# A Theoretical Exploration of the Photoinduced Breaking Mechanism of the Glycosidic Bond in Thymine Nucleotide

## TL;DR

This paper explores how UV light can break DNA's glycosidic bond, which may lead to cancer, using quantum chemical methods to identify different possible pathways.

## Contribution

The study proposes a direct UV excitation pathway for glycosidic bond cleavage, offering new insights into DNA damage mechanisms and drug design.

## Key findings

- Direct UV excitation via the singlet excited state path has a low energy barrier (~16 kcal/mol) and is kinetically favorable.
- The triplet excited state path has a moderate energy barrier (~27 kcal/mol) and is also feasible.
- The doublet excited state path has a high energy barrier (~49 kcal/mol) and is kinetically unfavorable.

## Abstract

DNA glycosidic bond cleavage may induce cancer under the ultraviolet (UV) effect. Yet, the mechanism of glycosidic bond cleavage remains unclear and requires more detailed clarification. Herein, quantum chemical studies on its photoinduced mechanism are performed using a 5′-thymidine monophosphate (5′-dTMPH) model. In this study, four possible paths were examined to study the glycosidic bond cleavage. The results showed that, upon excitation, the electronic transition from the π bonding to π antibonding orbitals of the thymine ring leads to the damage of the thymine ring. Afterwards, the glycosidic bond is cleaved. At first, the doublet ground state (GS) path of glycosidic bond cleavage widely studied by other groups is caused by free electron generated by photoirradiation, with a kinetically feasible energy barrier of ~23 kcal/mol. Additionally, then, the other three paths were proposed that also might cause the glycosidic bond cleavage. The first one is the doublet excited state (ES) path, triggered by free electron along with UV excitation, which can result in a very-high-energy barrier ~49 kcal/mol that is kinetically unfavorable. The second one is the singlet ES path, induced by direct UV excitation, which assumes DNA is directly excited by UV light, which features a very low-energy barrier ~16 kcal/mol that is favored in kinetics. The third one is the triplet ES path, from the singlet state via intersystem crossing (ISC), which refers to a feasible ~27 kcal/mol energy barrier. This study emphasizes the pivotal role of the DNA glycosidic bond cleavage by our proposed direct UV excitation (especially singlet ES path) in addition to the authorized indirect free-electron-induced path, which should provide essential insights to future mechanistic comprehension and novel anti-cancer drug design.