Tautomerism of nucleic acid bases and the effect of molecular interactions on tautomeric equilibria

Abstract

The change in tautomeric equilibria of purine and pyrimidine bases which may occur as a result of changes from an inert to polar environment of the base is examined in a general way. The contributions to the interaction energy between two molecules of 2-oxo-5-chloro-pyrimidine are compared specifically with those for 2-hydroxy-5-chloropyrimidine to show the influence of such an interaction on the relative stability of the oxo and hydroxy tautomeric forms. Similar effects are expected to change the relative order of stabilities of tautomers of purines and pyrimidine bases as a result of their interactions with their environment. The advantages of infrared studies of these equilibria for matrix isolated bases to provide information about the isolated bases, are discussed, and the extensive results from such studies over the past 14 years are reviewed. This review concentrates on studies of the biologically significant nucleic acid bases (1-methyluracil, 1-methylcytosine, 9-methyladenine and 9-methylguanine (9-MG) and several related model compounds). The technique for these studies is reviewed and illustrated with specific examples. For all of these bases except the guanosine analog 9-MG, only one tautomeric form is found to occur in the inert matrix environment, and it is the same form found for the base in polar solutions. However, for 9-MG the normal “oxo” tautomer (G) is found to be in approximately 1:1 equilibrium with the rare “hydroxy” tautomer (G*) in the inert (Ar or N 2) gas matrix. These results contrast sharply with the studies of guanine residue in more polar environments where only the oxo form is found. The possible biological significance of this finding may be considerable, since G* will form a base pair with thymine rather than cytosine, possibly leading to spontaneous mutation. Finally, recent results from theoretical ab initio calculations of relative stabilities of the nucleic acid bases are reviewed and summarized. These results show the importance of making such calculations with large enough basis sets and estimate the effects of including electron correlation and correcting for zero point vibrational energies.