QM/MM studies on photo-induced cycloaddition and (6-4) reactions of the thymidine:4-selenothymidine dimer in aqueous solution

Selenonucleobases have garnered increasing interest from both experimental and theoretical communities for their promising roles in photodynamic therapy and DNA crosslinking. Similar to the extensively investigated thymidine:4-thiothymidine system, the selenium-modified thymidine:4-selenothymidine (Tp ^4Se T) dimer may also exhibit significant photochemical activity within DNA duplexes. However, its detailed photochemical reaction mechanisms remain largely unexplored. Herein, we employed high-level MS-QM(CASPT2//CASSCF) method to explore excited-state decay, [2 + 2] cycloaddition and (6 − 4) reactions of Tp ^4Se T in aqueous solution. Our calculations revealed five possible nonadiabatic decay channels enabling population of the T ₁ state from the initial S ₂ state, mediated by two multi-state intersections of S ₂ /S ₁ /T ₂ /T ₁ and S ₁ /T ₂ /T ₁ . Following population of the T ₁ state, the [2 + 2] cycloaddition proceeds via a stepwise, nonadiabatic mechanism. That is, the pathway starts from Tp ^4Se T in the T ₁ state via the T _1CC or T _1CSe intermediates and ultimately ends up with Se ⁵ -selenetane in the S ₀ state. Subsequent transformation of Se ⁵ -selenetane into the Se ⁵ -(6 − 4) product occurs through a concerted reaction in the ground state, characterized by the simultaneous cleavage of the C ₄ –Se ₈ bond and formation of the S ₈ –H ₉ bond. This study provides detailed mechanistic insights into the photoreactivity of selenonucleobases in DNA duplexes at the molecular level.