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.

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, , 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 S, T, T, and S states, we have suggested the feasible excited-state relaxation mechanisms of these two important epigenetic halogenated DNA nucleosides. The initially populated spectroscopic bright ππ* state in the Franck-Condon (FC) region is the S state both for 5CldCyd and 5BrdCyd under 295 nm irradiation. The excited S state first evolves into its minimum S1-MIN and rapidly undergoes efficient IC to the S state the nearby low-lying S/S conical intersection. The corresponding energy barrier of the S → S IC path in 5CldCyd is estimated to be 4.6 kcal mol 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 S state can partially slowly undergo ISC to transfer to the T state. Because the small spin-orbit couplings (SOCs) of S/T and S/T are estimated to be less than 5.0 cm at the QM(CASPT2)/MM level, the ISC involved T formation is not so efficient. The resulting T state from the minor S → T and S → T → T ISCs will first relax to its minimum T1-MIN and continue to approach the nearby accessible T/S crossing point, followed by further T → S ISC to the S state. Relatively, the T → S ISC of 5BrdCyd is significantly enhanced by a large T/S SOC of 32.9 cm at the T/S 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.