Insight into reaction mechanism and product formation a C8-purine radical in RNA: A theoretical perspective

We have investigated the base release, strand scission and cyclization reactions, induced by the C8 radical site in the adenine-8-yl ribonucleotide radical. Structural and energetic calculations are performed using hybrid (B3LYP) and double hybrid (B2PLYP) density functionals together with the 6-31 + G(d,p) basis set. Aqueous medium is simulated by the conductor-like polarized continuum model with ε = 78.4. Several rotamers exist in aqueous solution, which are fully studied herein. H-abstraction reactions of H2′ or H5′ of the ribose unit are found to be strongly exothermic, which can drive subsequent reactions. The barrier height for H2′ abstraction is estimated to 10.7-11.8 kcal/mol, which is ca. 5.0 kcal/mol higher than for H5′ abstraction. For rotamers 1 and 1′, the cyclization product is the only one, whereas base release and strand rupture reactions are forbidden in aqueous solution. For conformers 2 and 2′, glycosidic bond breakage has a barrier of 14.9 kcal/mol, which is comparable to that of the cyclization reaction. These are in striking contrast to the C3′O3′ bond rupture (strand scission), for which the barrier height is significantly lower. Thus, the yield of the cyclization products is strongly dependent on both the local conformation between the 2′OH and the 3′ phosphate groups and solvation effects. The unpaired spin distribution plays a significant role in the reactions.