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.