The 2'-Deoxyadenosine-5'-phosphate Anion, the Analogous Radical

Oct 21, 2005 - The 2'-Deoxyadenosine-5'-phosphate Anion, the Analogous Radical, and the Different Hydrogen-Abstracted Radical Anions: Molecular Struct...
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J. Phys. Chem. B 2005, 109, 22053-22060

22053

The 2′-Deoxyadenosine-5′-phosphate Anion, the Analogous Radical, and the Different Hydrogen-Abstracted Radical Anions: Molecular Structures and Effects on DNA Damage Ruobing Hou,†,‡ Jiande Gu,*,†,§ Yaoming Xie,† Xianghui Yi,| and Henry F. Schaefer III*,† Center for Computational Chemistry, UniVersity of Georgia, Athens, Georgia 30602-2525, School of Chemistry and Chemical Engineering, Guangxi Normal UniVersity, Guilin, Guangxi 541004, People’s Republic of China, Drug Design & DiscoVery Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, People’s Republic of China, and Guilin Normal College, Guilin, Guangxi 541004, People’s Republic of China ReceiVed: May 10, 2005; In Final Form: August 3, 2005

The 2′-deoxyadenosine-5′-phosphate (5′-dAMP) anion and its related radicals have been studied by reliably calibrated theoretical approaches. This study reveals important physical characteristics of 5′-dAMP radical related processes. One-electron oxidation of the 5′-dAMP anion is found on both the phosphoryl group and the adenine base with electron detachment energies close to that of phosphate. Partial removal of electron density from the adenine fragment leads to an extended π system which includes the amine group of the adenine. Although the radical-centered carbon increases the extent of bonding with its adjacent atoms, it usually weakens the chemical bonds between the atoms at the R- and β-positions. This tendency should be important in predicting the reactivity of the sugar-based radicals. The overall stability sequence of the H-abstracted 5′-dAMP anionic radicals is consistent with the analogous results for the H-abstracted neutral radicals of the adenosine nucleoside: aliphatic radicals > aromatic radicals. The negatively charged phosphoryl group attached to atom C5′ of the ribose does not change this energetic sequence. All the H-abstraction produced 5′-dAMP radical anions are distonic radical anions. Studies have shown that the charge-radical-separating feature of the distonic radical anions is biologically relevant. This result should be important in understanding the reactive properties of these H-abstraction-produced anion radicals.

1. Introduction Extensive investigations1-11 of both DNA and related model systems have indicated that the original sources of DNA damage are closely related to particular radicals. The gas-phase study of DNA-related processes is the most direct way to reveal the intrinsic properties of the DNA components. Gas-phase experimental studies of DNA have been extended from free nucleic acid bases12-21 to individual nucleotides.22-30 For example, Strittmatter et al.22 have measured dissociation energies of deoxyribose nucleotide dimer anions. Several gas-phase studies of H/D exchange for nucleotides have been performed by Crestoni,23 Green-Church,24 Freitas,25 and Robinson26 and their co-workers. Vrkic and O’Hair27 have reported a study of the nucleotide ions. Very recently, conformations of deprotonated and protonated mononucleotides in the gas phase have been determined by Gidden and Bowers.28 NMR experiments for 2′-deoxythymidine have been reported by Stueber et al.29 Several free radicals derived from adenosineinduced damage in DNA have been reported by Flyunt et al.5 and Chatgilialoglu et al.30 While nucleotides have been wellstudied in gas-phase experimental investigations, a few theoretical studies of nucleotides directed at the relationship between DNA structure and biological function have been performed. Gresh et al.31 studied the interaction of hydrated Zn(II) and Mg* Corresponding authors: J.G., [email protected]; H.F.S., [email protected]. † University of Georgia. ‡ Guangxi Normal University. § Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. | Guilin Normal College.

Figure 1. Atom numbering scheme for 2′-deoxyadenosine-5′-phosphate (5′-dAMP): C, gray; N, blue; O, red; P, yellow; H, white.

(II) cations with 5′-guanosine monophosphate. Conformational studies of the 2′-deoxyribonucleotides containing pyrimidine and purine nucleic acid bases have been carried out by Shishkin et al.32,33 Hydrogen bond lengths between DNA base pairs and even between two nucleotides have been predicted by Guerra et al.34 Geometries, interaction energies, and vibrational frequencies of base pairs, nucleoside pairs, and nucleotide pairs were studied at the minimum basis set self-consistent field level by Hobza’s group.35 The mechanism for damage to DNA by low-energy electrons has been studied at different levels of theory by several research groups.36-41 An X-ray crystal structure of 2′-deoxyadenosine-5′-phosphate (5′-dAMP, Figure 1) was determined42-45 as long ago as 1973. The important roles of the 5′-dAMP radicals in the strand scission of nucleic acids have been summarized in several good reviews.1-4 To obtain a better understanding of electronic influences on DNA biochemistry, computational methods have

10.1021/jp0524375 CCC: $30.25 © 2005 American Chemical Society Published on Web 10/21/2005

22054 J. Phys. Chem. B, Vol. 109, No. 46, 2005 been combined with experimental approaches to evaluate the ionization potentials of the 5′-dAMP anion in the gas phase and in aqueous solution.46-49 Theoretical methods have also been used to explore the structures and the relative stabilities of the deoxyribose radicals in order to understand the role of the sugar-based radicals in the strand scission of DNA.50 Recent synergy between theory and experiment has resulted in the development of a DFT bracketing technique which has advanced the understanding of the interaction of molecules with excess negative charge by providing a reliable method for electron attachment and detachment energy determinations.51 With this reliably calibrated B3LYP/DZP++ approach, systematic studies of the electronic properties of the H-abstracted adenine radicals and of the H-abstracted adenosine radicals have been completed.52,53 As an effort toward the systematic understanding of the physical properties of radicals related to the components of DNA, this carefully calibrated B3LYP/DZP++ approach is applied here to study the geometric, energetic, and electronic properties of the 5′-dAMP anion, its one-electron oxidized radical, and its H-abstracted radicals. We emphasize that both polarization and diffuse basis functions are necessary and have been included (see below) in the present studies. These findings should be of value in understanding the phenomena occurring during the nascent stage of the radical-induced strand scission of DNA. In particular, the H-abstracted nucleotide radical anions implicated by experiments1,3,4 in strand scission have never been explored theoretically. 2. Theoretical Methods Previous research has demonstrated that the B3LYP method predicts reasonable results for DNA bases, nucleosides, base pairs, and anions.41,52-57 The B3LYP functional is a combination of Becke’s three-parameter HF/DFT hybrid exchange functional (B3)58,59 with the dynamical correlation functional of Lee, Yang, and Parr (LYP).60 In the present study, optimized geometries and natural charges for the 5′-dAMP anion, its one-electron oxidized radical, and its H-abstracted radicals were determined using the B3LYP approach. For the closed-shell anion, the restricted B3LYP formalism is employed, while the unrestricted formalism is used for the radicals. The GAUSSIAN 98 systems of DFT programs61 were used in the computations. The geometrical optimizations and vibrational analyses for the 5′-dAMP anion, 5′-dAMP neutral radical, and H abstracted anionic radicals were carried out using double-ζ quality basis sets with polarization and diffuse functions (denoted as DZP++). The DZP++ basis sets were constructed by augmenting the Huzinage-Dunning62-64 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 even-tempered 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. The even-tempered orbital exponents were determined according to the prescription of Lee and Schaefer65

Rdiffuse )

(

)

1 R 1 R2 + R 2 R2 R3 1

where R1, R2, and R3 are the three smallest Gaussian orbital exponents of the s- or p-type primitive functions for a given atom (R1 < R2 < R3). The final DZP++ set contains 6 functions per H atom (5s1p/3s1p), 19 functions per C, N, or O atom

Hou et al.

Figure 2. Bond lengths of the optimized structure of 5′-dAMP anion and its one-electron oxidized radical (units in Å). Numbers from top are 5′-dAMP anion, 5′-dAMP radical, and the crystallographic data.45

(10s6p1d/5s3p1d), and 27 functions per P atom (12s8p1d/ 7s5p1d), yielding a total of 504 contracted Gaussian functions for the 5′-dAMP anion. This basis has the tactical advantage that it has previously been used in comprehensive calibrative studies51 of a wide range of electron affinities. To analyze the distribution of the unpaired electron, (KohnSham) molecular orbitals and spin density plots were constructed from the appropriate B3LYP/DZP++ density. Natural Population Atomic (NPA) charges were determined using the B3LYP functional and the DZP++ basis set with the Natural Bond Order (NBO) analysis of Reed and Weinhold.66-69 To explore the effects of electron transfer on the structure of 5′-dAMP, the adiabatic electron detachment energy (DEad) was computed as the difference between the absolute energies of the appropriate neutral and anion species at their respective individually optimized geometries

DEad ) Eneut - Eanion Vertical detachment energies (VDEs) were evaluated as the differences between the absolute energies of the neutral and the anion species, both at the optimized anion geometry.

VDE ) Eneut(anion opt) - Eanion(anion opt) The 5′-dAMP anion in the B-form of DNA was selected as the initial structure of geometry in the present study. Previous conformation study has shown that this form is the most stable one on the potential energy surface.70 Standard nomenclature used in ref 70 is adopted in this research. 3. Results and Discussions A. 5′-dAMP Anion. Structure. The fully optimized geometry of the 2′-deoxyadenosine-5′-phosphate anion obtained from the selected initial structure is depicted in Figure 2. Typical B-DNA geometrical features are predicted for the optimized 5′-dAMP anion. Specifically, the ribose ring has the C2′-endo-C3′-exo conformation, and the adenosine is in the anti arrangement. The root mean square (rms) difference of the bond lengths between the experimental45 and theoretical values is 0.033Å, and the rms difference of the bond angles amounts to 3.0°. The largest bond length difference has been found to be 0.079 Å (P-O3′). Since the O3′ atom in the theoretical model has a very different environment compared to the crystal structure, this relatively large variation is reasonable. The O-P-O′ angles are predicted to be from 103.5° to 124.5°, which are similar to the experimental values,45 from

Molecular Structures and DNA Damage 105.7° to 117.3°. The theoretical P-O5′-C5′ and O5′-C5′-C4′ angles are 122.6° and 112.0°, about 4° larger than those in the crystallographic determination45 (118.1° and 109.6°). The dihedral angle γ (O5′-C5′-C4′-C3′), which characterizes the position of the 5′-phosphate group relative to the sugar and base in the nucleotide, is evaluated to be 61.7°, larger than that in the crystal structure (47.0°)45 but close to the earlier theoretical estimation (57°)71 for B-DNA. For the dihedral angle χ (O4′C1′-N9-C8), the calculated value of 77.2° is qualitatively consistent with the experimental measurement45 of 63.4°. The theoretical value of the dihedral angle β (P-O5′-C5′-C4′), reflecting the steric hindrance between the phosphate group and the sugar moiety, restricts O5′-C5′ rotation and is -101.1°. This angle is comparable to the fiber diffraction result (-146°) for B DNA double helices in the right-hand screw sense by Sasisekharan et al.72 Overall, the B3LYP/DZP++ approach reproduces the crystallographic geometrical parameters well. It should be noted that the geometric parameters might be different in the biological systems where base pairing and hydration are important. The Weinhold natural population analysis (NPA) for the 5′dAMP anion shows that the NPA charge of the adenine fragment is -0.31 au, about 0.02 au more negative than that for the neutral adenosine nucleoside.57 Clearly, the excess charge on the 5′dAMP anion is essentially located on the phosphoryl group, although there is a small amount of negative charge transfer from the phosphate to base as indicated by the NPA charge distribution. B. The 5′-dAMP Radical: One-Electron-Oxidized Product of 5′-dAMP. 5′-dAMP radical is the initial product of the oneelectron oxidation of the 5′-dAMP anion. However, it is usually difficult to observe this radical in experiments due to the rapid hole migration to guanine in DNA.3 Therefore, theory provides a suitable approach to examine the properties of this radical. Structure. The fully optimized bond lengths of the 5′-dAMP radical are depicted in Figure 2 along with those of the 5′-dAMP anion for comparison. Earlier research suggested that the oxidation has a high preference for the base part of the adenine nucleoside and nucleotide.1,74,75 Our results suggest that, in the one-electron oxidation product, the anion’s “last” electron seems to be removed from both the base and the phosphate moiety. This can be seen from the geometric changes in these two fragments. For the radical, significant bond length distances (compared to the anion) can be observed for C8-N9 (-0.013 Å), C5-C6 (0.011 Å), C6-N6 (0.025 Å), N1-C2 (0.009 Å), C2N3 (0.013 Å), N3-C4 (-0.012 Å), and C4-C5 (0.008 Å) in adenine. Another interesting geometric feature is that the amino group is coplanar with the purine cycle. On the other hand, the increase in O1-P and O2-P (0.010 and 0.016 Å) distances and the significant decreases in O3′-P and O5′-P (-0.038 and -0.042 Å) signify the charge redistribution in the phosphate group. Charge alteration in the phosphate also influences the O-P-O′ bond angles. The O3′-P-O5′ bond angle is reduced to 114.2° in the radical, about 10° less than that for the anion. On the other hand, the P-O5′-C5′ and the O5′-C5′-C4′ bond angles in the radical are 122.5° and 111.2°, almost the same as those in the 5′-dAMP anion (122.6° and 112.0°). It is important to note that the length of the C5′-O5′ bond in the radical increases to 1.445 Å, about 0.027 Å longer than that in anion, implying a weakened C5′-O5′ bond. This suggestion is further supported by the decrease in the Wiberg bond index from 0.90 to 0.85. Meanwhile, the C1′-N9 glycosidic bond is basically unaffected by oxidation. Therefore, in the one-electron

J. Phys. Chem. B, Vol. 109, No. 46, 2005 22055 TABLE 1: NPA Charge Distribution of 5′-dAMP Anion and Its Electron-Detached Neutral Radical (in au) 5′-dAMP anion 5′-dAMP radical

phosphate

sugar

adenine

-1.28 -0.65

0.59 0.68

-0.31 -0.03

oxidation process, single strand breaks (SSBs) might originate with the cleavage of the C5′-O5′ bond in DNA. Charge Distributions. The total NPA charges on the phosphoryl group, ribose, and adenine are -0.65, 0.68, and -0.03 au (Table 1) for the radical. Compared to the 5′-dAMP anion, the phosphate moiety in the radical loses about 0.63 electrons and the base loses about 0.28 au of negative charge. The NPA charge variation on the sugar is less significant ( raH4-(C4′) > raH1-(C1′) > raH2-(C2′) > raH5-(C5′). Structure raH3- is the most favorable of the ribose radicals from an energetic point of view. It is obvious that the strong intramolecular H-bonding in raH3- makes significant contributions to its stability. However, considering that the H-bonding energy is usually less than 10 kcal/mol,84 the stability of raH3is expected to be close to that of raH1- without the latter’s intramolecular H-bond. Therefore, the stabilities of raH3-, raH1-, and raH5- might be similar in DNA. A related H-bonding pattern also stabilizes raH2- by about 10 kcal/mol. After an intramolecular H-bonding energy correction, the stability sequence of the ribose-radicals should be raH4-(C4′) > raH1-(C1′) ∼ raH3-(C3′) ∼ raH5-(C5′) > raH2-(C2′), which is consistent with the fact that strand scission resulting from abstraction of H4′ has been detected in many systems.3 In 2002 Toure et al. predicted a related sequence for the neutral thymidine 3′,5′-diphosphoric acid radicals using the B3LYP/6-31G(d)//HF/3-21G(d) method,85 C4′ > C5′ > C1′ > C3′ > C2′. Use of a different base in the model may thus have little influence on the stability order. On the other hand, theoretical studies on the radicals obtained from 2′-deoxyriboadenosine have suggested53 C1′ > C4′ > C5′ > C3′ > C2′. These results seem to imply that the influence of the phosphoryl group on the relative stability of the sugar-based radical is more important than that of the base. Experimental observation of the formation of radical anion raH3- is rare. This has been interpreted as due either to the limited accessibility of H3′ or to its reduced stability.3 Our results suggest that the limited accessibility interpretation should be more reasonable. The Weinbold NPA charges listed in Table 5 demonstrate that the abstraction of a H atom from the sugar moiety does not result in significant charge redistribution. Compared to the 5′-dAMP anion, the NPA charge shifts slightly from sugar to base in raH1-. This minor degree of charge transfer represents the effects of the bonding intensification around the radical center. Similar effects may be seen for raH5-, for which a small amount of electron density is transferred from the phosphate to the sugar. It should be noted that the slight charge shift appearing in raH2- and raH3- should not be attributed to the radical center; rather, it should be considered as due to the effects of

Molecular Structures and DNA Damage

J. Phys. Chem. B, Vol. 109, No. 46, 2005 22057

Figure 4. Geometries of the dAMP anion and its sugar-based ribose radical anions, with bond lengths in Å: C, gray; N, blue; O, red; P, yellow; and H, white.

TABLE 3: Geometries of the Sugar Moiety within the Sugar-Based Radicals Arising from Hydrogen Abstraction from the 5′-dAMP Anion C1′-C2′

C2′-C3′

C3′-C4′′

C4′-O4′

O4′-C1′

conformation

1.505 1.499 1.538 1.537 1.538 1.537

1.541 1.489 1.504 1.540 1.532 1.533

1.539 1.549 1.511 1.498 1.548 1.538

1.452 1.449 1.438 1.379 1.461 1.442

1.373 1.422 1.433 1.441 1.419 1.425

C3′-exo C3′-endo C2′-endo C2′-endo C2′-endo-C3′-exo C2′-endo-C3′-exo

raH1-

raH2raH3raH4raH55′-dAMP anion

TABLE 4: H Atom Abstraction Energies Yielding the Sugar-Based Radical Anions (5′-dAMP- f raHx- + H) ∆E in kcal/mol raH1-

raH2raH3_ raH4raH55′-dAMP neutralb

98.0 99.1 89.9 96.0 100.3 110.9

∆E in eV 4.25 4.30 3.90 4.16 4.35 4.81

TABLE 5: Weinhold NPA Charge Distributions for the Ribose-Based Radical Anions

∆∆E in kcal/mol 8.2 9.2 0.0 6.1 10.5 21.1

a

∆∆E is the H abstraction energy, relative to the formal reaction 5′-dAMP- f raH3- + H. b Energy for the process 5′-dAMPanion f 5′-dAMP neutral radical + e-.

the intramolecular H-bondselectron density on the oxygens of phosphoryl group shifts to the proton linked to the sugar. The spin density analysis (Figure 5) reveals that the unpaired electron of the sugar-based radical is actually well localized around the carbons from which the H atom has been abstracted.

raH1-

raH2raH3raH4raH55′-dAMP anion

phosphate

sugar

adenine

-1.27 -1.24 -1.22 -1.27 -1.22 -1.28

0.61 0.55 0.54 0.57 0.53 0.59

-0.34 -0.31 -0.32 -0.30 -0.31 -0.31

Notice that the NPA analysis shows that the negative charge is located on the phosphoryl group. These well-localized unpaired electrons illustrate typical distonic radical anion character. Geometries of Base-Radical Anions. The optimized structures of the four base-radical anions (raH6- to raH9-) are depicted in Figure 6, which highlights the most interesting structural features. The geometrical parameters of the 2′deoxyribose-5′-phosphate moiety are basically unchanged in the

22058 J. Phys. Chem. B, Vol. 109, No. 46, 2005

Hou et al.

Figure 5. The spin density of the 5′-dAMP neutral radical and the sugar-based anionic radicals. Isosurface values are 0.002 atomic unit.

TABLE 6: H Abstraction Energies of the Base-Radical Anions: (5′-dAMP- f raHx- + H)a raH6-

raH7raH8raH9raH35′-dAMP anionb

∆E in kcal/mol

∆E in eV

∆∆E in kcal/mol

101.1 101.9 112.1 125.2 89.9 110.9

4.38 4.42 4.86 5.43 3.90 4.81

11.3 12.1 22.2 35.3 0.0 21.1

a ∆∆E is the H abstraction energy relative to the reaction 5′-dAMPf raH3- + H. b Energy for the process 5′-dAMP anion f 5′-dAMP neutral radical + e-.

Figure 6. The geometries of the base-radical anions, with bond lengths in Å. Bond distances from top to bottom are raH6-, raH7-, raH8-, and raH9-. Color representations are as follows: C, gray; N, blue; O, red; P, yellow; H, white.

formation of the adenine-centered base-radical anions (See Supporting Information). The N6 Base-Radicals (raH6- and raH7-) are qualitatively similar in their structures. The different orientations of H(N6) are expected to have little influence on their physical properties. The bond length variations in raH6- (compared to the 5′-dAMP anion) display typical characteristics of a conjugated system: significant bond length decreases have been observed for C6N6 (-0.05 Å), N1-C2 (-0.03 Å), N3-C4 (-0.02 Å), C5-N7 (-0.02 Å), and C8-N9 (-0.01 Å), while crucial bond length increases are predicted for C6-N1 (0.04 Å), C2-N3 (0.03 Å), C4-C5 (0.02 Å), and N7-C8 (0.01 Å). Similar structural changes may be seen for raH7-. The geometrical features of these two anionic radicals suggest that the unpaired electron in the N6 H-abstracted radical is delocalized on the adenine base. The bond length variations of the base moiety are consistent with previous studies of the neutral radicals of the adenine base and adenosine nucleoside.52,53 This consistency suggests that the negative charge on the anionic radicals mainly resides on the phosphoryl group, and the radical is less influenced by negative charge on its neighboring groups. Note that the glycosidic bond distance C1′-N9 slightly increases in these anionic base radicals (by about 0.01 Å), and the formation of the base radicals might be connected to the base release related mechanisms. Stability and Charge Distribution of Base-Radical Anions. The H atom abstraction energies for the base radicals are summarized in Table 6. The radicals generated at the nitrogen atom and at the aromatic carbons have the following relative

TABLE 7: NPA Charge Distributions for the Base-Radical Anions (in au) raH6raH7raH8raH95′-dAMP anion

phosphate

sugar

adenine

-1.27 -1.27 -1.28 -1.26 -1.28

0.60 0.60 0.59 0.61 0.59

-0.33 -0.33 -0.31 -0.34 -0.31

energetic sequence: raH6-(N6a) ∼ raH7-(N6b) < raH8-(C2) < raH9-(C8), which matches the sequence revealed in the previous studies of free adenine base and the adenosine nucleosides.52,53 As expected, raH6- and raH7- have similar stabilities. It is important to note that the H abstraction energies for the raH6- and raH7- are smaller than the electron detachment energy of the 5′-dAMP anion, which is consistent with the experimental observation that one-electron-oxidized adenines usually lead to deprotonated species.1 Moreover, the high energy needed for the formation of the C2 and C8 centered radical anions (4.86 eV for raH8- and 5.43 eV for raH9-) prevents the neutral 5′-dAMP radical from being deprotonated to form C2 and C8 centered radicals. Accordingly, N6,N6-dimethyladenine radicals are found to be stable in experiments.1, 86 The NPA charge distributions summarized in Table 7 reveal the basically similar charge distributions for the phosphate moiety. A small amount of negative charge transferred from the sugar moiety to the base in raH9- might flow through the glycosidic C1′-N9 bond to the radical center on C8. The spin density plots (Figure 7) for the base radicals illustrate two kinds the radicals: N-generated radicals are delocalized over the base, including the amino group, and C-generated radicals are localized on the carbon atoms. The former displays the features of a conjugated π system, while the latter shows typical σ radical characteristics. These characteristics are in good agreement with the geometric variations discussed above.

Molecular Structures and DNA Damage

J. Phys. Chem. B, Vol. 109, No. 46, 2005 22059 It is to be noted that all the H-abstraction-produced 5′-dAMP radical anions are distonic radical anions. Studies have shown that the charge-radical-separating feature of the distonic radical anions is biologically relevant.87-89 This consideration should be important for the reactive properties of these H-abstractionproduced anion radicals. Acknowledgment. This research was supported by the U.S. National Science Foundation, Grant CHE-0136186. Supporting Information Available: A complete citation of ref 61 and geometries of aliphatic-radical anions and geometries of base-radical anions. This material is available free of charge via the Internet at http://pubs.acs.org. References and Notes

Figure 7. Spin densities of the base radical anions. Isosurface values are set at 0.002 atomic units.

Similar to the sugar-based radicals, the spin density and the negative charge on the base radicals are well separated. It is interesting to note that the overall stability sequence of the H-abstracted 5′-dAMP anionic radicals follows the previous study52 for the H-abstracted neutral radical of the adenosine nucleoside: aliphatic radicals > aromatic radicals. The negatively charged phosphoryl group attached to atom C5′ of the ribose does not change this energetic sequence. This phenomenon could be the direct result of the formation of distonic radical anions of the nucleotides. 4. Concluding Remarks The present study of the 2′-deoxyadenosine-5′-phosphate anion, its one-electron oxidized radical, and its H-abstracted radical anions reveals the following important physical characteristics of 5′-dAMP radical related processes: (1) One-electron oxidation of the 5′-dAMP anion happens on both the phosphoryl group and the adenine base moiety. However, the adenine moiety is expected to be unaffected during the nascent step of the oxidation. The negative charge transfer from phosphoryl group to base should occur during the geometric relaxation process of formation of the 5′-dAMP radical. The electron detachment energy is close to that of phosphoryl group. On the other hand, since the presence of counterions and the influence of solvent are known to increase the ionization potential of the phosphoryl group, the electron might be detached directly from the adenine moiety in aqueous solutions. (2) Partial removal of electron density on the adenine fragment leads to an extended π system which includes the amino group of the adenine. (3) While the creation of a radical-centered carbon atom strengthens the bonds to adjacent atoms, it usually weakens the chemical bonds between the atoms at the R- and β-positions. This tendency might be important in predicting the reactivity of the sugar-based radicals. (4) The overall stability sequence of the H abstracted 5′-dAMP anionic radicals is consistent with that for the H-abstracted neutral radicals of adenosine: aliphatic radicals > aromatic radicals. The negatively charged phosphoryl group attached to atom C5′ of the ribose does not change this energetic sequence. This phenomenon could be the direct result of the formation of distonic radical anions of the nucleotides.

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