Nucleobase tautomer

A relatively large number of investigations reporting dynamics simulations for nucleobases, nucleobase tautomers, nucleotides, derivatives, WC pairs and quartets in different solvation conditions has been published in the last years. Recent overviews of the field can be found in Refs. (Alexandrova et al. 2010 Barbatti et al. 2010a). In this section, we shortly review the dynamics of isolated bases focusing on which relaxation mechanism these works have proposed for each molecular system. 

Metals can have an electronic effect on hydrogen bonding altering the strength of this supramolecular interaction or even result in the formation of rare nucleobase tautomers allowing the stabilization of mismatched basepairs. 

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 . ... 

Transient absorption experiments have shown that all of the major DNA and RNA nucleosides have fluorescence lifetimes of less than one picosecond [2—4], and that covalently modified bases [5], and even individual tautomers [6], differ dramatically in their excited-state dynamics. Femtosecond fluorescence up-conversion studies have also shown that the lowest singlet excited states of monomeric bases, nucleosides, and nucleotides decay by ultrafast internal conversion [7-9]. As discussed elsewhere [2], solvent effects on the fluorescence lifetimes are quite modest, and no evidence has been found to date to support excited-state proton transfer as a decay mechanism. These observations have focused attention on the possibility of internal conversion via one or more conical intersections. Recently, computational studies have succeeded in locating conical intersections on the excited state potential energy surfaces of several isolated nucleobases [10-12]. 

There are numerous other modifications of nucleobases possible, many of which are biologically relevant in that they lead to alternations in p/fa values, changes in tautomer structure as well as their base pairing patterns (55). Examples include ligands such as N6-methoxyadenine, which is a promutagen (66, 67) as well as 8-oxoadenine and 8-oxoguanine (68), which are known mutagens. 

The question whether rare tautomers of the natural nucleobases (e.g., imino forms of A or C, or enol forms of either G or T) may be involved in base mis-pairing events is central to mutagenesis. It has, however, not been unambiguously answered as yet. Originally proposed by Watson and Crick (156) as well as later by Topal and Fresco (157), experimental evidence for such possibilities is still lacking. Rather, nucleobases in mispairs have frequently been demonstrated to... 

Replacement of the proton at N1 of G by a metal ion has qualitatively similar consequences as substitution of the imino proton of T and U. The Pt(II) binding to this site increases the basicity of the purine ring, but it is not clear how the residual electron density is distributed. The N1 platinated guanine bases titrate with a pA a of 5 (176, 177), and from the high pD dependence of the H8 resonances in the H NMR spectra it is concluded that the most likely protonation site is N7 (cf. Fig. 16). In its protonated state, the nucleobase represents again a metal-stabilized rare tautomer. 

The very same philosophy can also be applied to metal complexes. Indeed, metal compounds containing methylated nucleobases [e.g., 1,9-dimethylguanine (1,9-DiMeG) (258), 7,9-DiMeG (131a, 259), 6,9-DiMeG (258), 1,9-DiMeA (260), 6,9-DiMeA (52), or 6,6,9-trimethylguanine (6,6,9-TriMeA) (53)] have been reported, but only in one case has the effect of metal ion coordination on the tautomer equilibrium of a nucleobase (adenine) been measured (52). 

Pairing Schemes. Metal coordination to a nucleobase can have a major influence on hydrogen-bonding properties, ranging from steric blockage to polarization effects, nucleobase ionization, and stabilization of rare tautomers. The window of nucleobase neutrality is clearly altered as a consequence of metal coordination. 

Although blues prepared from unsubstituted uracil, thymine and related bases (e.g., 6-methyluracil, 5,6-dihydrouracil etc.) were the first to be prepared and tested, their composition is the least clear. The author suspects that there is still long way to go to fully understand the nature of these blues . It is possible that there are even blues built on different principles. A main obstacle to the elucidation of Pt blues derived from the unsubstituted pyrimidine nucleobases lies in their versatility as ligands. Not only is there the possibility that these ligands bind to metal ions, specifically Pt, via N(l) or N(3) or (only with uracil) C(5), but also many possible combinations of two or more binding sites, e.g., N(l),0(2) N(3),0(2) N(3),0(4) N(1),N(3) N(3),0(2),0(4) N(1),0(2),N(3),0(4) etc. (Scheme 6). A series of these binding patterns has been established by X-ray crystal-structure analyses [68-70], and others are likely on the basis of spectroscopic studies [71] [72] or from comparison with results obtained for N(l) substituted derivatives. The possibility of different tautomers of platinated forms being... 

We have presented nonadiabatic ab initio molecular dynamics simulations of the photophysical properties of a variety of nucleobases and base pairs. In addition to the canonical tautomers a number of rare tautomers have been investigated. Moreover, effects of substitution and solvation have been studied in detail. The simulations of nonradiative decay in aqueous solution, in particular, demonstrate the strength of the na-AIMD technique employed here as it permits the treatment of solute and solvent on an equal footing. Condensed phase calculations can be directly compared with those in the gas phase because the same computational setup can be used. 

Life, as we know it, is based on replication, which on a molecular level is realized by DNA base pairing. However, the scheme with four nucleobases of DNA does not necessarily represent the only way to achieve molecular replication [1], Furthermore, there are alternate pairing schemes and structures and interactions between the bases that can lead to mutations, for example by proton transfers that lead to different tautomers. For all these reasons the study of interactions between individual nucleobases and of the properties of isolated base pairs at the most fundamental level is important and such studies are possible in the gas phase. 

DNA/RNA nucleobases and several tautomers and derivatives that only the natural systems have barrierless MEPs connecting the FC region to the (gs/TnT )CI. In all the other studied purine derivatives, we have found different minima and energy barriers along the 1 (tttt HL) MEP and thus hindering the ultrafast relaxation. 

Figure 16.1. Dependence of the existence of Watson-crick base-pairing on the position of the equilibria between tautomers of the canonical nucleobases. Watson-Crick base pairing would not exist if the bond energy of the C=O double bond were lower by only a few kcal/mol relative to that of the C=C and C=N bonds.

The present work discusses some properties of thiouracil nucleobases calculated at the B3LYP/6-31+G(d,p) computational level, namely, their structures, most stable tautomers, proton affinities and deprotonation enthalpies, hydrogenation, interaction with water, and base pairing, in order to shed a certain light on the problem of why their functioning in RNA and modified DNA base pairs is so unusual. 

Another aspect of the thio substitution of nucleobases and uracil in particular arises due to a highly probable link between the spontaneous point mutations developing during the RNA replication and likely describing by the Lowdin mechanism of double proton transfer [19] and the occurrence of the rare enol tautomers of uracil viewed as a major factor responsible for the formation of the nucleobase pairing mismatches (see Ref. [20] and references therein). This aspect addresses to the question of how thio substitution alters the order of stability of tautomers (see also Refs. [21, 22]). 

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