Quantum Mechanics/Molecular Mechanics Studies on the Excited-State Relaxation Mechanisms of Cytidine Analogues: 2′-Deoxy-5-Methylcytidine and 2′-Deoxy-5-Hydroxymethylcytidine in Aqueous Solution

We have used the high-level QM(CASPT2//CASSCF)/MM method to investigate the excited-state properties and decay pathways of two important cytidine analogues, i.e., 2'-deoxy-5-methylcytidine (5mdCyd) and 2'-deoxy-5-hydroxymethylcytidine (5hmdCyd), in aqueous solution. In view of the computed minimum-energy structures, conical intersections, and crossing points, and the relevant excited-state decay paths including the different internal conversion (IC) and intersystem crossing (ISC) routes in and between the S₁, T₁, T₂, and S₀ states, we finally provided the feasible excited-state relaxation mechanisms of these two important epigenetic DNA nucleosides. Upon 285 nm photoexcitation, the lowest spectroscopically bright S₁(ππ*) state is initially populated in the Franck-Condon (FC) region in both solvated systems and then mainly occurs direct IC to the ground state through the nearby accessible S₁/S₀ conical intersection, with the QM(CASPT2)/MM computed energy barriers of 9.5 and 1.6 kcal/mol for 5mdCyd and 5hmdCyd, respectively. In addition, the S₁(ππ*) state can partially hop to the T₁(ππ*) state directly or is mediated by the T₂(ππ*) state. In comparison to the favorable singlet-mediated IC channel, the minor S₁→T₁ and S₁→T₂→T₁ ISCs would take place slowly. Subsequently, the T₁ state will further approach the nearby T₁/S₀ crossing point to slowly deactivate to the S₀ state. Due to the T₁/S₀ crossing point above the T1-MIN as well with the small T₁/S₀ SOC, i.e., 9.8 kcal/mol and 0.3 cm^-1 in 5mdCyd and 8.7 kcal/mol and 1.9 cm^-1 in 5hmdCyd, the slow ISC would trap the system in the T₁ state for a long time. The present work rationalizes the excited-state dynamics of 5mdCyd and 5hmdCyd in aqueous solution and could provide mechanistic insights into understanding the photophysics and photochemistry of similar epigenetic DNA nucleosides and their derivatives.