Theoretical Study On The Mechanism Of Hydroxyl-radical-induced Damage To Uridine

The mechanism of hydroxyl-radical-induced damage to uridine have been investigated using the density functional theory(DFT). The main job include as follows:1. Theoretical study on the mechanism and kinetics for the reaction of uridine with?OHThe mechanism for the addition reaction and hydrogen abstraction of uridine with?OH has been investigated at the B3LYP/6-311+G(d,p) level. The effect of the solvent was also taken into account, using water and benzene as models for polar and non-polar surroundings. The rate constants and the branching ratios of each pathway were evaluated using canoical variational transition state theory(CVT) at 298 K and the normal body temperature 310 K for all of the modeled environments.The reaction of ?OH with uridine mainly undergoes addition and hydrogen abstraction reactions. Seven pathways were characterized, including four addition pathways and three hydrogen abstraction pathways. The addition reactions are the dominant reaction pathways,with contributions to the overall reaction being around 99.9%, and the hydrogen abstraction reaction can be neglected. Thermodynamically, the cis-U6 OH adduct is the most stable product,but the cis-U5 OH is predicted to be the main pathway. This indicates that the kinetic factors are more dominant than the thermodynamic factors. The cis-U5 OH adduct was found to be the major product, with contributions to the overall reaction being around 59.0%- 71.6% in gas、polar and non-polar surroundings at 298 K and 310 K. The reaction proceeds most easily in non-polar surroundings, and with most difficulty in polar surroundings, but the relative probabilities are at the same order: cis-U5 OH >trans-U5 OH > trans-U6 OH > cis-U6 OH > UN3H8 > UC5H10 > UC6H11. A direct dynamic calculation was performed and the rate constants were calculated. The calculatedand available experimental rate constant for this reaction was around 109 dm-3 mol-1 s-1 in aqueous solution at 298 K, the good agreement between them supports the methodology used in this work.2. Theoretical study on the isomerization reaction mechanism of5-hydroxy-6-peroxyl-5,6-dihydrouridine and 5-peroxyl-6-hydroxy-5,6-dihydrouridineIn the presence of O2, the adducts of the U+?OH reaction could react with O2 at diffusion controlled rates, yielding peroxyl radicals: 5-hydroxy-6-peroxyl-5,6-dihydrouridine(5-OH-6-OO-DHU) and 5-peroxyl-6-hydroxy-5,6-dihydrouridine( 5-OO-6-OH-DHU), including eight diastereomers. The isomerization reaction mechanism of the eight peroxyl radicals has been investigated at the B3LYP/6-311+G(d,p)level. Bicyclic and ring-open products have been obtained.Three possible pathways were considered, designated as paths A, B, and C. Path A:the cis diastereomers undergo hydrogen transfer and intramolecular cleavage of C5-C6 bond, leading to the ring-opening products; Path B: the trans diastereomers undergo hydrogen transfer and cyclization reaction, leading to the cyclization products; Path C: the5-OO-6-OH-DHU undergo intramolecular cleavage of N1-C6 bond, leading to the ring-opening products. Path A and C lead to the pyrimidine ring-opening reactions, and path B lead to the cyclization reactions. The reaction barriers of path C are the highest.The hydrogen transfer reactions are the rate-determining steps for both paths A and B,and explicit water molecules will certainly affect the hydrogen transfer processes.Therefore, we further investigated the water mediated mechanisms of the isomerization reaction. The water molecule affect the hydrogen transfer processes as a proton bridge,which greatly affect the reaction barriers. It increased the reaction barriers of both path A and B, and drastically decreased the reaction barriers of path C. Path A is still the main reaction pathway, and path B and C are competitive reaction.This paper studies the reaction of ?OH with uridine using theory method. The main reaction pathways are determined, and the subsequent reactions with their products are found. Providing the necessary and reliable theoretical data for the further study of thedetailed isomerization reaction mechanism of uridine peroxyl radicals.