Intrastrand Photolesion Formation in Thio-Substituted DNA: A Case Study Including Single-Reference and Multireference...

Area of Science:

• Photochemistry
• Molecular Biology
• Quantum Chemistry

Background:

• Thionucleobases, DNA analogs, are used in pharmacology and photochemotherapy.
• Thionucleobases can lead to DNA photodamage, forming 6-4 pyrimidine-pyrimidone photoproducts (6-4PPs).

Purpose of the Study:

• To elucidate the mechanism of 6-4PP formation in thionucleobases.
• To investigate the role of triplet excited states in photolesion generation.

Main Methods:

• Quantum-mechanical calculations.
• Multiconfiguration pair-density functional theory (MCP-DFT).
• Complete active space second-order perturbation theory (CASPT2).
• Kohn-Sham density functional theory (KS-DFT).

Main Results:

• Three distinct mechanisms for 6-4PP formation were identified.
• The study highlights the importance of triplet excited states in photolesion generation.
• Multireference approaches are essential for accurately describing the potential energy surface.

Conclusions:

• Understanding thionucleobase photochemistry is crucial for prodrug development.
• Triplet excited states play a significant role in the formation of DNA photolesions.
• Advanced computational methods are necessary for detailed mechanistic studies.