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Abstract

Motivated by its potential use as a photosensitizer in photodynamic therapy, we report the first ab initio quantum mechanics/molecular mechanics (QM/MM) study of 4-thiothymidine in aqueous solution. The core chromophore 4-thiothymine was described using the multiconfigurational CASSCF and CASPT2 QM methods, while the ribose and the solvent water molecules were treated at the MM level (CHARMM and TIP3P, respectively). The minima of the five lowest electronic states (S₀, S₁, S₂, T₁, and T₂) and six minimum-energy intersections were fully optimized at the QM(CASSCF)/MM level, and their energies were further refined by single-point QM(CASPT2)/MM and CASPT2 calculations. The relevant spin–orbit couplings were also computed. We find that (1) there are three efficient photophysical pathways that account for the experimentally observed ultrafast formation of the lowest triplet state with a quantum yield of nearly unity, (2) the striking qualitative differences in the photophysical behavior of 4-thiothymine and thymine originate from the different electronic structure of their S₁ states, and (3) environmental effects play an important role. The present QM/MM calculations provide mechanistic insight that may guide the design of improved photosensitizers for photodynamic therapy.