Experimental and theoretical investigation of the mechanism of radiation-induced radical formation in hydrogen-bonded cocrystals of 1-methylcytosine and 5-fluorouracil

The process of stabilizing radiation damage in the base pair of 1-methylcyt osine (1-MeC):5-fluorouracil (5-FU) has been investigated. The formation of free radicals in purines and pyrimidines is influenced by the matrix in wh ich they are irradiated. Of particular interest are the systems in which tw o different nucleic acid bases are complexed, providing situations that app roximate the close proximity of bases in nucleic acid polymers. Detailed EP R/electron-nuclear double resonance experiments show that only the N3 proto nated cytosine anion and the N1 deprotonated uracil cation are observed in single crystals of 1-MeC:5-FU, X-irradiated, and observed at 10 K. Upon war ming one observes a radical formed by net hydrogen addition to C6 on uracil , and an allylic radical on the C4-C5-C6 region of the uracil. No cytosine C5 or C6 H-addition radicals are observed. The implications that free radic al damage is transferred from the cytosine moiety to the uracil moiety in 1 -MeC:5-FU is discussed. Single point calculations were performed on the opt imized geometries at the B3LYP/6-311G(2df,p) level to obtain accurate energ ies and spin population's. To obtain electron affinities of the neutral par ent molecules, the larger 6-311+G(2df,p) basis set was used. Results show t hat the cytosine base will be the preferred site of electron addition, and the uracil base will be the site of electron loss. Additional studies were performed to investigate the influence of the hydrogen-bonded crystal matri x on the stabilities of the initial radical ions. On the basis of these stu dies, a proton shuttle mechanism is proposed that provides an efficient tra nsfer of charge away from the initial sites of electron addition or electro n loss, leaving behind neutral radical sites that are less susceptible to r ecombination.