridge was found to be about three times as fast as a nonassisted transfer, underscoring the importance of the solvent for the reaction mechanism [98IJQ855]. In addition to the relative stabilities of the cytosine tautomers, the structures and properties of some cytosine derivatives have been investigated, mainly those of 5-hydroxycytosine 111 and 5,6-dihydroxycytosine 112 (Scheme 73) [99JST1, 99JST49]. 

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 . ... 

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. 

An interesting feature was discovered by Sharma and co-workers494,495 in the crystal structure of isocytosine. Two tautomers of isocytosine (42 and 43) exist in an exact 1 1 ratio in the crystal. The tautomers are hydrogen-bonded to each other in a manner analogous to that proposed by Watson and Crick496,497 for the guanine-cytosine pair in DNA. It is worth underlining that the base pair of isocytosine was not obtained by expedient cocrystallization of the two components. It seems therefore probable that both forms 42 and 43 of isocytosine are of approximately equal stability and are present in comparable amounts in solution. 

Zhanpeisov, N. U. Sponer, J. Leszczynski, J. Reverse Watson-Crick isocytosine-cytosine and guanine-cytosine base pairs stabilized by the formation of the minor tautomers of bases. An ab initio study in the gas phase and in a water cluster, J. Phys. Ghent. A 1998,102,10374-10379. 

The rare nucleic acid base tautomers, ordinarily present to the extent of 0.01% relative to the preferred tautomers, can be stabilized by metals via coordination of lone-pair electrons. For example, the 4-imino-2-oxo tautomer of cytosine has Pt + bound to its group, while the 4-hydroxy-2-oxo tautomer of U and T bases is platmated at N-3. ... 

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. 

Scanlan, M. J., and Hillier, I. H. (1984). J. Am. Chem. Soc. 106, 3737—ab initio (3-21G) calculations for different tautomers of uracil, thymine, 5-fluorouracil, and cytosine solvent effects (continuous model) on stabilities of the tautomers. 

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. 

Theoretical estimations at the B3LYP level for the 298 K gas-phase acidities of all possible deprotonation sites of the most stable tautomers of cytosine predicted the almost equal acidity of the oxo and hydroxy forms (03JPC(A)4893). Relative stabilities... 

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... 

The effect of the solvent is usually modelled either by the use of the Onsager s self consistent reaction field (SCRF) [20] or by the polarizable continuum method (PCM) [21]. With regard to the relative stability of cytosine tautomers in aqueous solution, these methods provided results [14,15] which, in spite of some discrepancies, are in reasonable agreement with experimental data [3]. However, continuum-based methods do not explicitly take into consideration the local solvent-solute interaction which is instead important in the description of the proton transfer mechanism in hydrogen-bonded systems. A reasonable approach to the problem was recently proposed [22,23] in which the molecule of interest and few solvent molecules are treated as a supermolecule acting as solute, while the bulk of the solvent is represented as a polarizable dielectric. 

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