Distinct hydroxy-radical-induced damage of 3′-uridine monophosphate in RNA: A theoretical study

RNA strand scission and base release in 3′-uridine monophosphate (UMP), induced by OH radical addition to uracil, is studied at the DFT B3LYP/6-31 + G(d,p) level in the gas phase and in solution. In particular, the mechanism of hydrogen-atom transfer subsequent to radical formation, from C2′ on the sugar to the C6 site on the base, is explored. The barriers of (C2′-)H2′_a abstraction by the C6 radical site range from 11.2 to 20.0 kcal mol^-1 in the gas phase and 14.1 to 21.0 kcal mol^-1 in aqueous solution, indicating that the local surrounding governs the hydrogen-abstraction reaction in a stereoselective way. The calculated N1-C1′ (N1-glycosidic bond) and β-phosphate bond strengths show that homolytic and heterolytic bond-breaking processes are largely favored in each case, respectively. The barrier for β-phosphate bond rupture is approximately 3.2-4.0 kcal mol^-1 and is preferred by 8-12 kcal mol^-1 over N1-glycosidic bond cleavage in both the gas phase and solution. The β-phosphate bond-rupture reactions are exothermal in the gas phase and solution, whereas N1-C1′ bond-rupture reactions require both solvation and thermal corrections at 298 K to be energetically favored. The presence of the ribose 2′-OH group and its formation of low-barrier hydrogen bonds with oxygen atoms of the 3′-phosphate linkage are highly important for hydrogen transfer and the subsequent bond-breakage reactions.