The C5‐substituent effects on the formic acid‐assisted tautomerization of protonated cytosine: A lower isomerization barrier and potential biological importance

Abstract

The continuous oxidative products of 5‐methylcytosine are called the “three new DNA bases.” When it comes to 5‐formylcytosine and 5‐carboxylcytosine, the electron densities at N3 sites of both bases tend to be decreased due to the presence of the electron withdrawing groups of CHO and COOH. The vital steps for mutations of DNA are tautomerism in nucleotide bases. Although there are great deal of studies on the protonated new DNA bases in photophysical and photochemical reactivity, the relationship of pKa at N3 position with the intermolecular tautomerization barrier is seldom reported. The C5 atom of cytosine is substituted by the CH3, HOCH2, CHO, and COOH, and their isomerization barriers in the presence of HCOOH have nearly linear relationship with the pKa at N3 positions of these bases. The solvent water affects the activation free energies of these paths, and yet their isomerization mechanisms are still more favorable in aqueous solution. Meantime, the rate constants could be calculated by the conventional transition state theory with Wigner's tunneling correction. The corrected rate constant for these paths is very consistent with uncorrected results. Finally, the product and reaction complexes are in a fast tautomerism equilibrium, which is a synchronous double proton transfer mechanism. The product complexes may further dissociated into the monomers. These researches may give a chemical basis for differentiating 5‐fCyt and 5‐caCyt from Cyt, 5‐MeCyt, and 5‐HCyt in the protein‐DNA interactions which might be used for selective recognition.