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 (Tp4SeT) 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 Tp4SeT 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 Tp4SeT in the T1 state via the T1CC or T1CSe 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.