A QM/MM study on triplet decay of 6-thioguanine and 6-selenoguanine with explicit solvent

Motivated by their potential use as a photosensitizer in photodynamic therapy, we report an electrostatic embedding quantum mechanics/molecular mechanics (QM/MM) study of 6-selenoguanine and 6-thioguanine in water. We analyzed triplet-state nonradiative decay within quasi-Marcus theory and assessed the influence of solvation by comparing QM/MM with previous microsolvation and PCM models. Both molecules follow similar deactivation pathways, involving torsional distortion around the chalcogen center and decay through a T₁/S₀ crossing point. Experimental studies show that triplet decay of 6-selenoguanine (6SeGua) is 835 times faster than 6-thioguanine (6tGua) in water. The shorter T₁ lifetime of 6SeGua is due to its higher spin-orbit coupling (SOC) and lower activation barrier to reach the T₁/S₀ crossing point. Stronger hydrogen bonding in 6tGua stabilizes the T₁ minimum relative to the T₁/S₀ crossing point, thereby increasing the activation barrier for triplet decay. The decay rates obtained from QM/MM are in good agreement with the previous microsolvation model, indicating that both approaches capture the essential solvent effects. The findings underscore the role of solvent effects and hydrogen bonding in modulating the photophysical properties of chalcogen-substituted nucleobases.

All molecular dynamics simulations of 6SeGua and 6tGua were performed using AMBER 2023 with GAFF2 and the TIP3P water model. Representative equilibrated structures were used for QM/MM calculations within the COBRAMM framework using electrostatic embedding. The QM region was treated using TD-DFT within the Tamm-Dancoff approximation (TDA) at the CAM-B3LYP/6-311G* level, with electronic structure calculations performed using Gaussian 16. T₁/S₀ crossing points were optimized using an in-house CIOpt program. Spin-orbit coupling (SOC) matrix elements were calculated using the PySOC program based on the Breit-Pauli spin-orbit Hamiltonian with the effective charge approximation. Nonradiative ISC rates were estimated using a quasi-Marcus approach, and noncovalent interactions were analyzed using QTAIM and IGMH methods with Multiwfn.