STRUCTURE AND CONFORMATION OF N-4-HYDROXYCYTOSINE AND N-4-HYDROXY-5-FLUOROCYTOSINE - A THEORETICAL ABINITIO STUDY

Optimal molecular geometries and molecular energies were obtained for N4-hydroxycytosine and its 5-fluoro congener with the use of the theor etical ab initio quantum mechanical calculations within the Self Consi stent Field method corrected for the electron correlation effects by t he second-order Many Body Perturbation Theory (SCF + MBPT(2)). The 6-3 1G Gaussian basis set was employed. Several tautomeric and rotameric f orms were considered. For N4-hydroxycytosine and N4-hydroxy-5-fluorocy tosine the imino tautomer (in the conformation syn relatively to the N 3-nitrogen atom) appeared to be the most stable form. The imino tautom er of N4-hydroxy-cytosine in the anti rotameric form is by 12.8 kJ mol -1 less stable than the imino-syn form. The 5-fluoro substituent raise s the energy difference between the syn and anti rotamers up to 38.5 k J mol-1. The potential energy barrier for the syn-anti rotation in the imino form of N4-hydroxycytosine is estimated to be about 180 kJ/mol. The results presented in this paper suggest that the syn-imino and an ti-imino forms can be treated as two structural isomers that do not in terconvert at temperatures relevant to biochemical conditions. The the oretical results also show that the amino tautomeric forms do not comp ete with the imino forms in the gas-phase and in non-polar and weakly- polar environment. In a polar environment (e.g., in aqueous solutions) , however, one may expect an increased population of the amino forms. Qualitatively, the results of the present study agree well with the av ailable experimental and theoretical data for N4-hydroxycytosine and s ome of its derivatives. The implications of the present study are disc ussed in relation to the molecular mechanisms of mutagenesis caused by NH2OH and of enzyme (thymidylate synthase) inhibition by N4-hydroxyde oxycytidine monophosphate.