Density Functional Theory Studies of Electron Interaction with DNA: Can Zero eV Electrons Induce Strand Breaks?

The discovery of DNA strand breaks induced by low energy secondary electrons sparks a necessity to elucidate the mechanism. Through theoretical studies based on a sugar−phosphate−sugar model that mimics a backbone section of the DNA strand, it is found that bond cleavages at 3‘ or 5‘C−O sites after addition of an electron are possible with a ca. 10 kcal/mol activation barrier. Moreover, the potential energy surfaces show that dissociation at both sites is highly favorable thermodynamically. Although the phosphate group in DNA is not a favored site for electron attachment because of competitive electron transfer to the bases, any electrons which attach to phosphates on first encounter may induce strand breaks even when the electron energy is near zero eV. These findings have profound implication as low energy secondary electrons are abundantly generated in all types of ionization radiation

Hydrogen Atom Loss in Pyrimidine DNA Bases Induced by Low-Energy Electrons: Energetics Predicted by Theory

In addition to inducing DNA strand breaks, low-energy electrons (LEEs) also have been shown to induce fragmentation of pyrimidine bases (uracil, thymine, and cytosine) in the gas and condensed phases. Loss of a hydrogen atom from a DNA base−electron adduct initiates chemical modification of the base, which can cause permanent damage to the base as well as to DNA. Thus, the energetics of hydrogen atom loss reactions from anionic bases is crucial to understanding the mechanism of LEE-induced damage to DNA and its component bases. Following our previous report on LEE interactions with uracil [J. Phys. Chem. B 2004, 108, 5472−5476], in this work we investigate LEE interactions with thymine and cytosine. The adiabatic potential energy surface along each N−H or C−H bond is explored up to 3 Å at the DFT level. The changes in energy, enthalpy, and free energy (ΔE, ΔH, and ΔG) for a complete separation of an H atom or a methyl (amino) group from the anionic base as well as bond dissociation energies of neutral bases are calculated at the CBS-Q level. The electron affinities of the DNA base thymine and cytosine and their H-deleted neutral fragments are also calculated. All N−H bonds are more susceptible to LEE-induced fragmentation than C−H bonds, with N1−H as the most vulnerable site. Since N1 is the site of the glycosidic bond between the deoxyribose and the base in DNA, the vulnerable nature of this site toward bond rupture suggests that LEEs are likely to induce base release in DNA. Investigations along these lines are under way

Low Energy Electron Interactions with Uracil: The Energetics Predicted by Theory

Low energy electrons (LEEs) induce strand breaks and base damage in DNA and RNA via fragmentation of molecular bonding. This includes the formation of hydrogen atoms from N−H and C−H bond dissociations in the bases thymine, cytosine and uracil, respectively. To better understand the dissociation of uracil induced by LEEs, we theoretically characterized the potential energy surfaces (PESs) along the N−H and C−H bonds of the uracil anion, as well as the energetics involved. The PESs show that an activation barrier of less than 1 eV exists for the N1−H dissociation with rather flat PES beyond N−H = ∼1.5 Å. The PESs for C5−H and C6−H show larger barriers, which increase monotonically with bond stretching. All the N−H and C−H bond dissociations are endothermic; the adiabatic PESs suggest the energy threshold for formation of hydrogen from N−H and C−H bonds are in the order:  0.78 (N1−H) 3−H) 6−H) 5−H). The H-deleted uracil radicals (U-yl radical family) are found to have exceptionally high adiabatic electron affinities, namely, 3.46 (N1), 3.8 (N3), 2.35 (C5), and 2.67 eV (C6). During the H bond breaking process of an uracil transient anion, these electron affinities compensate the extra energy needed to break the N−H or C−H bonds. This process may therefore explain the large hydrogen yield found experimentally from uracil upon attachment of LEEs. Potential applications of this process for the synthesis of uracil analogues using LEE irradiation are suggested

Density Functional Theory Studies of Electron Interaction with DNA: Can Zero eV Electrons Induce Strand Breaks?

The discovery of DNA strand breaks induced by low energy secondary electrons sparks a necessity to elucidate the mechanism. Through theoretical studies based on a sugar−phosphate−sugar model that mimics a backbone section of the DNA strand, it is found that bond cleavages at 3‘ or 5‘C−O sites after addition of an electron are possible with a ca. 10 kcal/mol activation barrier. Moreover, the potential energy surfaces show that dissociation at both sites is highly favorable thermodynamically. Although the phosphate group in DNA is not a favored site for electron attachment because of competitive electron transfer to the bases, any electrons which attach to phosphates on first encounter may induce strand breaks even when the electron energy is near zero eV. These findings have profound implication as low energy secondary electrons are abundantly generated in all types of ionization radiation

DFT Calculations of the Electron Affinities of Nucleic Acid Bases: Dealing with Negative Electron Affinities

To better understand the cause of the diversity in reported values of the electron affinities (EAs) for DNA bases, we performed a series of DFT (B3LYP functional) calculations at different basis set sizes. Through investigation of (1) trends in the values of EAs, (2) the excess electron spin distribution of the anion radical dependence on basis set size, (3) effect of the excess electron on ZPEs, we are able to identify the features of a basis set that allows for dipole-bound and continuum states to compete with molecular states for the electron. Smaller basis sets that confine the excess electron to the molecule allow for reasonable estimates of relative valence electron affinities excluding dipole-bound states and suggest the order of adiabatic valence electron affinities to be U ≈ T > C ≈ I (hypoxanthine) > A > G with G nearly 1 eV less electron affinic than U. Combining the best estimates from theory and experiment we place the adiabatic valence electron affinities of the pyrimidines as zero to +0.2 eV, whereas the purines A and G are predicted to be clearly negative with electron affinities of ca. −0.35 and −0.75 eV, respectively. The virtual states (i.e., negative electron affinities) for A and G in the gas-phase become relevant to biology when their energies are lowered to bound states in solvated systems. Indeed, our calculations performed including the effect of solvation (PCM model) show that all EAs for the DNA bases are positive and have the same relative order as found with the compact basis sets in the gas-phase calculations

DFT Investigation of Dehalogenation of Adenine−Halouracil Base Pairs upon Low-Energy Electron Attachment

The energetics of the dehalogenation of adenine−halouracil base pairs (A5XU), upon attachment of low-energy electrons, was investigated by use of density functional theory. These results are compared to those of single halouracils reported previously [J. Phys. Chem. A 2002, 106, 11248−11253]. Using the B3LYP functionals it was found that the gas phase adiabatic electron affinities (EA) of halogenated base pairs (A5BrU 0.59, A5ClU 0.56, A5FU 0.47 eV) are higher than that of AU (0.32 eV) and are slightly higher or comparable to the other DNA abundant base pair, guanine−cytosine (0.49 eV). Base pairing with adenine slightly decreases the EA of the halouracils, in contrast to the substantial increase in EA on base pairing of natural bases; as a result, the probability of electron capture by halouracils when in double-stranded DNA is suggested to be substantially reduced relative to that in single-stranded DNA. Even though the activation barriers for dehalogenation are small for both BrU−A and ClU−A, only the former has negative values of both ΔH (−0.95 kcal/mol) and ΔG (−1.52), while the latter has negative ΔG (−0.28) but positive ΔH (1.27). Infinite separations into halogen anions plus the remaining A−U-5-yl neutral radical are energetically unfavorable owing to sizable halide ion, radical interactions as reported earlier for non base paired halouracils. It is found that base pairing does not change the reactive nature of the uracil-5-yl radical. The results suggest that the radiosensitization properties of halouracils should be less effective in double-stranded DNA than in single-stranded DNA

DFT Investigation of Dehalogenation of Adenine−Halouracil Base Pairs upon Low-Energy Electron Attachment

The energetics of the dehalogenation of adenine−halouracil base pairs (A5XU), upon attachment of low-energy electrons, was investigated by use of density functional theory. These results are compared to those of single halouracils reported previously [J. Phys. Chem. A 2002, 106, 11248−11253]. Using the B3LYP functionals it was found that the gas phase adiabatic electron affinities (EA) of halogenated base pairs (A5BrU 0.59, A5ClU 0.56, A5FU 0.47 eV) are higher than that of AU (0.32 eV) and are slightly higher or comparable to the other DNA abundant base pair, guanine−cytosine (0.49 eV). Base pairing with adenine slightly decreases the EA of the halouracils, in contrast to the substantial increase in EA on base pairing of natural bases; as a result, the probability of electron capture by halouracils when in double-stranded DNA is suggested to be substantially reduced relative to that in single-stranded DNA. Even though the activation barriers for dehalogenation are small for both BrU−A and ClU−A, only the former has negative values of both ΔH (−0.95 kcal/mol) and ΔG (−1.52), while the latter has negative ΔG (−0.28) but positive ΔH (1.27). Infinite separations into halogen anions plus the remaining A−U-5-yl neutral radical are energetically unfavorable owing to sizable halide ion, radical interactions as reported earlier for non base paired halouracils. It is found that base pairing does not change the reactive nature of the uracil-5-yl radical. The results suggest that the radiosensitization properties of halouracils should be less effective in double-stranded DNA than in single-stranded DNA

Investigation of Proton Transfer within DNA Base Pair Anion and Cation Radicals by Density Functional Theory (DFT)

Proton-transfer reactions in two DNA base pair anion and cation radicals are treated by density functional theory to aid our understanding of the possible contributions of these reactions to electron and hole transfer in DNA. The proton-transfer transition structures for both the GC and IC anion and cation radicals are found. For both anion and cation radicals, it is the proton at the N1 guanine (G) site, or hypoxanthine (I) site, that transfers to cytosine. The forward and reverse activation energies as well as reaction enthalpies and free energy changes are calculated. These calculations show that small activation energies of 1 and 3 kcal/mol are present for the GC anion and cation, respectively. The predicted free energy change for the proton transfer is favorable for GC anion radical (−3 kcal/mol) but is slightly unfavorable for the GC cation radical (1.4 kcal/mol). Both of these values compare well with experimental estimates. Remarkably, the IC anion radical system shows no activation energy toward proton transfer and a large free energy change favoring the proton transferred state (−7 kcal). Electron affinities (EA) and ionization potentials (IP) of the two base pairs are also calculated and reported

Density Functional Theory Studies of Electron Interaction with DNA: Can Zero eV Electrons Induce Strand Breaks?

The discovery of DNA strand breaks induced by low energy secondary electrons sparks a necessity to elucidate the mechanism. Through theoretical studies based on a sugar−phosphate−sugar model that mimics a backbone section of the DNA strand, it is found that bond cleavages at 3‘ or 5‘C−O sites after addition of an electron are possible with a ca. 10 kcal/mol activation barrier. Moreover, the potential energy surfaces show that dissociation at both sites is highly favorable thermodynamically. Although the phosphate group in DNA is not a favored site for electron attachment because of competitive electron transfer to the bases, any electrons which attach to phosphates on first encounter may induce strand breaks even when the electron energy is near zero eV. These findings have profound implication as low energy secondary electrons are abundantly generated in all types of ionization radiation

Energetics of the Radical Ions of the AT and AU Base Pairs: A Density Functional Theory (DFT) Study

In this work, we present DFT calculations of the energetics of the base-pair anion and cation radicals of adenine−thymine (AT) and adenine−uracil (AU). At the B3LYP/6-31+G(d) level, we find that the adiabatic electron affinities (AEAs) are 0.30 eV for AT and 0.32 eV for AU. These values are both positive but slightly smaller than previously reported values for the AEA of guanine−cytosine (GC) and the hypoxanthine−cytosine base pair (IC). Furthermore, the AT and AU anion radical vertical electron detachment energies are also smaller than those of GC and IC, with that of AT only about half of GC's. For electron transfer between two identical isolated base pairs, the reorganization energies, λ, are calculated to be AT(0.76), AU(1.06), IC(1.25), and GC(1.31 eV). These results indicate that the AT base pair has a shallow trap depth and provides a favorable route for electron transfer, which explains previous experimental results that electron-transfer rates were higher in polydAdT than in polydGdC. Values of the ionization energies reported are in good agreement with the best estimates of previous work. For hole transfer, the reorganization energies, λ, are calculated to be AT(0.37), AU(0.53), IC(0.66), and GC(0.70 eV). These suggest that hole transfer through sequences of stacked AT base pairs may be most favorable. Base-pairing energies are also reported, which show that the formation of cation and anion radicals tends to increase base-pairing energies substantially, with cations more strongly affected than anions. We further show that whereas the predicted electron affinity of the individual base hypoxanthine (abreviated “I”) is very slightly more than that of cytosine, base pairing in IC increases the relative electron affinity of cytosine in relation to that of hypoxanthine. Thus, we find that as I approaches C the electron transfers from I to C so that the electron localizes preferentially on cytosine in the fully optimized IC base-pair anion radical