Understanding Electron Attachment to the DNA Double Helix: The

Sep 7, 2006 - The electron distributions, natural population analysis, and geometrical features of the models examined illustrate that the influence o...
0 downloads 8 Views 372KB Size
Download PDF
19696

J. Phys. Chem. B 2006, 110, 19696-19703

Understanding Electron Attachment to the DNA Double Helix: The Thymidine Monophosphate-Adenine Pair in the Gas Phase and Aqueous Solution Jiande Gu,*,†,‡ Yaoming Xie,‡ and Henry F. Schaefer III*,‡ Drug Design & DiscoVery Center, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, CAS, Shanghai 201203 P. R. China, and Center for Computational Chemistry, UniVersity of Georgia, Athens, Georgia 30602-2525 ReceiVed: July 28, 2006

Electron attachment to the 2′-deoxythymidine-5′-monophosphate-adenine pairs (5′-dTMPH-A and 5′-dTMP-A) has been investigated at a carefully calibrated level of theory (B3LYP/DZP++) to investigate the electronaccepting properties of thymine (T) in the DNA double helix under physiological conditions. All molecular structures have been fully optimized in vacuo and in solution. The adiabatic electron affinity of 5′-dTMPH-A in the gas phase has been predicted to be 0.67 eV. Solvent effects greatly increase the electron capture ability of 5′-dTMPH-A. In fact, the adiabatic electron affinity increases to 2.04 eV with solvation. The influence of the solvent environment on the electron-attracting properties of 5′-dTMPH-A arises not only from the stabilization of the corresponding radical anion through charge-dipole interactions, but also by changing the distribution of the unpaired electron in the molecular system. The unpaired electron is covalently bound even during vertical attachment, due to the solvent effects. Solvent effects also weaken the pairing interaction in the thymidine monophosphate-adenine complexes. The phosphate deprotonation is found to have a relatively minor influence on the capture of electrons by the 5′-dTMPH-A species in aqueous solution. The electron distributions, natural population analysis, and geometrical features of the models examined illustrate that the influence of the phosphate deprotonation is limited to the phosphate moiety in aqueous solution. Therefore, it is reasonable to expect that electron attachment to nucleotides will be independent of monovalent counterions in the vicinity of the phosphate group in aqueous solution.

I. Introduction The formation of radical anions in DNA fragments has been long thought to be closely related to processes such DNA damage and repair,1-6 charge transfer along DNA,7-15 and the cascade of reactions leading to mutations.1,3,4,16 Recent experimental and theoretical studies have demonstrated that electron attachment to DNA fragments may induce strand breaks in DNA via dissociative electron attachment.17-21 The electron capture characteristics of DNA fragments in the different surroundings are thus of importance in understanding processes of biochemical importance. Individual nucleic acid bases (NABs) in the gas phase are experimentally observable, while the precise determination of their tiny electron affinities (EA) remains challenging.4,22-30 Experimental estimates of electron affinities suggest that all the pyrimidines have very small EA values (∼0.1 eV for T, C, and U).26 Negative electron affinities have also been reported for A and C in gas-phase experiments.4,28 Further progress in the investigation of the excess charge in DNA extends to the Watson-Crick base pairs,31,32 nucleosides,33-36 and even nucleotides.37 However, experimental determinations of the EAs for the base pairs, nucleosides, and nucleotides are rare or nonexistent. In a pioneering experimental study, Bowen et al. recently determined the vertical detachment energy (VEA) of some substituted AT pairs.32b * Correspomding authors. E-mail: J.G., [email protected]; H.F.S., [email protected]. † Shanghai Institute of Materia Medica. ‡ University of Georgia.

Theoretical studies of the individual nucleobase EAs have produced a range of results.30,38-45 While second-order MøllerPlesset perturbation theory (MP2) yields negative adiabatic electron affinity (EAad) values ranging from -1.19 to -0.25 eV for the five DNA/RNA bases,41,45 density functional theory (DFT) methods predict small positive EAad values for both U and T.41,43,44 Comprehensive calibrative studies have shown that electron affinities can be reliably predicted from systematically applied DFT methods.46 With this approach, the best estimates yield experiment-consistent EAad values close to zero (the range 0.0 ( 0.3 eV includes all five NA bases) with the ordering of U > T > C ∼ G > A.43 Negative EAad values for the GC pair and the AT pair have been predicted by HF and MP2 studies.47-52 On the other hand, the calibrated DFT methods predict positive EAs for the Watson-Crick base pairs,44,53-57 a result confirmed in the laboratory for AT by the Johns Hopkins group.32b Efforts toward understanding electron attachment to DNA have been extended to larger DNA units. Semiempirical methods were first applied to evaluate the EAs of nucleosides and nucleotides.58,59 Later, more reliable predictions of the electron affinities of nucleosides,60 nucleoside pair,61 and nucleotides62,63 have been made with the calibrated B3LYP/DZP++ approach. Studies of electron attachment to nucleosides and nucleotides have also led to the elucidation of the mechanisms of chargeinduced strand breaks in DNA.61-68 Investigations reveal that the formation of a nucleobase-centered radical anion is the key step in either C3′-O3′ and C5′-O5′ (see Figure 1 for atom numbering) σ bond breakage62-67 or N1-glycosidic bond rupture in DNA induced by low-energy electrons.68 Such findings raise

10.1021/jp064852i CCC: $33.50 © 2006 American Chemical Society Published on Web 09/07/2006

Electron Attachment to the DNA Double Helix

J. Phys. Chem. B, Vol. 110, No. 39, 2006 19697 TABLE 1: Electron Affinities of Nucleic Acid Bases, Nucleosides, the AT Base Pair, Nucleoside Pair, and Nucleotide-Nucleobase Pair (in eV)j

Figure 1. Atomic numbering of the 2′-deoxythymidine-5′-monophosphate-adenine Watson-Crick pairs: 5′-dTMPH-A and 5′-dTMP-A. Atom O3 of the phosphate group is deprotonated in 5′-dTMP--A.

new questions as to the effects of hydration and ionization on these systems. Solvent effects on the EAs of nucleotides have thus far been estimated on the basis of the gas-phase structures.62,63 Moreover, nucleotides are anionic under physiological conditions. Dianions of nucleotides have been found to be stable only when a solvent is present.62 DFT studies to date of the DNA-related metastable dianions in the gas phase lack theoretical rigor;69 as discussed by Simons,69 highly sophisticated (e.g., using complex coordinates) theoretical methods must be used to describe such systems. Therefore, any conclusion that the electron-arresting tendencies of the nucleotides are independent of the deprotonation of the phosphate group in aqueous solution62 needs to be examined carefully. In the present study, electron attachment to 2′-deoxythymidine-5′-monophosphate (5′-dTMPH and 5′-dTMP-) hydrogenbonded with adenine (see Figure 1) has been investigated at a reliable level of theory (B3LYP/DZP++). This was done in an effort to reveal the trends in EAs of thymine (T) in the DNA double helix under physiological conditions and to understand the influences of counterions. This model has been selected on the basis of the fact that the EA of thymine is significantly larger than that of adenine43 and that the excess electron is located (in a simple picture) on thymine in either AT or dAdT radical anions.57,61 Therefore, the ribose-phosphate moiety attached to the adenine is expected to have less influence on the EA of the thymine in the paired nucleotides. The electron-drawing propensities of the neutral and anionic nucleotide-nucleobase pairs (5′-dTMPH-A and 5′-dTMP--A) have been studied in aqueous solution here using the static isodensity surface polarized continuum model (IPCM).70 In addition, electron attachment to the neutral nucleotide-nucleobase pair (5′dTMPH-A pair) has been studied in the gas-phase in order to isolate the solvent effects. II. Theoretical Methods The optimized geometries, zero-point vibrationally corrected energies, and natural charges for the model formed by the 2′deoxythymidine-5′-monophosphate (5′-dTMP-)-adenine (A) pair were determined using the B3LYP71,72 approach with double-ζ quality basis sets extended to include polarization and diffuse functions (denoted as DZP++). The DZP++ basis sets were constructed by augmenting the Huzinage-DunningHay73,74 set of contracted double-ζ Gaussian functions with one set of p-type polarization functions for each H atom and one set of five d-type polarization functions for each C, N, O, and P atom [Rp(H) ) 0.75, Rd(C) ) 0.75, Rd(N) ) 0.80, Rd(O) ) 0.85, Rd(P) ) 0.60]. To complete the DZP++ basis, one eventempered diffuse s function was added to each H atom, while sets of even-tempered diffuse s and p functions were centered on each heavy atom. This basis has the tactical advantage that

A T dT 5′-dTMPH AT dAdTi 5′-dTMPH-A 5′-dTMPH 5′-dTMPH-A 5′-dTMP--A

EAad

VEAa

VDEb

Gas Phase -0.37 (-0.28)c 0.06 (0.20)c 0.31 (0.44)d 0.28 (0.44) 0.19 (0.36)e 0.43 (0.60) 0.67 (0.80)

-0.45 -0.30 0.05 0.01 -0.03 0.20 0.32

-0.29 0.36 0.94d 0.99 0.63 1.14 1.42

Aqueous Solutionh 1.96f 2.04 2.34g 2.01

1.53f 1.65 1.58g 1.61

2.60f 2.51 3.15g 2.46

a VEA ) Eneutral - Eanion; the energies are evaluated at the optimized neutral structures. b VDE ) Eneutral - Eanion; the energies are evaluated at the optimized anion structures. c Reference 43. d Reference 60. e Reference 57. f Reference 63. g Based on the structures optimized in the gas phase. h IPCM model, using water as solvent with  ) 78.39. i Reference 61. j Values with zero point vibrational corrections are given in parentheses.

it has previously been used in comprehensive calibrative studies46 of a wide range of electron affinities. Geometries of the models in aqueous solutions were optimized by the B3LYP/DZP++ approach in the presence of the solvent effects modeled using the static isodensity surface polarized continuum model (IPCM)70 with a dielectric constant representative of water ( ) 78.39). More sophisticated solvation models have been discussed elsewhere.75 However, in light of the size of the system considered here (50 atoms, 711 contracted Gaussian basis functions) and the fact that complete structural optimizations were carried out, the IPCM model was chosen. The GAUSSIAN 03 system of DFT programs76 was used for the computations. Adiabatic electron affinities (EAad) were predicted as differences between the total energies of the appropriate molecular ensemble and the corresponding radical anionic species at their respective optimized geometries: EAad ) Eneutral - Eanion for 5′-dTMPH-A and EAad ) Eanion - Edianion for 5′-dTMP--A. The natural population analysis (NPA) charges were determined using the B3LYP functional and the DZP++ basis set via the natural bond orbital (NBO) analysis of Reed and Weinhold.77-80 Our structural optimization of the isolated radical dianion of 5′-dTMP shows that, due to the charge-charge repulsion, the deprotonated phosphate group tends to form an intramolecular H-bond between the proton at O3′ of the sugar and the O2 atom of the 5′-phosphate group (see Figure 1). Further investigation demonstrates that even the neutral 5′-dTMPH is more stable when it adopts the intramolecular H-bonding conformation. Therefore, this intramolecular H-bonding conformation was selected as the initial structure for 5′-dTMPH and 5′-dTMPin this study. III. Results and Discussion A. Electron Affinities. Gas Phase. The adiabatic electron affinity of the nucleotide-nucleobase pair 5′-dTMPH-A in the gas phase has been predicted to be 0.80 eV, 0.20 eV higher than that for dAdT (0.60 eV,61 see Table 1). The increase in the EAad from the nucleotide 5′-dTMPH to the nucleotidenucleobase pair 5′-dTMPH-A amounts to 0.36 eV, which is comparable to the increase of EAad from T to AT (0.16 eV increase57) and from dT to dAdT (0.16 eV increase61). The

19698 J. Phys. Chem. B, Vol. 110, No. 39, 2006

Figure 2. The SOMO of the radical anion of 5′-dTMPH-A at its equilibrium geometry in the gas phase.

Figure 3. The SOMO of the electron vertically attached radical anion of 5′-dTMPH-A in the gas phase.

influence on EAad by the pairing of A or dA is rather similar for T, dT, and 5′-dTMPH. Accordingly, the unpaired electron density should reside primarily on the thymidine moiety within the radical anion of 5′-dTMPH-A, analogous to that predicted for the anionic nucleobase AT- pair and the nucleoside dAdTpair.57,61 This conclusion may be further justified by the examination of the orbital in which the “last” electron occupies. Plots of the singly occupied molecular orbital (SOMO) for the radical anion of 5′-dTMPH-A demonstrate that the unpaired electron is mainly located on the thymidine moiety (Figure 2). The same general feature has been found for the AT- pair and the dAdT- pair,57,61 and the inclusion of phosphate at the 5′ position of the thymidine does not qualitatively change the distribution of the unpaired electron. To understand the formation of a radical anion it is important to first evaluate the vertical electron affinity (VEA), which determines the necessary energy needed in a fast electron capture step.81 The positive VEA value of 5′-dTMPH-A (0.32 eV) suggests that dTMPH should be a good electron captor in DNA. The fact that the VEA of 5′-dTMPH-A is 0.32 eV, about 0.12 eV larger than that of isolated 5′-dTMPH (VEA ) 0.01 eV), indicates that the hydrogen-bonding between 5′-dTMPH and adenine significantly improves the electron capture ability. The SOMO of the vertically electron attached anion depicted in Figure 3 reveals that the radical anion may have some dipolebound characteristics at this primitive stage of formation. The positive VEA value of 5′-dTMPH-A ensures that the autodetachment of an electron does not take place in the subsequent step, in which geometric relaxation of the electron attached species leads to the more stable covalent bound anion. Our further examination of the stability of the radical anion of 5′-dTMPH-A involved the evaluation of the vertical detachment energy (VDE). A substantial vertical detachment energy of 1.42 eV is predicted on the basis of the optimized structure of the 5′-dTMPH-A radical anion. For comparison, the VDEs of dTMPH- and AT- are 0.99 and 0.63 eV, respectively. Pairing between dTMPH and A increases the VDE of the dTMPH- anion by about 0.43 eV, a substantial amount. Recent experimental and theoretical studies17,63-68,81-84 reveal that the negative charge in nucleoside and nucleotide anions might induce glycosidic bond breaking, with an activation energy of 19 kcal/mol (0.82 eV)68 for nucleoside dT- or phosphate-sugar C-O σ bond cleavage in nucleotides. Theo-

Gu et al.

Figure 4. The SOMO of the radical anion of 5′-dTMPH-A in aqueous solution.

Figure 5. The SOMO of the electron-vertically attached radical anion of 5′-dTMPH-A in aqueous solution.

Figure 6. The SOMO of the radical dianion of the 5′-dTMP--A pair in aqueous solution.

retical analysis also suggests an activation energy of 14 kcal/ mol or 0.60 eV for C5′-O5′ σ bond rupture in 5′-dTMPH-.63 With a VDE value of 1.42 eV, one may expect that once the anionic 5′-dTMPH-A nucleotide nucleobase pair is formed, it might be able to undergo the subsequent C-O σ bond cleavage or the N1-glycosidic bond rupture process. However, caution should be taken when this conclusion is applied. The VDE of the nucleotide-nucleobase pair is expected to be somewhat higher than that for the nucleotide-nucleotide pair. Aqueous Solution. The experimental determination of the electron affinity of a species in solution has been unapproachable until rather recently. However, the ability to observe and manipulate large clusters in the laboratory brings this target into closer range.85-88 Can one state that the electron affinity of a large cluster such as (H2O)100 is the EA of liquid water? This is likely to remain a controversial subject for some time,85-88 indeed being the source of some tension between gas-phase and condensed-phase scientists. In the meantime, one measure of the electron-capturing ability of a molecule in solution is the energy difference between the solvated molecule and the analogous solvated molecular anion. Such an energy difference in any case corresponds to the electron affinity of the molecule uniformly microsolvated by a large but finite number of water molecules. Solvent effects greatly improve the electron-capture ability of 5′-dTMPH-A. On the basis of the optimized geometries in aqueous solution, the EAad and VEA of 5′-dTMPH-A have been predicted to be 2.04 and 1.65 eV. From Table 1, these values correspond to increases of 1.37 and 1.33 eV compared to those in the gas phase. Hydration also increases the electronic stability of the radical anion. The VDE of the radical anion of 5′-dTMPH-A is 2.51 eV in aqueous solution. The influence of the solvent environment on the electron affinity of 5′dTMPH-A is not only in stabilizing the corresponding radical anion through charge-dipole interactions but also by changing

Electron Attachment to the DNA Double Helix

J. Phys. Chem. B, Vol. 110, No. 39, 2006 19699

Figure 7. Two views of the fully optimized geometries for the neutral nucleotide-nucleobase pair 5′-dTMPH-A in the gas phase (bold) and in aqueous solution (ordinary print). All bond distances are in angstroms. Color representations are red for O, gray for C, blue for N, orange for P, and white for H.

TABLE 2: Natural Population Analysis (NPA) Charges on the Phosphate Moiety and the Ribose Moiety of 5′-dTMPH-A, 5′-dTMP--A, and the Corresponding Radical Anions in Aqueous Solutiona radical radical dianion of anion of 5′-dTMPH-A 5′-dTMP--A 5′-dTMPH-A 5′-dTMP--A P O1 O2 O3 O5′

2.59 -1.15 -1.07 -1.05 -0.88

Phosphate 2.55 -1.21 -1.22 -1.07 -0.90

2.59 -1.15 -1.07 -1.05 -0.88

2.55 -1.21 -1.22 -1.07 -0.90

C5′ C4′ O4′ C3′ O3′ C2′ C1′

-0.04 0.08 -0.66 0.12 -0.83 -0.45 0.34

Ribose -0.04 0.08 -0.66 0.12 -0.86 -0.45 0.34

-0.04 0.08 -0.67 0.12 -0.83 -0.45 0.34

-0.04 0.08 -0.67 0.12 -0.86 -0.45 0.34

a

All results in atomic units.

the distribution of the unpaired electron in the molecule. The SOMO of the radical anion of 5′-dTMPH-A in Figure 4 demonstrates that the unpaired electron is more localized on the thymine moiety in aqueous solution than for the analogous gas-phase system (Figure 2). The most striking phenomenon in the distribution of the unpaired electron is that the excess electron is unambiguously covalently bound (even during the vertical attachment procedure) due to the solvent effects (Figure 5). The phosphate moiety of nucleotides is deprotonated under physiological conditions. To understand electron attachment to dTMP in DNA, it is necessary to explore the influence of this phosphate-deprotonation on 5′-dTMPH-A in aqueous solution. The EAad of the phosphate-deprotonated 5′-dTMP--A pair is predicted to be 2.01 eV based on the corresponding optimized geometries in aqueous solution. The small EAad difference (0.03

TABLE 3: NPA Charges on the Base Moieties of 5′-dTMPH-A, 5′-dTMP--A, and the Corresponding Radical Anions in Aqueous Solutiona 5′-dTMPH-A 5′-dTMP--A [5′-dTMPH-A]- [5′-dTMP--A]N1 C2 O2 N3 C4 O4 C5 C6 CM

-0.53 0.93 -0.73 -0.70 0.74 -0.73 -0.16 0.10 -0.61

-0.53 0.93 -0.73 -0.70 0.73 -0.73 -0.16 0.10 -0.61

N9 C8 C6 N7 C5 N1 C4 C2 N4 N3

-0.61 0.29 0.41 -0.59 0.02 -0.62 0.49 0.34 -0.82 -0.67

-0.61 0.29 0.41 -0.59 0.02 -0.62 0.49 0.34 -0.82 -0.67

a

Thymine

Adenine

-0.56 0.91 -0.80 -0.74 0.57 -0.89 -0.22 -0.13 -0.60

-0.56 0.91 -0.80 -0.74 0.57 -0.89 -0.22 -0.13 -0.60

-0.61 0.29 0.40 -0.59 0.01 -0.63 0.48 0.33 -0.83 -0.67

-0.61 0.29 0.40 -0.59 0.01 -0.63 0.48 0.33 -0.83 -0.67

All results in atomic units.

eV) between 5′-dTMP--A and 5′-dTMPH-A in aqueous solution is concordant with previous results61 for the hydrationcorrected EAad of 3′-dCMPH and 3′-dCMP- based on the gasphase optimized geometries. The phosphate deprotonation has relatively small influence on the VEA and the VDE of the 5′dTMPH-A species. The VEA of 5′-dTMP--A is predicted to be 1.61 eV, while that for 5′-dTMPH-A is 1.65 eV (0.04 eV larger). The VDE of [5′-dTMP--A]- is 2.46 eV, while that for [5′-dTMPH-A]- is 2.51 eV (0.05 eV larger). Therefore, the hypothesis62 that the electron-trapping proclivities of the nucleotides are independent of the counterion in aqueous solution is supported. The electron distributions provide insight into this

19700 J. Phys. Chem. B, Vol. 110, No. 39, 2006

Gu et al.

Figure 8. Two views of the fully optimized geometries of the radical anion of the nucleotide-nucleobase pair 5′-dTMPH-A in the gas phase (bold) and in aqueous solution (ordinary print). All bond distances are in angstroms. See Figure 7 caption for color representations.

Figure 9. Two views of the fully optimized geometries of the neutral nucleotide-nucleobase pair 5′-dTMPH-A (ordinary print) and the corresponding phosphate-deprotonated pair 5′-dTMP--A (bold) in aqueous solution. All bond distances are in angstroms. The hydrogen atom marked with * does not exist in 5′-dTMP--A. See Figure 7 caption for color representations.

phenomenon. The SOMO of the radical dianion of 5′-dTMP-A pair (displayed in Figure 6) shows that the distribution of the excess electron is visually indistinguishable from that of the radical anion of 5′-dTMPH-A (Figure 4). The influence of the phosphate-deprotonation is limited to the phosphate moiety in the hydrated 5′-dTMPH. This may be seen from the NPA charge distribution analysis in Tables 2 and 3. The only difference between the NPA charges may be seen in the phosphate moiety, when one compares the 5′-dTMPH-A and 5′-dTMP--A species in aqueous solution. On the other hand, the NPA charge

variations caused by electron attachment are able to be observed in the thymine moiety due to the solvent effects (Table 3). Most quantum chemical computational research on solvent effects is predicated on optimized geometrical structures in the gas phase. To justify the reliability of this approach, we also evaluated the electron affinities of 5′-dTMPH-A in aqueous solution based on geometries optimized in the gas phase. The results listed in Table 1 illustrate that this approach provides reasonable estimates for the EAad (2.34 eV), VEA (1.58 eV), and VDE (3.15 eV) of the corresponding neutral species.

Electron Attachment to the DNA Double Helix

J. Phys. Chem. B, Vol. 110, No. 39, 2006 19701

Figure 10. Two views of the fully optimized geometries of the radical anion [5′-dTMPH-A]- (ordinary print) and the radical dianion [5′-dTMP-A]- (bold) in aqueous solution. All bond distances are in angstroms. The hydrogen atom marked with * does not exist in the radical dianion [5′-dTMP--A]-. See Figure 7 caption for color representations.

B. Geometries. The fully optimized geometries of the neutral 2′-deoxythymidine-5′-monophosphate-adenine pair (5′-dTMPHA) and the corresponding radical anion in the gas phase and in aqueous solution are depicted in Figures 7 and 8, along with the parameters of the H-bonds, respectively. For the neutral species (Figure 7), the most obvious geometric variations between gas phase and solution structures involve the two hydrogen bonds. The H4(A)‚‚‚O4(dTMPH) and N3(A)‚‚‚H3(dTMPH) H-bonds in aqueous solution are 1.900 and 1.852 Å, 0.014 and 0.055 Å longer than those predicted for the gas-phase (1.886 and 1.797 Å), respectively. Hydration would thus seem to reduce the extent of H-bonding between A and 5′-dTMPH. Note that these two H-bonds are 1.890 and 1.797 Å for the gas-phase dAdT pair61 and 1.889 and 1.799 Å for the gas-phase AT pair.57 Thus, solvent effects on the H-bonding appear to be more important than influences from the sugar and phosphate components. Hydration also weakens the pairing interaction in the radical anion of 5′-dTMPH-A. The predicted bond lengths of H4‚‚‚ O4 and N3‚‚‚H3 of the radical anion of 5′-dTMPH-A are 1.717 and 2.042 Å in aqueous solution, while the corresponding values are 1.608 and 2.021 Å (0.109 and 0.021 Å shorter) in the gasphase, respectively (Figure 8). Structural alterations caused by electron attachment to the pyrimidine ring of thymine in the presence of solvent effects are related to those in the gas phase. The bond distance increases in C6-N1 and C5-C6 are about 0.05 Å (1.384 vs 1.433 Å; 1.359 vs 1.411 Å) for the hydrated species. The corresponding increases in the gas phase are about 0.05-0.06 Å (1.384 vs 1.431 Å; 1.357 vs 1.416 Å). Since the excess electron density resides primarily around the C5-C6-N1 fragment (see Figure 1) of thymine,60,61 the similar geometric variations observed in this part of the hydrated complex suggest that the location of the excess charge on the base moiety is not strongly influenced by the solvent. Exploring the influence of the deprotonated phosphate on the structure may provide a geometrical rational for understanding

the phosphate-deprotonation-independent feature of the electron capture proneness of the nucleotides in aqueous solution. The optimized structures of the neutral and the deprotonated species 5′-dTMPH-A and 5′-dTMP--A (Figure 9) and the corresponding radical anions (Figure 10) in aqueous solution reveal that the influence of the deprotonation occurs primarily at the phosphate moiety. The H-bonding between thymine and adenine undergoes only a quantitive change with the deprotonation of phosphate. The H4‚‚‚O4 and N3‚‚‚H3 bond distances increase by less than 0.004 Å before the attachment of an excess electron. The influence of the deprotonation of phosphate on the radicals structure is small but noticeable; the H4‚‚‚O4 and N3‚‚‚H3 bond distance increases are 0.008 and 0.015 Å, respectively. The excess electron density in electron-attached DNA is mainly located on the nucleobases. The nearly identical structural parameters of the base moiety for the radical anion of 5′dTMPH-A and the radical dianion of 5′-dTMP--A demonstrate that the deprotonation at the phosphate of the nucleotide does not qualitatively alter the charge distribution of the excess electron in the electron-attached nucleotides in aqueous solution. The latter result is consistent with the NPA charge distribution analysis noted above. Therefore, it is reasonable to expect that the electron-attracting dispositions of the nucleotides will be independent of monovalent counterions around the phosphate group in aqueous solution.62 IV. Conclusions This exploration of electron attachment to the 2′-deoxythymidine-5′-monophosphate-adenine Watson-Crick pair enables us to predict the trends for thymine (T) in the DNA double helix under physiological conditions. The adiabatic electron affinity of the nucleotide-nucleobase pair 5′-dTMPH-A in the gas phase is predicted to be 0.67 eV, and the excess electron resides primarily on the thymidine moiety within the radical anion of 5′-dTMPH-A. The positive vertical electron affinity of 5′-dTMPH-A suggests that dTMPH is a good electron captor in DNA and that electron detachment should not take place in

19702 J. Phys. Chem. B, Vol. 110, No. 39, 2006 the subsequent step, in which geometric relaxation further stabilizes the electron-attached anion. A vertical detachment energy of 1.42 eV has been predicted for the radical anion of 5′-dTMPH-A, which one may expect to undergo subsequent C-O σ bond rupture or N1-glycosidic bond cleavage without significant electron autodetachment for this radical anion. It should be noted that although the backbone of the adenosine might have less influence on the EA of the thymine in the paired nucleotides, the stacking interactions of the neighboring bases in DNA double-helix might further increase the electron affinity of thymine in the absence of solvent effects. However, the important discovery that the quantum transport of charge in the DNA double-helix is gated by the thermal motions of the hydrated counterions89 seems to suggest that the stacking influence on electron attachment to the base in aqueous solution is less significant. Solvent effects greatly improve the electron-capture ability of 5′-dTMPH-A. The influence of the solvent environment on the electron affinities of 5′-dTMPH-A arises not only from the stabilization of the corresponding radical anion through charge-dipole interactions but also by changing the distribution of the unpaired electron in the molecule. The unpaired electron is covalently bound, even during the vertical attachment process, due to solvent effects. Solvent effects also weaken the pairing interaction in the 5′-dTMPH-A complexes. Phosphate deprotonation has quantitative influences on the electron-trapping aptitudes of 5′-dTMPH-A species in aqueous solution. The recent hypothesis62 that the electron-arresting abilities of the nucleotides are independent of the deprotonation of the phosphate group in aqueous solution is thus supported. The electron distributions, the NPA charges, and the structural features of the models studied illustrate the fact that the influence of the phosphate deprotonation is limited to the phosphate moiety in an aqueous solution. Therefore, it is reasonable to expect that the electron-drawing propensities of the nucleotides will be independent of the monovalent cations around the phosphate group in aqueous solution. Finally, we would like to emphasize that the present study was performed by explicitly incorporating solvation effects. In previous studies, the influence of the solvent was evaluated on the fixed geometries obtained in the gas phase, while in this investigation the influence of the solvent on the geometry and the electron affinities are directly studied. The present results clearly demonstrate that the influence of the solvent on the geometry is important. Moreover, the critical conclusion that the electron affinities of the nucleotides are independent of depotonation of the phosphate group and/or independent of the influence of the monovalenct cations around the phosphate group could only be confirmed through studies directly embodying the solvent effects. Acknowledgment. This research was supported by the National Science Foundation, Grant CHE-0451445. J.G. was supported by the “Knowledge Innovation Program” of the Chinese Academy of Sciences. Supporting Information Available: Complete ref 76. This material is available free of charge via the Internet at http:// pubs.acs.org. References and Notes (1) Steenken, S.; Telo, J. P.; Novais, H. M.; Candeias, L. P. J. Am. Chem. Soc. 1992, 114, 4701. (2) Becker, D.; Sevilla, M. D. In AdVances in Radiation Biology; Lett. J. T., Sinclair, W. K., Eds.; Academic Press: New York, 1993; Vol. 17, pp 121-180.

Gu et al. (3) Colson, A. O.; Sevilla, M. D. Int. J. Radiat. Biol. 1995, 67, 627. (4) Desfrancois, D.; Abdoul-Carime, H.; Schermann, J. P. J. Chem. Phys. 1996, 104, 7792. (5) Kelley, S. O.; Barton, J. K. Science 1999, 283, 375. (6) Ratner, M. Nature 1999, 397, 480. (7) Hall, D. B.; Holmlin, R. E.; Barton, J. K. Nature 1996, 382, 731. (8) Steenken, S. Biol. Chem. 1997, 378, 129. (9) Taubes, G. Science 1997, 275, 1420. (10) Cai, Z.; Sevilla, M. D. J. Phys. Chem. B 2000, 104, 6942. (11) Messer, A.; Carpenter, K.; Forzley, K.; Buchanan, J.; Yang, S.; Razskazovskii, Y.; Cai, Z.; Sevilla, M. D. J. Phys. Chem. B 2000, 104, 1128. (12) Giese, B.; Spichty, M. Chem. Phys. Chem. 2000, 1, 195. (13) Giese, B.; Spichty, M.; Wessely, S. Pure Appl. Chem. 2001, 73, 449. (14) Berlin, Y. A.; Burin, A. L.; Ratner, M. A. J. Am. Chem. Soc. 2001, 123, 260. (15) Bixon, M.; Jortner, J. J. Phys. Chem. A 2001, 105, 10322. (16) Huels, M. A.; Hahndorf, I.; Illengerger, E.; Sanche, L. J. Chem. Phys. 1998, 108, 1309. (17) Boudaiffa, B.; Cloutier, P.; Hunting, D.; Huels, M. A.; Sanche, L. Science 2000, 287, 1658. (18) Pan, X.; Cloutier, P.; Hunting, D.; Sanche, L. Phys. ReV. Lett. 2003, 90, 208102. (19) Caron, L. G.; Sanche, L. Phys. ReV. Lett. 2003, 91, 113201. (20) Zheng, Y.; Cloutier, P.; Hunting, D.; Wagner, J. R.; Sanche, L. J. Am. Chem. Soc. 2004, 126, 1002. (21) Barrios, R.; Skurski, P.; Simons, J. J. Phys. Chem. B 2002, 106, 7991. (22) Chen, E. C. M.; Chen, E. S. D.; Wentworth, W. E. Biochem. Biophys. Res. Commun. 1990, 171, 97. (23) Wiley J. R.; Robinson, J. M.; Chen, E. C. M.; Chen, E. S. D.; Wentworth, W. E. Biochem. Biophys. Res. Commun. 1991, 180, 841. (24) Hendricks, J. H.; Lyzpustina, S. A.; de Clercq, H. L.; Bowen, K. H. J. Chem. Phys. 1996, 104, 7788. (25) Desfrancois, D.; Perquet, V.; Bouteiller, Y.; Schermann, J. P. J. Phys. Chem. A 1998, 102, 1274. (26) Schiedt, J.; Weinkauf, R.; Neumark, D. M.; Schlag, E. W. Chem. Phys. 1998, 239, 511. (27) Chen, E. C. M.; Chen, E. S. D. J. Phys. Chem. B 2000, 104, 7835. (28) Periquet, V.; Moreau, A.; Carles, S.; Schermann, J. P.; Desfrancois, C. J. Electron Spectrosc. Relat. Phenom. 2000, 106, 141. (29) Hendricks, J. H.; Lyzpustina, S. A.; de Clercq, H. L.; Bowen, K. H. J. Chem. Phys. 1998, 108, 8. (30) Oyler, N. A.; Adamowicz, L. J. Phys. Chem. 1993, 97, 11122. (31) Desfrancois, C.; Abdoul-Carime, H.; Schulz, C. P.; Schermann, J. P. Science 1995, 269, 1707. (32) Nir, E.; Kleinermanns, K.; de Vries, M. S. Nature 2000, 408, 949. (b) Radisic, D.; Bowen, K. H.; Dabkowska, I.; Storoniak, P.; Rak, J. Gutowski, M. J. Am. Chem. Soc. 2005, 127, 6443. (33) Nir, E.; Imhof, P.; Kleinermanns, K.; de Vries, M. S. J. Am. Chem. Soc. 2000, 122, 8091. (34) Nir, E.; Muller, M.; Grace, L. I.; de Vries, M. S. Chem. Phys. Lett. 2002, 355, 59. (35) Nir, E.; Plutzer, C.; Kleinermanns, K.; de Vries, M. S. Eur. Phys. J. D. 2002, 20, 317. (36) Rozenberg, M.; Jung, C.; Shoham, G. Phys. Chem. Chem. Phys. 2003, 5, 1533. (37) Freitas, M. A.; Shi, S. D.; Hendrickson, C. L.; Marshall, A. G. J. Am. Chem. Soc. 1998, 120, 10187. (38) Sevilla, M. D.; Besler, B.; Colson, A. J. Phys. Chem. 1995, 99, 1060. (39) Desfrancois, C.; Abdoul-Carime, H.; Carles, S.; Periquet, V.; Schermann, J. P.; Smith, D. M. A.; Adamowicz, L. J. Chem. Phys. 1999, 110, 11876. (40) Smith, D. M. A.; Jalbout, A. F.; Smets, J.; Adamowicz, L. Chem. Phys. 2000, 260, 45. (41) Wetmore, S. D.; Boyd, R. J.; Eriksson, L. A. Chem. Phys. Lett. 2000, 322, 129. (42) Dolgounitcheva, O.; Zakrzewski, V. G.; Ortiz, J. V. J. Phys. Chem. A 2001, 105, 8782. (43) Wesolowski, S. S.; Leininger, M. L.; Pentchev, P. N.; Schaefer, H. F. J. Am. Chem. Soc. 2001, 123, 4023. (44) Li, X.; Sevilla, M. D.; Sanche, L. J. Am. Chem. Soc. 2003, 125, 8916. (45) Russo, N.; Roscano, M.; Grand, A. J. Comput. Chem. 2000, 21, 1243. (46) Rienstra-Kiracofe, J. C.; Tschumper, G. S.; Schaefer, H. F.; Nandi, S.; Ellison, G. B. Chem. ReV. 2002, 102, 231. (47) Colson, A. O.; Besler, B.; Sevilla, M. D. J. Phys. Chem. 1992, 96, 9787. (48) Al-Jihad, I.; Smets, J.; Adamowicz, L. J. Phys. Chem. A 2000, 104, 2994.

Electron Attachment to the DNA Double Helix (49) Smets, J.; Jalbout, A. F.; Adamowicz, L. Chem. Phys. Lett. 2001, 342, 342. (50) Saettel, N. J.; Wiest, O. J. Am. Chem. Soc. 2001, 123, 2693. (51) Smets, J.; Smith, D. M. A.; Elkadi, Y.; Adamowicz, L. J. Phys. Chem. A 1997, 101, 9152. (52) Dolgounitcheva, O.; Zakrzewski, V. G.; Ortiz, J. V. J. Phys. Chem. A 1999, 103, 7912. (53) Li, X.; Cai, Z.; Sevilla, M. D. J. Phys. Chem. B 2001, 105, 10115. (54) Li, X.; Cai, Z.; Sevilla, M. D. J. Phys. Chem. A 2002, 106, 9345. (55) Reynisson, J.; Steenken, S. Phys. Chem. Chem. Phys. 2002, 4, 5353. (56) Richardson, N. A.; Wesolowski, S. S.; Schaefer, H. F. J. Am. Chem. Soc. 2002, 124, 10163. (57) Richardson, N. A.; Wesolowski, S. S.; Schaefer, H. F. J. Phys. Chem. B 2003, 107, 848. (58) Harris, D. G.; Shao, J.; Anderson, J. M.; Marx, D. P.; Zimmerman, S. S. Nucleosides, Nucleotides, Nucleic Acids 2002, 21, 803. (59) Voityuk, A. A.; Michel-Beyerle, M.; Rosch, N. Chem. Phys. Lett. 2001, 342, 231. (60) Richardson, N. A.; Gu, J.; Wang, S.; Xie, Y.; Schaefer, H. F. J. Am. Chem. Soc. 2004, 126, 4404. (61) Gu, J.; Xie, Y.; Schaefer, H. F. J. Phys. Chem. B 2005, 109, 13067. (62) Gu, J.; Xie, Y.; Schaefer, H. F. J. Am. Chem. Soc. 2006, 128, 1250. (63) Bao, X.; Wang, J.; Gu, J.; Leszczynski, J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 5658. (64) Berdys, J.; Ansiewicz, I.; Skurski, P.; Simons, J. J. Am. Chem. Soc. 2004, 126, 6441. (65) Barrios, R.; Skurski, P.; Simons, J. J. Phys. Chem. B 2002, 16, 7991. (66) Berdys, J.; Ansiewicz, I.; Skurski, P.; Simons, J. J. Phys. Chem. A 2004, 108, 2999. (67) Berdys, J.; Skurski, P.; Simons, J. J. Phys. Chem. B 2004, 108, 5800. (68) Gu, J.; Xie, Y.; Schaefer, H. F. J. Am. Chem. Soc. 2005, 127, 1053. (69) Skurski, P.; Simons, J. J. Chem. Phys. 2000, 112, 6563. (70) Foresman, J. B.; Keith, T. A.; Wiberg, K. B.; Snoonian, J.; Frisch, M. J. J. Phys. Chem. 1996, 100, 16098.

J. Phys. Chem. B, Vol. 110, No. 39, 2006 19703 (71) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (72) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785. (73) Huzinaga, S. J. Chem. Phys. 1965, 42, 1293. (74) Dunning, T. H. J. Chem. Phys. 1970, 53, 2823. (b) Dunning, T. H.; Hay, P. J. Methods of Electronic Structure Theory; Schaefer, H. F., Ed.; Plenum: New York, 1977; pp 1-27. (75) Pliego, T. J.; Riveros, J. M. J. Phys. Chem. A 2001, 105, 7241. (b) Takano, Y.; Houk, K. N. J. Chem. Theory Comput. 2005, 1, 70. (76) Frisch, M. J.; et al. Gaussian 03, version c.02; Gaussian, Inc.: Wallingford CT, 2004. (77) Reed, A. E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys. 1985, 83, 735. (78) Reed, A. E.; Weinhold, F. J. Chem. Phys. 1985, 83, 1736. (79) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. ReV. 1988, 88, 899. (80) Reed, A. E.; Schleyer, P. R. J. Am. Chem. Soc. 1990, 112, 1434. (81) Huels, M. A.; Boudaiffa, B.; Cloutier, P.; Hunting, D.; Sanche, L. J. Am. Chem. Soc. 2003, 125, 4467. (82) Zheng, Y.; Cloutier, P.; Hunting, D. J.; Wagner, J. R.; Sanche, L. J. Am. Chem. Soc. 2004, 126, 1002. (83) Abdoul-Carime, H.; Gohlke, S.; Fischbach, E.; Scheike, J.; Illenberger, E. Chem. Phys. Lett. 2004, 387, 267. (84) Li, X.; Sevilla, M. D.; Sanche, L. J. Am. Chem. Soc. 2003, 125, 13668. (85) Verlet, J. R. R.; Bragg, A. E.; Kammrath, A.; Cheshnovsky, O.; Neumark, D. M. Science 2005, 307, 93. (86) Headrick, J. M.; Diken, E. G.; Walters, R. S.; Hammer, N. I.; Christie, R. A.; Cui, J.; Myshakin, E. M.; Duncan, M. A.; Johnson, M. A.; Jordan, K. D. Science 2005, 308, 1765. (87) Bragg, A. E.; Verlet, J. R. R.; Kammrath, A.; Cheshnovsky, O.; Neumark, D. M. J. Am. Chem. Soc. 2005, 127, 15283. (88) Coe, J. V.; Arnold, S. T.; Eaton, J. G.; Lee, G. H.; Bowen, K. H. J. Chem. Phys. 2006, 125, 014315. (89) Barnett, R. N.; Cleveland, C. L.; Joy, A.; Landman, U.; Schuster, G. B. Science 2001, 294, 567.