QM/MM Studies on Photoinduced 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 cross-linking. Similar to the extensively investigated thymidine:4-thiothymidine system, the selenium-modified thymidine:4-selenothymidine (Tp^4SeT) 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^4SeT in aqueous solution. Our calculations revealed five possible nonadiabatic decay channels enabling population of the T₁ state from the initial S₂ state, mediated by two multistate intersections of S₂/S₁/T₂/T₁ and S₁/T₂/T₁. Following population of the T₁ state, the [2 + 2] cycloaddition proceeds via a stepwise, nonadiabatic mechanism. That is, the pathway starts from Tp^4SeT in the T₁ state via the T_1CC or T_1CSe intermediates and ultimately ends up with Se⁵-selenetane in the S₀ state. Subsequent transformation of Se⁵-selenetane into the Se⁵-(6-4) product occurs through a concerted reaction in the ground state, characterized by the simultaneous cleavage of the C₄-Se₈ bond and formation of the S₈-H₉ bond. This study provides detailed mechanistic insights into the photoreactivity of selenonucleobases in DNA duplexes at the molecular level.