Computational Prediction of One-Electron Oxidation Potentials for Cytosine and Uracil Epigenetic Derivatives

Knowledge of the redox properties of cytosine (C), uracil (U), and their natural derivatives is essential for a deeper understanding of DNA damage, repair, and epigenetic regulation. This study investigates the one-electron oxidation potential (E_ox, V) using DFT (B3LYP-D3) and DLPNO-CCSD(T) methods with explicit/implicit (SMD) solvation model. Calculations in the gas phase and aprotic solvents such as acetonitrile showed a high correlation with experimental data (0.96-0.98). In aqueous solutions at pH 7, oxidation potentials are significantly influenced by deprotonation equilibria, as acidic molecules like 5caC become easier to oxidize upon deprotonation. The resulting oxidation potentials reflect a complex interplay of substituent effects, acidity, and protonation states. A pH-dependent model based on the Nernst equation for aqueous solutions demonstrated a correlation coefficient of 0.93. The calculated E_ox values for cytosine epigenetic derivatives in water, accounting for deprotonation effects, follow the trend: d_5caC < 5mC < 5caC < 5hmC < C < 5dhmC < 5fC, where "d_" deprotonated, "5ca" 5-carboxy, "5m" 5-methyl, "5hm" 5-hydroxymethyl, "5dhm" 5-dihydroxymethyl, "5f" 5-formyl.