Urate as a CO3•− Scavenger and Regulator of SOD-1 and OGG1 Enzymes: Insights from DFT, Molecular Docking, and Molecular Dynamics

The potency of urate, an abundant human plasma antioxidant, in preventing oxidative damage caused by the carbonate radical anion CO3•−, was studied using quantum chemical calculations. The influence of microhydration of CO3•−/CO32− and urate−/urate• couples on the thermodynamic and kinetics of the one-electron oxidation process was investigated. Depending on the degree of microhydration, the estimated rate constant for one-electron transfer is in the range of 2.0–7.3 × 109 M−1 s−1, in good agreement with the experimental value of 1.3 × 109 M−1 s−1. Modeling using vertical detachment energy and electron affinity, the driving forces of single electron transfer revealed urate(H2O)6− and CO3(H2O)9•− clusters as the most likely existing species in water. Molecular docking revealed a favorable interaction of urate with the catalytic pocket of SOD1. Urate binds more strongly to the anionic active center of SOD1 than the reference inhibitor LSC-1, indicating its potency to prevent HCO3−-supported CO3•− formation. In contrast, the known OGG1 inhibitor TH13264 shows substantially stronger binding than urate, indicating urate’s weaker affinity toward the DNA repair enzyme catalytic pocket. The molecular dynamics data indicate that urate binding does not destabilize either SOD1 or OGG1. In light of increasing evidence that the major source of oxidative stress could be CO3•−, rather than the commonly assumed hydroxyl radical HO•, the obtained results indicate the inherent ability of plasma to combat oxidative stress induced by this selective, milder oxidant. Such an ability with respect to the non-selective, highly reactive HO• does not exist in vivo.