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

Abstract

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•-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.