Quantum mechanics/molecular mechanics studies on mechanistic photophysics of epigenetic C5-halogenated DNA nucleosides: 2′-deoxy-5-chlorocytidine and 2′-deoxy-5-bromocytidine in aqueous solution†
Abstract
In this work, we have employed the high-level QM(CASPT2//CASSCF)/MM method to study the photophysical mechanisms of two important metabolized DNA/RNA nucleoside byproducts, i.e., 2′-deoxy-5-chlorocytidine (5CldCyd) and 2′-deoxy-5-bromocytidine (5BrdCyd), in aqueous solution. On the basis of our optimized minimum-energy structures, conical intersections, and crossing points, as well as the computed associated excited-state relaxation pathways involving the different internal conversion (IC) and intersystem crossing (ISC) processes in and between the S1, T1, T2, and S0 states, we have suggested the feasible excited-state relaxation mechanisms of these two important epigenetic halogenated DNA nucleosides. The initially populated spectroscopic bright 1ππ* state in the Franck–Condon (FC) region is the S1 state both for 5CldCyd and 5BrdCyd under 295 nm irradiation. The excited S1 state first evolves into its minimum S1-MIN and rapidly undergoes efficient IC to the S0 state via the nearby low-lying S1/S0 conical intersection. The corresponding energy barrier of the S1 → S0 IC path in 5CldCyd is estimated to be 4.6 kcal mol−1 at the QM(CASPT2)/MM level, while it is found to be an almost barrierless process in 5BrdCyd. In addition to this very efficient IC, the S1 state can partially slowly undergo ISC to transfer to the T1 state. Because the small spin–orbit couplings (SOCs) of S1/T1 and S1/T2 are estimated to be less than 5.0 cm−1 at the QM(CASPT2)/MM level, the ISC involved T1 formation is not so efficient. The resulting T1 state from the minor S1 → T1 and S1 → T2 → T1 ISCs will first relax to its minimum T1-MIN and continue to approach the nearby accessible T1/S0 crossing point, followed by further T1 → S0 ISC to the S0 state. Relatively, the T1 → S0 ISC of 5BrdCyd is significantly enhanced by a large T1/S0 SOC of 32.9 cm−1 at the T1/S0 crossing point. The present work rationalizes the excited-state dynamics of 5CldCyd and 5BrdCyd in aqueous solution and could provide mechanistic insights into understanding the photophysics of similar halogenated DNA nucleosides and their derivatives.