Effects of substituent and excess electron attachment on proton transfer between the radiosensitizer base pairs in aqueous solution

We investigate the proton transfer reaction of radiosensitizing drugs 5-substituted thymine-adenine (5XT-A, X = Br, OCN) in water solutions through the density functional theory (DFT) computations. The relaxed three-dimension potential energy surfaces (PESs) along the two-hydrogen bond of 5XT-A are constructed to reveal the possible proton transfer pathways. The calculations show that the single proton transfer of 5XT-A undergoes a lower energy barrier than that of normal base pair (5OCNT-A < 5BrT-A < T-A). With considering the excess electron attachment, the anion base pair (T -A)(-) possesses higher energy barrier associated to the proton transfer process. However, the (5XT-A, X = Br, OCN)- anions could dissociate into T-center dot-A radical, which can promote the intermolecular proton transfer reaction between base pairs. It is found that both the neutral and anionic 5-subsituted base pairs can contribute to DNA mutation through the easier proton transfer reaction, which is qualitatively demonstrated by the substituent-induced hydrogen bond enhancement. Our results are helpful to understand the mechanism of enhanced DNA damage in radiotherapy, and are prospective for the design of radiosensitizing drugs without the biotoxicity. (c) 2022 Elsevier B.V. All rights reserved.

Automated summary

This study investigates the proton transfer reaction of radiosensitizing drugs 5-substituted thymine-adenine in water solutions using density functional theory computations. The calculations reveal that the proton transfer of 5-substituted thymine-adenine has a lower energy barrier and can contribute to DNA mutation. These findings are important for understanding the mechanism of enhanced DNA damage in radiotherapy and designing biotoxicity-free radiosensitizing drugs.