Electron Attachment-Induced DNA Single Strand Breaks:  C_3‘−O_3‘ σ-Bond Breaking of Pyrimidine Nucleotides Predominates

Abstract

A detailed understanding of DNA strand breaks induced by low energy electrons (LEE) is of crucial importance for the advancement of many areas of molecular biology and medicine. To elucidate the mechanism of DNA strand breaks by LEEs, theoretical investigations of the electron attachment-induced C3'-O3' sigma-bond breaking of the pyrimidine nucleotides have been performed. Calculations of 2'-deoxycytidine-3'-monophosphate and 2'-deoxythymidine-3'-monophosphate in their protonated form (denoted as 3'-dCMPH and 3'-dTMPH) have been carried out with the reliably calibrated B3LYP/DZP++ theoretical approach. Our results demonstrate that the transfer of the negative charge from the pi*-orbital of the radical anion of pyrimidines to the DNA backbone does not pass through the N1-glycosidic bond. Instead, the migration of the excessive negative charge through the atomic orbital overlap between the C6 of pyrimidine and the C3' of ribose most likely represents a pathway that subsequently leads to the strand breaks. The proposed mechanism of the LEE-induced single strand breaks in DNA assumes that the formation of the base-centered radical anions is the first step in this process. Subsequently, these electronically stable radical anions may undergo either C-O bond breaking or N-glycosidic bond rupture. The present investigation of 3'-dCMPH and 3'-dTMPH yields an energy barrier of 6.2-7.1 kcal/mol for the C3'-O3' sigma-bond cleavage. This is much lower than the energy barriers required for the C5'-O5' sigma-bond and the N1-glycosidic bond break. Therefore, we conclude that the C3'-O3' sigma-bond rupture dominates the LEE-induced single strand breaks of DNA.

Stable Valence Anions of Nucleic Acid Bases and DNA Strand Breaks Induced by Low Energy Electrons

“…Thus very low barriers are required to explain the SSB yield observed experimentally [1,2]. A mechanism based on the formation of a stable anionic species could be an alternative for the nonadiabatic mechanism proposed by the Simons group [36,[78][79][80]. Indeed, in a series of studies, described in the previous sections, we showed that in the presence of species having proton-donor properties the stable valence anions of nucleobases rather than resonances are formed.…”

“…The DNA damage process is thought to begin with anionic states localized on pyrimidine bases and, accordingly, all theoretical studies concerning the breakage mechanism have focused on pyrimidine bases or their nucleotides [29,36,[78][79][80]. This supposition is based on the electron affinities of isolated nucleobases.…”

“…Very recently a proposal for SSB formation based on adiabatically stable anions localized on nucleobases has been published by the Leszczynski group [79,80].…”

Interactions between low energy electrons and DNA: a perspective from first-principles simulations

“…Numerous theoretical studies using both wavefunction and DFT methods support the notion that strand breaks can be triggered by such low energy electrons. Bao et al [72,105] calculated the activation energies for bond cleavage in the pyrimidine nucleotides and found that C-O strand breaks should dominate at near-zero energies. By calculating the detachment energies from the base they also showed that it is feasible that electron attachment to the nucleobase can trigger bond cleavage [114].…”

Interaction of low-energy electrons with the purine bases, nucleosides, and nucleotides of DNA

“…Li et al 50,51 and Gu and co-workers [52][53][54][55][56][57][58][59] have carried out related electronic-structure studies of nucleoside ͑base+ sugar͒ and nucleotide ͑nucleoside + phosphate͒ neutrals, anions, and radicals with a view of elucidating the energetics of electron attachment and of cleaving both the phosphodiester C-O bonds of the backbone and the N-glycosidic base-sugar bonds. Condensedphase experiments on thymidine and a single-strand oligonucleotide have demonstrated that slow electrons do indeed break the C-O phosphate-sugar bonds as well as the C-N base-sugar bonds, [60][61][62] and C-O bond breaking was also found in gas-phase DA to a model phosphodiester.…”