Protection Against Radiation-Induced DNA Damage by Amino Acids

J. Phys. Chem. B 2009, 113, 5633–5644

5633

Protection Against Radiation-Induced DNA Damage by Amino Acids: A DFT Study N. R. Jena,*,† P. C. Mishra,‡ and S. Suhai† DiVision Molecular Biophysics (B020), Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 580, D - 69120 Heidelberg, Germany, and Department of Physics, Banaras Hindu UniVersity, Varanasi-221005, India ReceiVed: NoVember 28, 2008; ReVised Manuscript ReceiVed: February 20, 2009

Direct and indirect radiation-induced DNA damage is associated with the formation of radical cations (G•+) and radical anions (G•-) of guanine, respectively. Deprotonation of G•+ and dehydrogenation of G•- generate guanine neutral radical [G(-H)•] and guanine anion [G(-H)-], respectively. These products are of worrisome concern, as they are involved in reactions that are related to certain lethal diseases. It has been observed that guanyl radicals can be repaired by amino acids having strong reducing properties that are believed to be the residues of DNA-bound proteins such as histones. As a result, repair of G(-H)• and G(-H)- by the amino acids cysteine and tyrosine has been studied here in detail by density functional theory in both the gas phase and aqueous medium using the polarized continuum and Onsager solvation models of self-consistent reaction field theory. Solvation in aqueous medium using three explicit water molecules was also studied. Four equivalent tautomers of each the above radical and anion that will be formed through proton and hydrogen loss from all of the nitrogen centers of guanine radical cation and guanine radical anion, respectively, were considered in the present study. It was found that in both the gas phase and aqueous medium, normal guanine can be retrieved from its radical-damaged form by a hydrogen-atom-transfer (HT) mechanism. Normal guanine can also be retrieved from its anionic damaged form in both the gas phase and aqueous medium through a two-electron-coupled proton-transfer (TECPT) mechanism or a one-step hydrogen-atom- and electron-transfer (OSHET) mechanism. The present results are discussed in light of the experimental findings. G - e- f [G•+] f G(-H)• + H+

1. Introduction Oxidative DNA damage is a major hurdle for genome integrity and causes several life-degrading phenomena and diseases, such as aging,1 cancer,2 and neurodegenerative diseases.3 Damage to DNA is mainly caused by its interactions with radiation, different chemicals, and electron- or hole-transfer species.4,5 DNA damage is manifested as base modification,6 base release,7 strand breakage,8 mutation,9 DNA-protein crosslinking,10 and so on. The direct interaction of high-energy radiation with doublestranded DNA involves the removal of an electron from the DNA. The hole created in this way migrates over a long distance through a hopping mechanism,11 eventually ending on a guanine (G) base of DNA because guanine has the lowest oxidation potential among all DNA bases.12 This creates a guanine radical cation (G•+), which is a precursor of many pathological conditions inside living cells as a result of its involvement in many diverse reactions.13-15 For example, G•+ in double-stranded DNA can react with H2O, leading to the formation of the highly mutagenic species 8-oxoguanine (8-oxoG).13,14 It has been found that G•+ deprotonates quite rapidly (rate constant ) 107 s-1)16 in DNA, giving rise to guanyl radical [G(-H)•] (eq 1), which is another potential precursor involved in DNA damage. * Corresponding author. E-mail: [email protected]. † Deutsches Krebsforschungszentrum (DKFZ). ‡ Banaras Hindu University.

(1)

This reaction has been observed by pulse radiolysis,16 transient absorption spectroscopy,17 electron spin resonance (ESR) studies,18 and X-ray photoelectron spectroscopy.19 Both experimental20 and theoretical21 studies have revealed the primary deprotonation site to be the N1 position of guanine in an aqueous environment. In DNA, guanine is paired with cytosine (C), and it is believed that the N3 position of C (pKa ) 4.45) accepts the proton liberated from the N1 position of G•+ (pKa ) 3.9), producing a pair that can be denoted as G(-H1)•:C(H3)+.22 The N2 imino protons are also sensitive toward deprotonation of the guanine radical cation.20b,21b,c Thus, environmental and hydration effects are suggested to play a crucial role in different phenomena that involve DNA.23 The mutagenesis associated with guanyl radical starts immediately after its trapping of O2 or superoxide anion (O2•-) at the C5 position, yielding the deadly imidazolone (Iz) residue.13,15 Hydration of Iz can generate another deleterious product called oxazolone (Oz).24 These two products have been found to be involved in the GC f CG transversion mutation25 that interferes in the normal gene functioning. The mechanism of radiation-induced DNA damage and its effects are summarized in Figure 1. Other than DNA damage by direct interaction with highenergy radiation, DNA can also be damaged indirectly as a result of the generation of low-energy electrons (LEEs)26 (energy ) 0-20 eV) along the ionization path (Figure 1). DNA alteration by LEEs has been extensively studied both experimentally and theoretically by Sanche and co-workers,27 Illenberger and co-

10.1021/jp810468m CCC: $40.75  2009 American Chemical Society Published on Web 03/31/2009

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Jena et al.

Figure 2. Atom numbering scheme for guanine.

Figure 1. Mechanisms of radiation-induced DNA damage.

workers,28 Sevilla and co-workers,29 Schaefer and co-workers,30 Leszczynski and co-workers,31 and others.32 It has been established that the capture of LEEs [or dissociative electron attachment (DEA)] by DNA components initiates the formation of transient negative ions (Figure 1), which subsequently undergo dissociation reactions, yielding varieties of DNA fragmented ions such as H-, O- OH-, CN-, CNO-, or radicals.28,29,33 However, the dominant DEA channel is dehydrogenation of the base (e.g., G), which mainly arises as a result of NsH bond cleavage.28 Base dehydrogenation can produce either an anion (eq 2)

involved in the process of guanyl radical repair. Moreover, even though the formation of guanine anion is a subject of concern, little is known regarding the potential mechanisms of the conversion of the anion to normal guanine. We also do not know if the mild redox amino acids can play significant role in the repair process of guanine anions to guanine. For these reasons, we have investigated repair of both G(-H)• and G(-H)- forms of damaged guanine to normal guanine by amino acids that contain thiol (cysteine) and phenol (tyrosine) side chains (oxidation potential of 0.9 V for each). These amino acids are believed to have high electron-donating capabilities. In the present study, we have considered all possible tautomers of guanine that can be formed through proton and hydrogen-atom loss from the different nitrogen centers (i.e., N1, N2, and N9) of G•+ and G•-, respectively. 2. Computational Details

G + e- f [G•-] f G(-H)- + H•

(2)

or a radical (eq 3)

G + e- f [G•-] f G(-H). + H-

(3)

DEA of DNA bases is the primary cause of DNA alteration by LEEs, which ultimately leads to base release (as a result of direct electron capture by bases) and strand breakage (as a result of indirect effects, i.e., electron transfer from the base to phosphate)26-28,32 (Figure 1). Even though dehydrogenation is not a dominant channel for guanine anions,28b even its small occurrence can hinder normal cell functioning severely. A mass spectrometric study34 has also confirmed the formation of dehydrogenated guanine dianion upon electron attachment to guanine manoanion, which can be even more lethal. As DNA base radicals and anions are preliminary factors of DNA damage, their repair should be initiated at an early stage so that the normal base structures can be retrieved, before they become involved in further deleterious reactions (Figure 1). The living system has its own defense mechanism to protect itself from exogenous and endogenous causes of damage. It is believed that residues of a DNA-binding proteins, such as histone, might repair one-electron-oxidized guanine by donating one of its electrons.35 In this context, amino acids having oxidation potentials less than that of guanine (1.29 V at pH 7) that can transfer one electron to guanine in a favorable manner are of paramount importance.35,36 The occurrence of such reactions has already been observed by the flash-quench technique,37 ESR,38 pulse radiolysis,39 and other experimental36,40,41 studies. No theoretical study of this electron-transfer reaction from the amino acids to DNA bases has been reported so far. Further, as the guanine radical cation undergoes rapid deprotonation, its repair to guanine can involve both electron and proton transfers. Therefore, it is desirable to investigate redox amino acids as likely sources for such charge transfers that might be

Repair of guanyl radicals and anions by cysteine (CysSH) and tyrosine (TyrOH) were studied using the three-parameter hybrid B3LYP density functional,42 along with double-ζ (6-31G**) and triple-ζ (6-311++G**) basis sets. All geometry optimization calculations to locate stationary points were carried at the B3LYP/6-31G** level of theory. It was followed by single-point energy calculations at the B3LYP/6-311++G** level of theory employing the geometries obtained at the B3LYP/6-31G** level. Vibrational frequency analysis was also carried out at the level of geometry optimization. Zero-point energy corrections to the total energy and thermal energy corrections to the enthalpy were made, and Gibbs free energy calculations were performed at a temperature of 298.15 K. Reactant complexes (RCs), intermediate complexes (ICs), and product complexes (PCs) were characterized by all real frequencies, whereas transition states (TSs) were characterized by one imaginary frequency each. The vibrational mode of each TS for the imaginary frequency was found to connect the corresponding RC and PC. All calculations were carried out using the Gaussian 03 program,43 and all structures and related vibrations were viewed using the GaussView44 program. The influence of an aqueous medium (ε ) 80) on all reaction steps was investigated using two different solvation models, namely, the polarizable continuum model (PCM)43 and the Onsager model45 of the self-consistent reaction field (SCRF) theory, as implemented in the Gaussian 03 program. The results for the repair reactions obtained by these solvation calculations were compared with those in which three specific water molecules were hydrogen-bonded to the N3, O6, N7, and N9 positions of guanine (Figure 2). Solvent effects due to specific water molecules were investigated by geometry optimization calculations at the B3LYP/6-31G* level of theory, followed by single-point energy calculations at the B3LYP/6-311++G** level of theory. Gas-phase zero-point energy corrections and thermal energy corrections yielding the enthalpy and Gibbs free energy were taken to be valid for the single-point energy calculations in both the gas phase and aqueous medium.

Protection Against DNA Damage by Amino Acids

J. Phys. Chem. B, Vol. 113, No. 16, 2009 5635

Figure 3. Potential energy surfaces for the reactions of CysSH with (a) G(-H1)•, (b) G(-H2a)•, (c) G(-H2b)•, and (d) G(-H9)•. Structures of different complexes were obtained at the B3LYP/6-31G** level. Relative ZPE-corrected total energies calculated with respect to the G(-H1)•sCysSH reactant complex at the B3LYP/6-311++G** level of theory in the gas phase and aqueous medium (PCM and Onsager values in parentheses and braces, respectively) are also given. The imaginary vibrational frequencies (ν) associated with all TSs are given in cm-1, and the spin densities located on different species obtained at the B3LYP/6-311++G** level of theory in aqueous medium (PCM) are shown in brackets.

3. Results and Discussion 3.1. Reaction of Guanyl Radicals with CysSH. The atom numbering scheme of guanine adopted in the present study is shown in Figure 2. Deprotonation of G•+ from the N1, N2, and N9 sites will generate G(-H1)•, G(-H2a)•, G(-H2b)•, and G(-H9)• radicals, respectively (Figure 2). These four radicals are tautomeric equivalents of one another and might play an important role in DNA hole migration. The proton that could be cleaved from the carbon center (C8) requires high energy28b

and, as will be discussed later, will generate a highly unstable radical [G(-H8)•]. Therefore, in the present study, we consider repair of guanyl radicals through their reactions with cysteine and tyrosine that are formed by N-deprotonation of G•+ only. The potential energy surfaces (PESs) relevant to reactions of CysSH with (a) G(-H1)•, (b) G(-H2a)•, (c) G(-H2b)•, and (d) G(-H9)• are depicted in Figure 3. The numbers presented therein correspond to relative ZPE-corrected energy values calculated with respect to G(-H1)sCysSH complex in both


Jena et al.

TABLE 1: ZPE-Corrected Barrier Energies (∆E) and Enthalpy (∆H) and Free Energy (∆G) Changes (kcal/mol) for the G(-H)• + CysSH f G + CysS• Reaction G(-H1)•

G(-H2a)•

G(-H2b)•

G(-H9)•

level of theory

∆E

∆H

∆G

∆E

∆H

∆G

∆E

∆H

∆G

∆E

∆H

∆G

B3LYP/6-31G** B3LYP/6-311++G** B3LYP/6-311++G** (ε ) 80)a

7.15 7.71 -8.30 (-0.98)

6.56 7.12 -8.89 (-0.39)

8.20 8.76 -7.25 (2.03)

5.42 5.93 -7.68 (4.78)

6.10 6.64 -6.97 (5.46)

3.32 3.86 -9.75 (4.03)

6.42 7.05 -6.00 (9.06)

6.00 6.63 -6.42 (8.61)

7.37 8.00 -5.05 (10.08)

8.18 8.97 -5.58 (9.44)

7.73 8.52 -6.03 (9.02)

9.20 9.99 -4.56 (10.39)

a

Obtained by the polarized continuum model (values in parentheses obtained by the Onsager model).

the gas phase and aqueous medium (in parentheses and braces). The minima on the PESs correspond to reactant and product complexes, whereas the maxima correspond to transition states. Structural analysis suggests that the complexation of CysSH with G(-H2b)• and G(-H9)• involves similar hydrogen-bonding interactions, each having three intermolecular and two intramolecular hydrogen bonds. The SsH interatomic distances at the transition states follow the order G(-H2a)• < G(-H1)• < G(-H2b)• < G(-H9)•, whereas the NsH interatomic distances follow the order G(-H9)• < G(-H2b)• < G(-H2a)• < G(-H1)•. Thus, the SsH interatomic distances are almost twice the NsH interatomic distances, which indicates that, at the transition states, the proton has completely detached from S and migrated toward N (Figure 3). This also indicates that all transition states are virtually “late”. The relative stabilities of all of the species involved in the reactions of guanyl radicals with CysSH are presented in Table S1 (Supporting Information). From this table, it is clear that the N9-deprotonation of G•+ will be preferred in the presence of CysSH in both the gas phase and aqueous medium. It was found that the C8-deprotonation of guanine will generate a G(-H8)• radical, whose complex with CysSH will be about 22-29 kcal/mol less stable than the G(-H1)•sCysSH radical complex. This high instability shows that binding of CysSH to the C8 site would be quite unlikely to occur. For this reason, we did not consider G(-H8)• repair by CysSH in the present study. The ZPE-corrected reaction barrier energies and enthalpy and Gibbs free energy changes for the reactions of guanyl radicals with cysteine are presented in Table 1. It was found that the ZPE-corrected barrier energies of these reactions lie between approximately 6-9 kcal/mol in the gas phase at the B3LYP/ 6-311++G** level of theory (Table 1). However, if we consider the free energy changes in the gas phase, these barriers lie in the range of 4-10 kcal/mol, the order being G(-H9)• > G(-H1)•> G(-H2b)•> G(-H2a)•. Thus, in the gas phase, repair of G(-H2a)• would involve the lowest barrier, but the other barriers are also not high. Therefore, all of the repair reactions involving the different guanyl radicals would be feasible (Table 1). When the solvent effect as obtained using the PCM was considered, all of the barrier energies became negative (barrierless reactions, Table 1). The dramatic decrease in barrier energies could be an artifact of this model, probably arising from the weak NsH bonds at the transition states. Keeping this in mind, we recalculated the barrier energies using the Onsager solvation model in aqueous medium. This calculation yielded barrier-free energies that were non-negative, lying in the range of ∼2-10 kcal/mol, with the lowest barrier-free energy being associated with G(-H1) radical repair (Table 1). The reaction rate constants of the above reactions at a temperature of 300 K were calculated using Eyring’s equation46 and are presented in Table S2 (Supporting Information). These rate constants were found to lie in the range of 105-109 s-1 as

obtained at the B3LYP/6-311++G** level of theory in the gas phase (Table S2, Supporting Information). The orders of these rate constants are in satisfactory agreement with the experimental values obtained for electron transfer from a peptide containing amino acid derivatives (and structurally similar compounds) to guanyl radical in a plasmid DNA,36 which lie between 105 and 106 dm3 mol-1 s-1. However, the corresponding rate constants in aqueous medium obtained using the PCM lie between 1016 and 1019 s-1 (Table S2, Supporting Information). Interestingly, the reaction rate constants obtained using the Onsager solvation model are of the same order as those observed experimentally, namely, 105-1011 s-1 (Table S2, Supporting Information). The overall reaction, that is, G(-H)• + CysSH f G + CysS•, for all guanyl radicals considered here was found to be exothermic by about 3-11 kcal/mol at the B3LYP/6-31++G** level of theory (Table S3, Supporting Information). Thus, repair of the guanyl radical by deprotonation of the thiol group of CysSH would occur with the highest efficiency. The Mulliken spin densities and natural population analysis (NPA) charge densities localized on the guanine moiety during these reactions are presented in Table 2. NPA charges were obtained using natural bond orbital (NBO)47 analysis. It is evident from Table 2 and Figure 3 that, in both the gas phase and aqueous medium, during the progress of the reaction, at the TS, a small amount of the total radical spin (15-25%) that was fully centered on the guanyl radical at the RC has disappeared and a similar amount of spin density has appeared on CysSH. At the PC, it was found that cysteine has acquired the full radical spin density (CysS•), there being no spin density localized on guanine. This is due to the fact that, during the progress of the reaction, an electron belonging to the S atom of CysSH has been completely transferred to the guanyl radical, creating a hole in CysSH. As a result, the total spin density is localized only on the S atom of cysteine. The spin density distribution in the case of the product complex related to G(-H1)• guanyl radical reaction with cysteine in aqueous medium is displayed in Figure S1a (Supporting Information). The patterns of spin density distribution for other radical reactions were found to be quite similar. The charge density distribution at the PC indicates that, along with an electron transfer, a proton belonging to the thiol group of CysSH is also transferred to guanyl radical in one step (Table 2). The imaginary vibrational frequencies at the TSs were found to lie in the range 1472.5-1691.3 cm-1 (Figure 3). Given that the source of both electron and proton transfer is the same (CysSH), the reaction can be described as hydrogen-atom-transfer (HT) reaction, which is different from proton-coupled electron transfer (PCET),48,49 where the sources of the electron and proton are different. Our theoretical findings support the experimental observation of peptide radicals37 that are thought to be formed through binding with DNA following oxidative damage of the latter. 3.2. Reaction of Guanine Radicals with TyrOH. In studying the repair of guanyl radicals by tyrosine, we considered only



TABLE 2: NPA Charges (Q) and Mulliken Spin Densities (G) on Guanine during the Reaction G(-H)• + CysSH f G + CysS• B3LYP/6-31G** radical

b

RC

B3LYP/6-311++G** (ε ) 80)a

B3LYP/6-311++G**

TS

PC

RC

TS

PC

RC

TS

PC

0.06 0.99

-0.02 0.76

0.00 0.00

0.00 1.03

-0.06 0.74

-0.02 0.02

0.06 1.02

0.22 0.98

-0.02 0.00

-0.07 0.92

0.03 0.84

0.00 0.00

-0.08 1.02

0.02 0.77

0.00 0.00

-0.08 1.02

0.19 0.96

0.02 0.00

-0.03 1.04

0.01 0.86

0.05 0.10

0.03 1.01

-0.01 0.77

0.01 0.00

-0.02 1.00

0.18 0.95

-0.04 0.00

0.01 0.99

-0.11 0.85

0.06 0.10

-0.01 1.03

-0.12 0.86

0.00 0.08

0.09 1.08

0.06 0.98

0.01 0.00

•

G(-H1) Q F G(-H2a)• Q F G(-H2b)• Q F G(-H9)• Q F

a Obtained in aqueous medium using the polarized continuum model. complex.

the truncated phenolic part of TyrOH that is involved in the reaction. Structures of different complexes related to the reactions of TyrOH with (a) G(-H1)•, (b) G(-H2a)•, (c) G(-H2b)•, and (d) G(-H9)• at the minima and transition states of the PES are shown in Figure 4. Complexation of TyrOH with G(-H1)• involves a maximum number of hydrogenbonding interactions. The OsH interatomic distances at the different transition states follow the order G(-H2b)• < G(-H1)• < G(-H9)• < G(-H2a)•, whereas the NsH interatomic distances follow the order G(-H2a)• < G(-H2b)• < G(-H9)• < G(-H1)•. Unlike guanyl radical repair by CysSH, the OsH distance is less than the NsH distance at the transition states (Figures 3 and 4). This indicates that these transition states are virtually “early” and, as will be discussed later, would be associated with lower barrier energies than those of the corresponding reactions involving CysSH in the gas phase. Relative stabilities of the different complexes involved in the above reactions are presented in Table S4 (Supporting Information). From this table, it is quite evident that, at the RC, G(-H9)• makes the most stable complex with TyrOH in both the gas phase and aqueous medium. It indicates again that, in both the gas phase and aqueous medium, N9-deprotonation of G•+ would be preferred because of the presence of tyrosine. As in the case of cysteine, the G(-H8)•sTyrOH complex was also found to be highly unfavorable [by ∼22-29 kcal/mol relative to G(-H1)•sTyrOH]. Thus, tyrosine would not prefer its binding to the C8 site of the guanyl radical. This is in accordance with experimental observations showing that the yield of the carbon center radical due to radiation damage is lowest.28 ZPE-corrected barrier energies and the corresponding enthalpy and Gibbs free energy changes for the reaction of different guanyl radicals with TyrOH are presented in Table 3. It was found that, in the gas phase, the ZPE-corrected barrier energies for this reaction lie in the range of 1-4 kcal/mol at the B3LYP/ 6-311++G** level of theory (Table 3). The barrier energies are somewhat larger if the free energy changes are considered. The solvent effect of water obtained using the PCM reduces the barrier energies with respect to those in the gas phase to either close to or less than zero, indicating that the reactions would occur rapidly (Table 3). However, when the Onsager solvation model was used in place of the PCM, the calculated barrier energies became negative only in the cases of G(-H1)• and G(-H2b)• (Table 3). Further, it is noted that the barriers calculated using the Onsager model in the case of guanyl radical repair by TyrOH are less than those required for repair by CysSH in aqueous medium. This suggests that guanyl radical

b

RC ) reactant complex, TS ) transition state, PC ) product

repair would occur more efficiently by TyrOH than by CysSH. Further, the results obtained by the Onsager model suggest that, among all guanyl radical repair mechanisms, the one involving G(-H1)• would be most efficient by both CysSH and TyrOH in aqueous medium (Tables 1 and 3). The calculated rate constants involved in the reactions discussed above at the B3LYP/6-311++G** level of theory in the gas phase were found to lie in the range of 108-1011 s-1 (Table S5, Supporting Information). These rate constants are higher than the experimental values36 obtained for electrontransfer reactions involving models of peptides and plasmid DNA. The orders of these rate constants in aqueous medium obtained by the PCM are larger (1011-1016 s-1) than those in the gas phase. However, when the Onsager solvation model was used, the rate constants were found to be on the same order as those found in the gas phase (Table S5, Supporting Information). Some discrepancy between the observed and calculated rate constants is not surprising, as the experimental conditions cannot be fully reproduced in a theoretical calculation. Further, as the experimental rate constants were obtained for electron transfer from amino acid derivatives and structurally similar compounds to guanyl radicals in plasmid DNA, the values will be definitely different from those that correspond to hydrogen-transfer (HT) reactions involving isolated guanyl radical and amino acids. The nature of these reactions will be discussed in detail later. It was found that the reactions of all guanyl radicals with TyrOH at the B3LYP/6-311++G** level of theory are exothermic in both the gas phase and aqueous medium (Table S6, Supporting Information). The exothermicities of reactions involving G(-H1)• and G(-H9)• in the gas phase are highest and lowest, respectively. Considering the fact that the reaction involving G(-H1)• has the lowest barrier energy and a high exothermicity, its repair by tyrosine would be most favored in the gas phase. Nevertheless, normal guanine can be retrieved from all guanyl radical tautomers by tyrosine in both the gas phase and aqueous medium. The Mulliken spin densities and NPA charge densities localized on the guanine moiety during the above reactions are presented in Table 4. From this table and Figure 4, it is clear that, in both the gas phase and aqueous medium, at the TS, about 50-60% of the total radical spin density has been lost from the guanyl radical, and a similar amount of spin density has developed on TyrOH. At the PC, it was found that TyrOH has acquired the full spin density whereas guanine has none. This is due to the fact that, during the reaction, an electron from TyrOH is transferred to pair the unpaired guanyl radical electron;


Jena et al.

Figure 4. Potential energy surfaces for reactions of TyrOH with (a) G(-H1)•, (b) G(-H2a)•, (c) G(-H2b)•, and (d) G(-H9)•. Structures of different complexes were obtained at the B3LYP/6-31G** level of theory. Relative ZPE-corrected total energies calculated with respect to the G(-H1)•sTyrOH reactant complex using the B3LYP/6-311++G** level of theory in the gas phase and aqueous medium (PCM and Onsager values in parentheses and braces, respectively) are also given. The imaginary vibrational frequencies (ν) associated with all TSs are given in cm-1, and the spin densities located on different species obtained at the B3LYP/6-311++G** level of theory in aqueous medium (PCM) are shown in brackets.

TABLE 3: ZPE-Corrected Barrier Energies (∆E) and Enthalpy (∆H) and Free Energy (∆G) Changes (kcal/mol) for the G(-H)• + TyrOH f G + TyrO• Reaction G(-H1)• levels of theory

∆E

B3LYP/6-31G** 0.81 6-311++G** 1.27 B3LYP/6-311++G** (ε ) 80)a -5.38 (-1.48) a

G(-H2a)•

G(-H2b)•

G(-H9)•

∆H

∆G

∆E

∆H

∆G

∆E

∆H

∆G

∆E

∆H

∆G

0.66 1.12 -5.53 (-1.63)

1.26 1.72 -4.93 (-1.03)

2.98 3.54 -4.55 (3.37)

2.65 3.21 -4.88 (3.04)

3.69 4.25 -3.84 (3.69)

1.18 2.00 -0.98 (-10.15)

0.83 1.65 -1.33 (-10.53)

2.59 3.39 0.41 (-8.74)

2.61 4.19 -0.92 (3.93)

2.06 3.64 -1.46 (3.38)

4.52 6.10 0.99 (5.84)


as a result, TyrOH acquires a radical character. The pattern of the spin density distribution is shown in Figure S1d (Supporting Information). The charge density distribution at the PC indicates

that, along with an electron transfer, a proton has also been transferred from TyrOH to the guanyl radical in one step, making guanine electronically neutral (Table 4). The imaginary



TABLE 4: NPA Charges (Q) and Mulliken Spin Densities (G) on Guanine during the Reaction G(-H)• + TyrOH f G + TyrO• B3LYP/6-31G** radical

b

B3LYP/6-311++G**(ε ) 80)a

B3LYP/6-311++G**

RC

TS

PC

RC

TS

PC

RC

TS

PC

0.06 1.00

-0.19 0.61

-0.23 0.00

0.03 1.01

-0.12 0.59

0.01 0.00

0.02 1.00

0.18 0.97

0.01 0.00

0.03 1.00

-0.16 0.66

-0.34 0.00

0.02 0.98

-0.14 0.58

-0.04 0.00

0.06 1.02

0.22 0.95

-0.03 0.00

0.05 1.00

-0.23 0.54

-0.04 0.10

0.01 1.00

-0.21 0.54

-0.02 0.02

0.05 1.01

0.18 0.96

0.01 0.00

0.08 1.08

-0.19 0.45

-0.04 0.13

0.02 1.01

-0.28 0.50

-0.03 0.01

0.06 1.01

0.13 0.97

-0.02 0.01

•

G(-H1) Q F G(-H2a)• Q F G(-H2b)• Q F G(-H9)• Q F

a Obtained in aqueous medium using he polarized continuum model. complex.

Figure 5. Guanine radical repair by cysteine (CysSH) and tyrosine (TyrOH) via the hydrogen-atom-transfer (HT) mechanism. Here, +eand +H+ refer to gain of an electron and a proton, respectively, by guanyl radical.

vibrational frequencies at the TSs were found to lie in the range 1412.9-1604.1 cm-1 (Figure 4). This theoretical findings are in agreement with a previous theoretical study,50 where the HT mechanism was proposed to be the dominant pathway involving amino acid reactions. Thus, repair of guanyl radicals by CysSH and TyrOH in both the gas phase and aqueous medium starts following a hydrogenatom-transfer (HT) mechanism. As a consequence of this reaction, normal guanine is retrieved, and the amino acids acquires a radical character. This mechanism is depicted in Figure 5. 3.3. Reaction of Guanine Anions with CysSH. Potential energy surfaces of reactions of CysSH with (a) G(-H1)- (b) G(-H2a)-, (c) G(-H2b)-, and (d) G(-H9)- are displayed in Figure 6. From these results, the following points are noted: (i) The SsH and NsH interatomic distances are quite similar at the different transition states (Figures 3 and 6). This indicates that these transition states are virtually “central”. (ii) At the reactant complex, the SsH bond is slightly more elongated than that in its radical counterpart. This appears to be due to the anionic nature of the N atom of guanine to which they are hydrogen-bonded. (iii) In the reactions involving G(-H2b)- and G(-H9)-, the orientations of the corresponding amino groups are different (Figures 3 and 6). The relative stability pattern presented in Table S7 (Supporting Information) indicates that, in the case of guanyl anions, complexation of CysSH with G(-H1)- is involved in the strongest interaction among all of the tautomeric anion complexes. A higher basis set and solvation effects have a negligible impact on this stability. The results summarized in Table 5 indicate that the repairs of all of the guanine tautomeric anions have similar energy barriers (e1 kcal/mol at B3LYP/6311++G** level of theory) in the gas phase, which can be easily overcome with the help of thermal energy. The low barriers associated with these reactions are due to the fact that the anionic nature of guanine weakens the SsH bond of CysSH

b


at the reactant complexes (Figure 6). In going from the gas phase to aqueous medium, whereas the PCM lowers the barrier energies to negative values (barrierless process), the Onsager model significantly elevates them to positive values (Table 5). The calculated rate constants of the above reactions lie in the ranges of 1011-1013 s-1 in the gas phase and 1016-1017 and 108-1011 s-1 in aqueous medium as obtained by the PCM and Onsager models, respectively (Table S8, Supporting Information). Among the exothermicities associated with the abovementioned reactions, those corresponding to G(-H2a)- and G(-H9)- are highest and lowest, respectively, in the gas phase (Table S9, Supporting Information). Thus, it appears that the repair of guanyl anions by cysteine would be completed extremely rapidly. Upon examination of the NPA charge distributions obtained in both the gas phase and aqueous medium, presented in Table 6 and Figure 6, it is clear that, during the progress of the reaction, guanine becomes converted from the anionic to the neutral state by transferring its negative charge to cysteine. Simultaneously, cysteine donates its H atom attached to the thiol group to guanine. The imaginary frequencies at the TSs were found to lie in the range 252.6-623.4 cm-1 (Figure 6), which is appreciably smaller than those corresponding to the H-atom transfer during guanyl radical repair by CysSH. The electron transferred to cysteine becomes completely delocalized over sulfur, nitrogen, and oxygen atoms. It was found that, at the product complex, the highest occupied molecular orbital (HOMO) is localized only on the sulfur atom of cysteine, whereas the lowest unoccupied molecular orbital (LUMO) is localized over the whole guanine moiety (Figure S1b,c, Supporting Information). As a consequence of this reaction, normal guanine is retrieved. It is interesting to note that, in an experimental study involving dissociative electron attachment to cysteine, Illenberger and co-workers51 found dehydrogenation of the cysteine anion to be one of the predominant reaction channels. Formation of dehydrogenated cysteine anion was also observed in another experimental study.52 Considering the fact that guanyl anions are formed through dissociative electron attachment to guanine, it is quite obvious that cysteine will play a decisive role in LEEinduced DNA repair. 3.4. Reaction of Guanine Anions with TyrOH. The relative stabilities of complexation of TyrOH with G(-H1)- and G(-H2a)- are presented in Table S10 (Supporting Information). The corresponding reaction profile is displayed in Figure 7. For G(-H2b)- and G(-H9)-, we could not locate genuine transition


Jena et al.

Figure 6. Potential energy surfaces for the reactions of CysSH with (a) G(-H1)-, (b) G(-H2a)-, (c) G(-H2b)-, and (d) G(-H9)-. Structures of different complexes were obtained at the B3LYP/6-31G** level of theory. Relative ZPE-corrected total energies calculated with respect to the G(-H1)-sCysSH reactant complex using the B3LYP/6-311++G** level of theory in the gas phase and aqueous medium (PCM and Onsager values in parentheses and braces, respectively) are also displayed. The imaginary vibrational frequencies (ν) associated with all TSs are given in cm-1, and the charge densities located on different species obtained at the B3LYP/6-311++G** level of theory in aqueous medium (PCM) are shown in brackets.

TABLE 5: ZPE-Corrected Barrier Energies (∆E) and Enthalpy (∆H) and Free Energy (∆G) Changes (kcal/mol) for the G(-H)- + CysSH f G + (CysS)- Reaction G(-H1)-

G(-H2a)-

G(-H2b)-

G(-H9)-

level of theory

∆E

∆H

∆G

∆E

∆H

∆G

∆E

∆H

∆G

∆E

∆H

∆G

B3LYP/6-31G** B3LYP/6-311++G** B3LYP/6-311++G** (ε ) 80)a

-0.91 -0.35 -7.86 (2.67)

-1.34 -0.78 -8.29 (2.24)

-0.19 0.37 -7.14 (3.39)

-0.61 0.24 -6.34 (2.28)

-1.07 -0.22 -6.80 (1.82)

0.47 1.33 -5.26 (2.42)

-0.85 -0.14 -7.20 (0.46)

-1.27 -0.57 -7.62 (0.04)

-0.15 -0.54 -6.51 (1.16)

-0.72 0.22 -6.53 (4.10)

-1.04 -0.11 -6.86 (3.77)

-0.05 0.88 -5.12 (4.76)

a


states. When we tried to locate the corresponding product complexes even by attaching the H atom of the OH group of TyrOH to the N atoms of the above-mentioned anions and performing geometry optimization at the B3LYP/6-31G** level of theory, we found that the H atom returned to its original site, that is, TyrOH. Presuming that this might be an artifact associated with the lower basis set (6-31G**), we optimized

the geometries under consideration at the B3LYP/6-311++G** level of theory. We again obtained the same result for G(-H9)-, which might be a consequence of the fact that reaction of TyrOH with G(-H9)- is too endothermic to be accomplished. In contrast, for G(-H2b)-, we did find a genuine total energy minimum for the product complex where the H atom of the OH group was loosely bound to the N atom (NsH distance of



TABLE 6: NPA Charge Densities (Q) on Guanine during the Reaction G(-H)- + CysSH f G + (CysS)B3LYP/6-31G** radical -

G(-H1) G(-H2a)G(-H2b)G(-H9)-

b

B3LYP/6-311++G** (ε ) 80)a

B3LYP/6-311++G**

RC

TS

PC

RC

PC

TS

RC

TS

PC

-0.81 -0.83 -0.83 -0.86

-0.75 -0.76 -0.77 -0.78

-0.17 -0.19 -0.15 -0.16

-0.87 -0.88 -0.88 -0.89

-0.81 -0.79 -0.78 -0.77

-0.18 -0.18 -0.17 -0.16

-0.88 -0.89 -0.87 -0.91

-0.78 -0.76 -0.76 -0.75

-0.10 -0.11 -0.09 -0.13


b


Figure 7. Potential energy surfaces for the reactions of TyrOH with (a) G(-H1)- and (b) G(-H2a)-. Structures of different complexes were obtained at the B3LYP/6-31G** level of theory. Relative ZPE-corrected total energies calculated with respect to the G(-H1)-sTyrOH reactant complex obtained using B3LYP/6-311++G** level of theory in the gas phase and aqueous medium (PCM and Onsager values in parentheses and braces, respectively) are also displayed. The imaginary vibrational frequencies (ν) associated with all TSs are given in cm-1, and the charge densities located on different species obtained at the B3LYP/6-311++G** level of theory in aqueous medium (PCM) are shown in brackets.

TABLE 7: ZPE-Corrected Barrier Energies (∆E) and Enthalpy (∆H) and Free Energy (∆G) Changes (kcal/mol) for the G(-H)- + TyrOH f G + TyrO- Reaction G(-H1)-

G(-H2a)-

G(-H9)- a

level of theory

∆E

∆H

∆G

∆E

∆H

∆G

∆E

∆H

∆G

B3LYP/6-31G** B3LYP/6-311++G** B3LYP/6-311++G** (ε ) 80)b

-1.28 -0.79 -3.74 (-1.66)

-1.49 -1.00 -3.95 (-1.87)

-0.83 -0.34 -3.29 (-1.21)

-1.63 -1.41 -2.03 (-1.65)

-1.81 -1.57 -2.14 (-1.83)

-1.33 -1.09 -1.26 (-1.35)

4.04 3.02 -2.47 (10.23)

2.97 1.95 -3.54 (9.16)

6.72 5.70 -0.21 (12.91)

a

Second-order saddle point. b Obtained by the polarized continum model (values in parentheses obtained by the Onsager model).

1.10 Å, SsH distance of 1.473Å) (Figure S2b, Supporting Information). However, the overall reaction for the G(-H2b)repair was still found to be endothermic by ∼3 kcal/mol. Nevertheless, the repair reactions of the G(-H1)- and G(-H2a)- by TyrOH were found to be exothermic in nature (Table S11, Supporting Information). The barrier energies associated with the repair of G(-H1)and G(-H2a)- were calculated to be negative in both the gas phase and aqueous medium. These values are presented in Table 7. Although we could not find genuine transition states for the reactions of G(-H2b)- and G(-H9)- with TyrOH, we could locate a saddle point of order 2 for the latter reaction. The ZPEcorrected total energy and thermal-energy-corrected Gibbs free energy change required to reach this saddle point were found to be ∼3 and ∼6 kcal/mol, respectively, at the B3LYP/6311++G** level of theory (Table 7). These results indicate that this reaction would not occur rapidly in the gas phase. The endothermicities associated with the repair of G(-H2b)- and G(-H9)- by tyrosine also indicate that these reactions might not be favored. However, as the repairs of G(-H1)- and

G(-H2a)- by tyrosine require no barrier, which is accomplished by H-atom and electron transfer, these reactions would be very fast (rate constants of 1013-1015 s-1; Table S12, Supporting Information). The imaginary frequencies at the TSs were found to lie in the range of 600.3-780.3 cm-1 (Figure 7). The NPA charge densities associated with the product complexes of the above reactions suggest that the transferred electron is located mostly on the oxygen atom (80-90%) (Table 8). In this case, the HOMO is distributed over the whole tyrosine moiety, whereas the LUMO is located on guanine (Figure S1e,f, Supporting Information). Thus, the repair of guanine anions by cysteine and tyrosine in both the gas phase and aqueous medium is initiated by accepting one H atom from these amino acids, simultaneously donating its unpaired electron to them in one step (Figure 8). As a result, normal guanine is retrieved, and the amino acids became anions. As the overall reaction involves both H-atom and electron transfer in one step, it can be described as the two-electron-coupled proton-transfer (TECPT) mechanism or the one-step hydrogen-atom- and electron-transfer


Jena et al.

TABLE 8: NPA Charge Densities (Q) on Guanine during the Reaction G(-H)- + TyrOH f G + TyrOB3LYP/6-31G** b

radical -

G(-H1) G(-H2a)G(-H9)-

RC

TS

PC

RC

TS

PC

RC

TS

PC

-0.84 -0.84 -0.85

-0.74 -0.75 -0.73

-0.22 -0.13

-0.88 -0.85 -0.86

-0.73 -0.73 -0.72

-0.16 -0.12

-0.87 -0.85 -0.86

-0.72 -0.73 -0.73

-0.11 -0.10


Figure 8. Guanine anion repair by cysteine (CysSH) and tyrosine (TyrOH) through the two-electron-coupled proton-transfer (TECPT) mechanism or the one-step hydrogen- and electron-transfer (OSHET) mechanism. Here, -e- and +H · refer to loss of an electron and gain of a hydrogen atom, respectively, by guanine anion.

TABLE 9: ZPE-Corrected Barrier Energies (∆E) and Enthalpy (∆H) and Free Energy (∆G) Changes (kcal/mol) for the Guanyl Radical and Anion Repair Reactions Solvated in Three Explicit Water Molecules B3LYP/6-31G** species G(-H1)• + CysSH G(-H2a)• + CysSH G(-H1)• + TyrOH G(-H2a)• + TyrOH

B3LYP/6-311++G** (ε ) 80)a

3LYP/6-311++G**

∆E

∆H

∆G

Radical 0.02 -1.57 5.13 10.15 9.74 11.10 -0.42 -0.86 0.94 0.63 -0.42 3.09

B3LYP/6-311++G** ∆E 5.80 9.46 1.33 2.36

∆Ga

∆H 4.21 9.05 0.89 1.31

11.01 (2.03) 10.41 (4.03) 2.69 (-1.03) 4.82 (3.69)

b


in the corresponding radical repair reactions. The reaction rate constants (Table S13, Supporting Information) for guanine radical repair by CysSH were calculated to be on the order of 105 s-1, and the corresponding rate constants involving TyrOH were found to lie in the range of 109-1010 s-1 (Table S13, Supporting Information). However, the reaction rate constants involving the guanine anion repair are higher, lying in the range of 1011-1013 s-1 (Table S13, Supporting Information). A comparison of the results obtained using the PCM and Onsager solvation models with those obtained considering three specific water molecules (Table 9) suggests that, in cases of weakly hydrogen-bonded systems, the latter solvation model would represent the aqueous medium more accurately than the former. As the barrier-free energy changes and the corresponding reaction rate constants involved in the above reactions are low and high, respectively, the repair reaction by these amino acids would occur efficiently in biological media. 5. Biological Significance

(OSHET) mechanism. This type of reaction has already been observed for the reduction of neutral radicals by NADH analogues.53

As the barrier-free energy changes and the corresponding reaction rate constants involved in guanyl radical and anion repair by cysteine and tyrosine are low and high, respectively, normal guanine can be retrieved from both of its damaged forms, that is, the radical and anionic forms, by redox amino acids. Therefore, radiation-induced guanine damages should be repaired before the damaged base becomes involved in DNA causing deleterious consequences. This is probably the reason why biological systems are largely safe from disorders under normal conditions. It is quite interesting to note that, during the repair processes, the amino acids show flexibility and thus can acquire radical or anionic character.

4. Solvent Effect Due to Specific Water Molecules

6. Conclusions

As the results obtained by the two different solvation models are appreciably different, we investigated the effect of specific water molecules on the various reaction steps. For this purpose, we considered three explicit water molecules hydrogen-bonded to the N3, O6, N7, and N9 positions of each of the radicals and anions of guanine. These positions have been suggested to be the dominant sites for solvent interactions in DNA.54,55 As the H1 and H2a protons of guanine are most sensitive toward radiation-induced damage,20-22 we studied the effect of three specific water molecules in the repair of radicals and anions of G(-H1) and G(-H2a) by both CysSH and TyrOH. These results are presented in Table 9. Structures of the related transition states obtained by geometry optimization at the B3LYP/6-31G** level of theory are shown in Figure S3 (Supporting Information). From Table 9, we find that, usually, an appreciably higher barrier energy is required in the repair of the guanyl radical by CysSH than by TyrOH. However, the barrier energies required for the repair of guanine anion by both CysSH and TyrOH are comparable, and the barrier energies involved in these reactions are appreciably smaller than those

The following are the main conclusions of the present study: (a) Direct radiation-induced DNA damage in terms of the formation of guanine radicals can be repaired by the amino acids cysteine and tyrosine through a hydrogen-atom-transfer (HT) mechanism in both the gas phase and aqueous medium. As the barrier energies and reaction rate constants involved in these processes are low and high, respectively, the repair process should occur efficiently in biological media. (b) Indirect radiation-induced DNA damage in terms of the formation of guanine anions can also be repaired by the amino acids cysteine and tyrosine following a two-electron-coupled proton-transfer (TECPT) mechanism or a one-step hydrogenand electron-transfer (OSHET) mechanism in both the gas phase and aqueous medium. As the barrier energies and reaction rate constants involved in these processes are even lower and higher, respectively, than those related to the guanine radical repair, repair of the guanyl anion should be ultrafast in biological media. Thus, the present study reveals the interesting fact that normal guanine can be retrieved from its radical and anionic damaged

G(-H1)- + CysSH 0.38 0.24 G(-H2a)- + CysSH 0.81 G(-H1)- + TyrOH G(-H2a)- + TyrOH -0.85

Anion 0.10 1.12 1.41 1.13 2.15 (3.39) -0.08 1.38 1.38 1.06 2.52 (2.42) 0.55 2.06 1.20 0.94 2.45 (-1.21) -0.99 -0.80 -0.80 -0.94 -0.75 (-1.35)

a Barrier-free energy changes obtained by the Onsager solvation model are shown in parentheses for comparison.

Protection Against DNA Damage by Amino Acids forms by redox amino acids, before the damaged forms can become involved in biochemical processes. Acknowledgment. N.R.J. is grateful to Deutsches Krebsforschungszentrum (DKFZ) for a generous guest scientist fellowship. He also coordially thanks Professor Suhai’s group members for their support during his stay at DKFZ. Supporting Information Available: Relative stabilities of the different complexes involved in the reactions of guanine radicals and anions with CysSH and TyrOH, reaction rate constants and exothermicities for the same reactions, and reaction rate constants for the same reactions in the presence of three explicit water molecules (Tables S1-S13). Spin density distributions and HOMO and LUMO patterns for the product complexes of the reactions of guanine radicals and anions with CysSH and TyrOH (Figure S1). Structures of various species related to reactions of G(-H2b)• and G(-H9)• with TyrOH (Figure S2). Structures of transition states in the reactions of guanine radicals and anions with CysSH and TyrOH in the presence of three explicit water molecules (Figure S3). This information is available free of charge via the Internet at http://pubs.acs.org. References and Notes (1) (a) Ames, B. N. Free Radical Res. Commun. 1989, 7, 121–128. (b) Barnett, Y. A.; Barnett, C. R. Mech. Ageing DeV. 1998, 102, 165–176. (2) Loft, S.; Poulsen, H. E. J. Mol. Med. 1996, 74, 297–312. (3) Mecocci, P.; MacGarvey, U.; Beal, M. F. J. J. Neurochem. 1998, 71, 2034–2040. (4) von Sonntag, C. The Chemical Basis of Radiation Biology; Taylor and Francis: London, 1987. (5) Burrows, C. J.; Muller, J. G. Chem. ReV. 1998, 98, 1109–1151. (6) Cadet, J.; Douki, T.; Gasparutto, D.; Ravanat, J.-L. Mutat. Res. 2003, 531, 5–23. (7) (a) Scholes, M. L.; Schuchmann, M. N.; von Sonntag, C. Int. J. Radiat. Biol. 1992, 61, 443–449. (b) Sharma, K. K.; Purkayastha, S.; Bernhard, W. A. Radiat. Res. 2007, 167, 501–507. (8) (a) Kumar, A.; Sevilla, M. D. J. Am. Chem. Soc. 2008, 130, 2130– 2131. (b) Swiderek, P. Angew. Chem., Int. Ed. 2006, 45, 4056. (c) Martin, F.; Burrow, P. D.; Cai, Z.; Cloutier, P.; Haunting, D.; Sanche, L. Phys. ReV. Lett. 2004, 93, 068101. (9) (a) Cooke, M.; Evans, M. D.; DizDaroglu, M.; Lunec, J. FASB J. 2003, 17, 1195–1214. (b) Arimoto-Kobayashi, S.; Ando, Y.; Horai, Y.; Okamoto, K.; Hayatsu, H.; Lowe, J. E.; Greeen, H. L. Carcinogenesis 2002, 23, 1537–1540. (10) (a) Perrier, S.; Hau, J.; Gasparutto, D.; Cadet, J.; Favier, A.; Ravanat, J.-L. J. Am. Chem. Soc. 2006, 128, 5703–5710. (b) Xu, X.; Muller, J. G.; Ye, Y.; Burrows, C. J. J. Am. Chem. Soc. 2008, 130, 703–709. (11) (a) Giese, B.; Amaudrut, J.; Ko¨hler, A.-K.; Spormann, M.; Wessely, S. Nature 2001, 412, 318–320. (b) Ghosh, A. K.; Schuster, G. B. J. Am. Chem. Soc. 2006, 128, 4172–4173. (12) Steenken, S. Chem. ReV. 1989, 89, 503–520. (13) Kupan, A.; Saulier, A.; Broussy, S.; Seguy, C.; Pratviel, G.; Meunier, B. ChemBioChem 2006, 7, 125–133. (14) (a) Douki, T.; Cadet, J. Int. J. Radiat. Biol. 1999, 75, 571–581. (b) Llano, J.; Eriksson, L. A. Phys. Chem. Chem. Phys. 2004, 6, 4707–4713. (15) (a) Luo, W.; Muller, J. G.; Burrows, C. J. Org. Lett. 2001, 3, 2801– 2804. (b) Misiaszek, R.; Cream, C.; Joffe, A.; Geacintov, N. E. J. Biol. Chem. 2004, 279, 32106–32115. (16) Kobayashi, K.; Tagawa, S. J. Am. Chem. Soc. 2003, 125, 10213– 10218. (17) (a) Stemp, E. D. A.; Arkin, M. R.; Barton, J. K. J. Am. Chem. Soc. 1997, 119, 2921. (b) Shafirovich, V.; Dourandin, A.; Huang, W.; Geacintov, N. E. J. Biol. Chem. 2001, 276, 24621. (18) (a) Schiemann, O.; Turro, N. J.; Barton, J. K. J. Phys. Chem. B 2000, 104, 7214. (b) Hildebrand, K.; Schulte-Frohlinde, D. Free Radical Res. Commun. 1990, 11, 195. (19) Furukawa, M.; Kato, H. S.; Taniguchi, M.; Kawai, T.; Hatsui, T.; Kosugi, N.; Yoshida, T.; Aida, M.; Kawai, M. Phys. ReV. B 2007, 75, 045119. (20) Candeias, L. P.; Steenken, S. J. Am. Chem. Soc. 1989, 111, 1094. (b) Adhikari, A.; Kumar, A.; Becker, D.; Sevilla, M. D. J. Phys. Chem. B 2006, 110, 24171–24180.

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