Theoretical studies on photo-induced cycloaddition and (6-4) reactions of the thymidine:4-thiothymidine dimer in a DNA duplex

Thio-substituted nucleobases have received long-standing interest from experimental and theoretical scientists due to their potential applications in photodynamic therapy and crosslinking studies. Though the thymidine:4-thiothymidine dimer is an important structure in the DNA duplex, the molecular-level photoreaction mechanisms are still obscure. Herein, high-level QM/MM methods were adopted to investigate the photoinduced cycloaddition and (6-4) reactions of the thymidine:4-thiothymidine dimer in the DNA duplex, namely, d(ACCT(T)CGC:TGGAAGCG). Based on the calculated results, we identified five efficient nonadiabatic decay pathways to populate the T state from the initially occupied S state of TpT via two crucial intersection structures, i.e., S/S and S/T/S/T. Such photophysical processes are mainly localized on the 4-thiothymidine chromophore. After hopping to the T state, the light-induced [2+2] cycloaddition reaction could take place via a stepwise and nonadiabatic reaction pathway, which starts from TpT via T or T intermediates in the T state and ends up with S-thietane in the S state. By contrast, the concerted and thermal cycloaddition pathway in the ground state has a remarkable energy barrier, which is mechanistically less important. The subsequent generation of S-(6-4) from S-thietane is a concerted process in the S state with the simultaneous fission of the C-S bond and the formation of the S-H bond. In the end, we believe our present work will provide important mechanistic insights into photo-isomerization of thio-substituted nucleobases in DNA duplexes.