Abstract:The last decade has witnessed immense advances in our understanding of the effects of ionizing radiation on biological systems. As the genetic information carrier in biological systems, DNA is the most important species which is prone to damage by high energy photons. Ionizing radiations destroy DNA indirectly by forming low energy electrons (LEEs) as secondary products of the interaction between ionizing radiation and water. An understanding of the mechanism that leads to the formation of single and double strand breaks may be important in guiding the further development of anticancer radiation therapy. In this article we demonstrate the likely involvement of stable nucleobases anions in the formation of DNA strand breaks -a concept which the radiation research community has not focused on so far. In Section 21.1 we discuss the current status of studies related to the interaction between DNA and LEEs. The next section is devoted to the description of proton transfer induced by electron attachment to the complexes between nucleobases and various proton donorsa process leading to the strong stabilization of nucleobases anions. Then, we review our results concerning the anionic binary complexes of nucleobases with particular emphasize on the GC and AT systems. Next, the possible consequences of interactions between DNA and proteins in the context of electron attachment are briefly discussed. Further, we focus on existing proposal of single strand break formation in DNA. Ultimately, open questions as well perspectives of studies on electron induced DNA damage are discussed

The propensity of four representative conformations of 2(')-deoxyadenosine-5(')-monophosphate (5(')-dAMPH) to bind an excess electron has been studied at the B3LYP6-31++G(d,p) level. While isolated canonical adenine does not support stable valence anions in the gas phase, all considered neutral conformations of 5(')-dAMPH form adiabatically stable anions. The type of an anionic 5(')-dAMPH state, i.e., the valence, dipole bound, or mixed (valence/dipole bound), depends on the internal hydrogen bond(s) pattern exhibited by a particular tautomer. The most stable anion results from an electron attachment to the neutral syn-south conformer. The formation of this anion is associated with a barrier-free proton transfer triggered by electron attachment and the internal rotation around the C4(')-C5(') bond. The adiabatic electron affinity of the a_south-syn anion is 1.19 eV, while its vertical detachment energy is 1.89 eV. Our results are compared with the photoelectron spectrum (PES) of 5(')-dAMPH(-) measured recently by Stokes et al., [J. Chem. Phys. 128, 044314 (2008)]. The computational VDE obtained for the most stable anionic structure matches well with the experimental electron binding energy region of maximum intensity. A further understanding of DNA damage might require experimental and computational studies on the systems in which purine nucleotides are engaged in hydrogen bonding.

The excited state potential energy surface of 5-bromouracil has been studied with ab initio CASPT2//CASSCF calculations to rationalize the competition between the benign decay and the photolysis found experimentally. The surface is characterized by an extended region of degeneracy between S(1) and S(0). The access to this region has been studied with minimum energy path calculations from the FC structure, the seam of intersection has been mapped in detail, and the decay paths from different regions of the seam have been characterized. There are two decay paths with low barriers that are limiting cases for the actual decay dynamics. The first path involves the bromine elimination and leads to a region of near degeneracy between the ground and excited states, and the second one leads back to the reactant through a conical intersection between the two states. The conical intersection for benign decay is part of a seam that lies along the C(5)-Br stretching coordinate, and decay at the region of the seam with a stretched C(5)-Br bond leads to photolysis. Thus, the reactivity depends on the point of the seam at which decay to the ground state takes place. The low experimental photolysis quantum yield suggests that the energetically favored decay is the one that regenerates the reactant, while the low barriers computed to access the region of decay are in agreement with the measured picosecond excited state lifetime.

Most of theoretical data on the stability of radical anions supported by nucleic acid bases have been obtained for anions of isolated nucleobases, their nucleosides, or nucleotides. This approach ignores the hallmark forces of DNA, namely, hydrogen bonding and pi-stacking interactions. Since these interactions might be crucial for the electron affinities of nucleobases bound in DNA, we report for the first time on the stability of the thymine valence anion in trimers of complementary bases possessing the regular B-DNA geometry but differing in base sequence. In order to estimate the energetics of electron attachment to a trimer, we developed a thermodynamic cycle employing all possible two-body interaction energies in the neutral and anionic duplex as well as the adiabatic electron affinity of isolated thymine. All calculations were carried out at the MP2 level of theory with the aug-cc-pVDZ basis set. The two-body interaction energies were corrected for the basis set superposition error, and in benchmark systems, they were extrapolated to the basis set limit and supplemented with correction for higher order correlation terms calculated at the CCSD(T) level. We have demonstrated that the sequence of nucleic bases has a profound effect on the stability of the thymine valence anion: the anionic 5'-CTC-3' (6.0 kcal/mol) sequence is the most stable configuration, and the 5'-GTG-3' (-8.0 kcal/mol) trimer anion is the most unstable species. On the basis of obtained results, one can propose DNA sequences that are different in their vulnerability to damage by low energy electron.

In the present study, we consider the formation of a single strand break (SSB) in DNA via an alternative mechanism involving O-P bond splitting that was observed as a minor route to DNA damage induced by low-energy electrons (LEEs) or γ radiation. We postulate and characterize, at the B3LYP/6-31++G(**) level, a path that starts with LEE attachment to the nucleotide of thymine resulting in a stable valence radical anion localized on pyrimidine. In the next step, a proton is attached to the C5 position of thymine, producing a neutral monohydroradical of this nucleotide. This event triggers the subsequent intramolecular transfer of a sugar hydrogen atom from C3' or C5' to the C6 site of thymine. In the final elemental reaction, O-P bond dissociation takes place, which yields the phosphoryl radical and a cyclic ketone or aldehyde. Identification of the latter species as well as 5,6-dihydropyrimidines in DNA solutions irradiated with ionizing radiation could provide experimental confirmation of the suggested mechanism.

The stabilities of the valence anion of cytosine (C(-)) in model trimers of complementary base pairs that possess the B-DNA geometry but differ in base sequence are reported. In order to estimate the energetics of electron attachment to the middle cytosine incorporated in the trimer, a thermodynamic cycle employing all possible two-body interaction energies in the neutral and anionic duplex as well as the adiabatic electron affinity of isolated cytosine were developed. All calculations were carried out at the MP2 level of theory with the aug-cc-pVDZ basis set. We have demonstrated that contrary to the literature reports, concerning single stranded DNA, the sequence of nucleic bases has a profound effect on the stability of the cytosine valence anion. The anionic 3(')-CCC-5(') complex is the most stable configuration (EA=0.399 eV) and the 3(')-GCG-5(') trimer anion is the most unstable species (EA=-0.193 eV). Moreover, with the energetic correction for the presence of sugar-phosphate backbone all possible double stranded DNA sequences lead to the stable C(-). The predicted electron affinities of the cytosine anion have been compared to the results of analogous studies on the thymine anion published recently [M. Kobyłecka et al., J. Am. Chem. Soc. 130, 15683 (2008)]. The consequences of low-energy barrier proton transfer in the GC anion have been discussed in the context of induced by electrons DNA single strand breaks. The DNA sequences that should dramatically differ in their vulnerability to be damaged by low energy electrons have been proposed.

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