Tautomers, cytosine proton transfer

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 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. 

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]. 

Systems investigated the five most stable tautomers of cytosine are shown in Fig. 1. The tautomeric equilibrium among these species is based on the Cl C2, Cl C3 and C4 = = C5 interconversions. They may occur as direct proton transfer reactions in the gas phase, with activation energies ranging from 30 to about 37 kcal mol" , as suggested in a previous paper [19],... 

Figure 2. Scheme of the simulated proton transfer reactions occurring among mono- and dihydrated cytosine tautomers. 

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