Interaction of Guanine, Its Anions, and Radicals with Lysine in

Apr 14, 2007 - In a similar way, the adiabatic proton affinity (APA) can be defined. The atomic numbering schemes adopted for guanine and lysine in th...
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J. Phys. Chem. B 2007, 111, 5418-5424

Interaction of Guanine, Its Anions, and Radicals with Lysine in Different Charge States N. R. Jena and P. C. Mishra* Department of Physics, Banaras Hindu UniVersity, Varanasi-221005, India ReceiVed: January 14, 2007; In Final Form: February 25, 2007

Modification in DNA or protein structure can severely affect DNA-protein interactions and the functioning of biological systems. Some new insights into radiation-induced effects of guanine-lysine interactions have been obtained here by theoretical investigations. Geometries of zwitterionic and non-zwitterionic lysine in different charge states (neutral, radical cation, and protonated cation) were optimized employing the B3LYP/ 6-31G** and B3LYP/AUG-cc-pVDZ levels of hybrid density functional theory (DFT) and using the secondorder Møller-Plesset perturbation theory along with the 6-31G** basis set. In the case of neutral lysine in the gas phase, no zwitterionic structure was obtained. The non-zwitterionic structures of lysine in radical and protonated cationic forms are appreciably more stable than the corresponding zwitterionic structures in the gas phase as obtained at all levels of theory employed here. Binding of guanine and different dehydrogenated guanine radicals with lysine in different charge states was studied at the B3LYP/6-31G** level of DFT. When guanine makes a complex with the lysine radical cation, large amounts of spin and positive charge densities are transferred from the lysine radical cation to guanine and the guanine is thus converted from its normal form to the radical cationic form. Complexation of the lysine radical cation with the H1-hydrogenabstracted guanine radical leads to CO2 liberation and proton transfer from lysine. These results are compared with the available experimental ones.

1. Introduction Protein-DNA interactions are of paramount importance from the point of view of gene expression, regulation, and other nuclear processes.1-4 RNA-protein interactions are also very important due to the diverse structures and functions of RNA.3 In RNA, the individual bases are either involved in non-Watson Crick base pairs or are unpaired.3 At the functional level, RNA bases interact with different amino acids. Structural modifications of any of the amino acids or bases may affect functions of living cells. For example, exposure of DNA to ionizing radiation can lead to several deleterious effects, e.g., single and double DNA strand breaks, mutation, etc.5-8 Further, amino acid residues of DNA-binding proteins may repair oxidative DNA damage.9 Hence an understanding of various interactions involving individual nucleic acid bases and amino acids at the molecular level is essential. Interaction of high-energy radiation with DNA produces holes and electrons, migration of which in DNA gives rise to base radicals and ions.10,11 Dissociative electron attachment reactions, e.g., dehydrogenation reactions caused by low-energy electrons, can induce DNA damage by resonant transfer of energy and charge.12,13 Due to this reason, properties of DNA and RNA base radicals and ions and their effects on DNA base pairing have been studied extensively.14-19 However, interactions of dehydrogenated DNA bases with other important biomolecules, e.g., the amino acids, have rarely been studied. The effect of pH on structures and spectra of different amino acids has been studied by X-ray spectroscopy of liquid microjets.20 It was found that at basic pH (pH >10) and in aqueous media, neutral lysine exists in the zwitterionic form, where the R-amino group is deprotonated.20 In this state, lysine has an * Address for correspondence to this author. E-mail: [email protected], [email protected].

extended side chain without any intramolecular hydrogen bonding.20 A similar structure was found earlier in other studies in the gas phase.21,22 However, some experimental and density functional studies in the gas phase have suggested a cyclic structure for neutral lysine with an intramolecular hydrogen bond between the hydrogen atom of the carboxylic group and the nitrogen atom of the side chain amino group.23-25 Normally, lysine (Lys) exists in a cationic form in aqueous media at neutral pH.20 Due to high proton affinity and one extra amino group, it acquires the protonated form (LysH+) easily.26 The lowest energy structure of LysH+ has been found to be cyclic with an intramolecular hydrogen bond between the NH3+ and NH2 groups.21-23,27 The zwitterionic form of LysH+ has been found to be less stable than the non-zwitterionic form.22,26 However, on the basis of vibrational analysis, the structure of the lysine radical cation has been suggested to be zwitterionic in the aqueous environment, with extended side chain.28 Thus the structures of Lys in different charge states are not yet clearly known. Amino acids exist in non-zwitterionic forms in the gas phase.23 However, interactions of metals, ions, solvent molecules, or other chemical species with amino acids can cause structural perturbation stabilizing the respective zwitterionic forms.23,25,26,29 Further, such interactions can also produce different radical cations and induce fragmentation and protontransfer reactions.30-32 It has been found both experimentally and theoretically that the carboxylic group of glycine can donate a proton barrierlessly to the uracil anion during their interaction.33 Another similar result was also obtained for the interaction of X-irradiated substituted glycine with cytosine.34 Although the G-Lys interaction was found to be prominent among the different DNA base-amino acid interactions,4,35 it has not been studied in detail. Therefore, it is desirable to examine whether interaction of guanine with Lys can induce structural perturba-

10.1021/jp0703004 CCC: $37.00 © 2007 American Chemical Society Published on Web 04/14/2007

Guanine-Lysine Interaction tions in the latter molecule. Further, as dehydrogenation of guanine is a common radiation-induced DNA damage, it is worthwhile to study the interaction of dehydrogenated guanine with lysine in different charge states. In view of the reasons mentioned above, we have studied the following systems and the interactions involved in the same: (i) structures and stabilities of lysine in different charge states, (ii) interaction of neutral lysine with the dehydrogenated guanine radical and the deprotonated guanine anion, and (iii) interaction of the radical cation and the protonated cation of lysine with the dehydrogenated guanine radical. This study is expected to provide new insight into radiation-induced effects on DNA-protein interactions. 2. Computational Details Geometries of neutral non-zwitterionic lysine, and those of zwitterionic and non-zwitterionic forms of radical and protonated cationic lysine were optimized by using the hybrid density functional (B3LYP)36-38 theory employing the 6-31G** and AUG-cc-pVDZ basis sets. These structures were also optimized by using the second-order Møller-Plesset perturbation (MP2) theory39 and the 6-31G** basis set. Isolated dehydrogenated guanine radicals and deprotonated guanine anions were optimized at the B3LYP/6-31G** level of density functional theory. Complexes of dehydrogenated and deprotonated guanine with neutral lysine and complexes of the dehydrogenated guanine radical with the radical cation and the protonated cation of lysine were also optimized at the B3LYP/6-31G** level of density functional theory. While studying the interaction of guanine with lysine in different charge states, we considered the most stable conformation of the isolated latter species. Vibrational frequency analysis was carried out for all cases at the B3LYP/6-31G** and, in addition, for all species related to lysine at the B3LYP/ AUG-cc-pVDZ level of density functional theory to ensure that the optimized structures corresponded to minima on the potential energy surfaces. Zero-point energy (ZPE) corrections to total energy and thermal energy corrections to enthalpy at T ) 298.15 K for lysine in different charge states and for different guanine-lysine complexes were made in all the B3LYP geometry optimization calculations. The ZPE corrections obtained at the B3LYP/AUGcc-pVDZ level of theory were also considered to be valid for MP2/6-31G** geometry optimization calculations for lysine in different charge states since vibrational analysis could not be carried out in the latter level of calculations. All the calculations were performed employing the Windows versions of the Gaussian 98 (G98W)40 and Gaussian 03 (G03W)41 programs. For visualization of the optimized structures and vibrations, the GaussView program42 was employed. 3. Results and Discussion 3.1. Stabilities of Guanine Radicals and Anions. The calculated relative ZPE-corrected total energies and the thermal energy-corrected enthalpy change of different optimized dehydrogenated guanine radicals, the corresponding deprotonated guanine anions, and adiabatic electron affinities (AEAs) of the deprotonated guanine anions are presented in Table 1. The AEAs were obtained using the formula18,43

AEA ) E(optimized neutral system) - E(optimized anion) where E stands for the ZPE-corrected total energy. In a similar way, the adiabatic proton affinity (APA) can be defined. The atomic numbering schemes adopted for guanine and lysine in

J. Phys. Chem. B, Vol. 111, No. 19, 2007 5419 TABLE 1: Relative ZPE-Corrected Total Energies (∆E) and the Thermal Energy-Corrected Enthalpy Changes (∆H) (kcal/mol) (T ) 298.15 K) of Different Optimized Dehydrogenated Guanine Radicals and Corresponding Deprotonated Guanine Anions and Adiabatic Electron Affinities (AEA) (eV) of Deprotonated Guanine Anions guanine radical G(-H1)•

G(-H2a)• G(-H2b)· G(-H8)· G(-H9)·

∆E 0.00 -4.47 0.24 23.78 -1.78

∆H 0.00 -4.95 -0.21 23.63 -1.87

guanine anion G(-H1)-

G(-H2a)G(-H2b)G(-H8)G(-H9)-

∆E

∆H

AEA

0.00 -2.86 2.29 42.41 -4.54

0.00 -2.80 2.39 42.69 -4.48

2.28 2.21 2.19 1.47 2.40

this study are shown in Figure 1. The stabilities of different dehydrogenated guanine radicals follow the order G(-H2a) > G(-H9) > G(-H1) g G(-H2b) > G(-H8) (Table 1). If we consider the thermal energy-corrected enthalpy changes, this order changes to G(-H2a) > G(-H9) > G(-H2b) g G(-H1) > G(-H8) (Table 1). Abstraction of the H2a atom from the N2 site of guanine is found to result in the most stable radical (Table 1). The G(-H2a) radical is more stable than the G(-H1) radical by ∼4.5 kcal/mol (Table 1). This difference was found to be ∼5 kcal/mol at the B3LYP/DZP++ level of theory in an earlier study.44 Similar results have also been obtained by other authors.45 The difference in ZPE-corrected total energies and the thermal energy-corrected enthalpy changes between G(-H2a) and G(-H2b) radicals are ∼4 kcal/mol each (Table 1). Among the different optimized deprotonated guanine anions, the G(-H9) anion is found to be most stable (Table 1). The stabilities of the different deprotonated guanine anions follow the order G(-H9)- > G(-H2a)- > G(-H1) - > G(-H2b)- > G(-H8)- whether we consider ZPE-corrected total energies or the thermal energy-corrected enthalpy changes (Table 1). The G(-H1) and G(-H2a) deprotonated anions are found to be ∼4.5 and ∼1.7 kcal/mol less stable than the G(-H9) deprotonated anion if we consider the ZPE-corrected total energies (Table 1). The AEAs of the different deprotonated guanine anions lie between 1.47 and 2.40 eV (Table 1). The maximum and minimum values of AEAs correspond to G(-H9) and G(-H8) anions, respectively. A similar result was also previously obtained by Luo et al.44 These results show that the N9 site of guanine can be easily deprotonated while deprotonation of the C8 site would be most unfavored. 3.2. Structures of Lysine in Different Charge States. The zwitterionic structure of lysine was found to be unstable in the gas phase. Optimized structures and intramolecular hydrogenbonding distances (Å) in neutral non-zwitterionic lysine and zwitterionic and non-zwitterionic forms of lysine radical cation and protonated lysine cation obtained at the B3LYP/AUG-ccpVDZ level of density functional theory are presented in Figure 2. The structure of neutral non-zwitterionic lysine shown in Figure 2a corresponds to the lowest total energy structure at all the levels of theory employed here. In this structure, the COOH group is in the trans configuration and there is a strong intramolecular hydrogen bond between the H atom of the COOH group and the N atom of the terminal NH2 group, the H(COOH)-N(NH2) hydrogen-bonding distance being 1.827 Å (Figure 2a). This structure for neutral lysine was also suggested previously to be most stable.23-25 However, in some other previous studies, the structure of Figure 2b was found to be most stable.21,22 In the present study, ZPE-corrected total energies show that the structure of Figure 2b is 2.11 and 0.51 kcal/mol less stable than the structure of Figure 2a as obtained at the B3LYP/6-31G** and B3LYP/AUG-cc-pVDZ levels of

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Figure 1. Atomic numbering scheme in guanine and lysine.

theory, respectively. Thus the B3LYP/AUG-cc-pVDZ calculations predict that the structures of Figures 2a and 2b would both occur under ambient conditions, though with different abundances. The corresponding energy difference at the MP2/631G** level of theory was found to be 3.53 kcal/mol. In general, MP2/6-31G** results would be expected to be more accurate than those obtained by B3LYP/6-31G** calculations in view of a better treatment of electron correlation in the former approach. The structure shown in Figure 2c represents the most stable non-zwitterionic structure of the lysine radical cation. In this case, the COOH group is in the syn configuration and there is a weak intramolecular hydrogen bond between the O atom of the COOH group and an H atom of the NH2 group, the O(COOH)-H(NH2) interatomic distance being 2.247 Å (Figure 2c). In the most stable optimized zwitterionic form of the lysine radical cation, none of the oxygen atoms of the COO group are involved in intramolecular hydrogen bonding (Figure 2d). The OCO angle is appreciably less in the zwitterionic form (∼112°) than the corresponding angle in the non-zwiterionic form (∼124°) of the lysine radical cation. This zwitterionic structure (Figure 2d) after ZPE correction is found to be less stable than the non-zwitterionic structure (Figure 2c) by 9.40 and 11.28 kcal/mol at the B3LYP/6-31G** and B3LYP/AUGcc-pVDZ levels of theory, respectively. The corresponding energy difference at the MP2/6-31G** level of theory was found to be 10.11 kcal/mol. Hence, only the non-zwitterionic structure of lysine radical cation is likely to be observed in the gas phase. The most stable structure of the protonated lysine cation is shown in Figure 2e. The COOH group in this case prefers the syn configuration as in Figure 2c. Further, in this case, there is a strong intramolecular hydrogen bond between an H atom of the NH3+ group and the N atom of the side chain NH2 group. A similar structure has also been obtained previously for the protonated lysine radical cation.21-23,26,27 In one of the previous studies,26 it was remarked that the protonated amino group is involved in two intramolecular hydrogen bonds, one with the N atom of the side chain NH2 group and the other with the O atom of the COOH group (Figure 2e). We found the H(NH3+)N(NH2) and H(NH3+)-O(COOH) hydrogen-bonding distances at the B3LYP/AUG-cc-pVDZ level of theory to be 1.641 and 2.656 Å, respectively (Figure 2e). Thus, it seems that there would be only one intramolecular hydrogen bond in the protonated lysine cation (Figure 2e). In the optimized most stable zwitterionic structure of the protonated lysine cation, two strong intramolecular hydrogen bonds are formed involving the H atoms of the two protonated amino groups and the nearby O atoms of the OCO group (Figure 2f). The zwitterionic structure of the protonated lysine cation (Figure 2f) after ZPE correction is found to be less stable than the corresponding non-zwitterionic structure by 6.04

Figure 2. Optimized geometries obtained at the B3LYP/AUG-ccpVDZ level of theory: neutral lysine (a, b), lysine radical cation (c, d), and protonated lysine cation (e, f). Some interatomic and hydrogen bond distances (Å) (underlined) and CHelpG charges (in the unit of electronic charges) are given.

and 4.97 kcal/mol at the B3LYP/6-31G** and B3LYP/AUGcc-pVDZ levels of theory, respectively, while at the MP2/631G** level of theory, the corresponding energy difference was found to be 6.06 kcal/mol. This difference was previously found to be 10.52 kcal/mol at the B3LYP/6-31G* level of theory.26 Hence, it appears that only the non-zwitterionic structure of the protonated lysine cation would be observed in the gas phase. The CHelpG charges located at the various sites of lysine obtained at the B3LYP/AUG-cc-pVDZ level of theory are shown in Figure 2. It is found that charges are strongly rearranged in going from the non-zwitterionic to the corresponding zwitterionic structures (Figure 2). 3.3. Interaction between Guanine and Lysine and the Related Species. 3.3.A. Guanine or Dehydrogenated Guanine Radical and Neutral Lysine. It is known that the terminal amino group of lysine makes two hydrogen bonds with the O6 and N7 atoms of guanine.3,35 However, among several optimized conformations of the G-lys complex, we found the most stable structure to be that in which there are three hydrogen bonds between the two molecules, i.e., the H7a(Lys)-O6(G), O1b-

Guanine-Lysine Interaction

J. Phys. Chem. B, Vol. 111, No. 19, 2007 5421 TABLE 2: Relative ZPE-Corrected Total Energies (∆E) and the Thermal Energy-Corrected Enthalpy Changes (∆H) (kcal/mol) (T ) 298.15 K) of Different Optimized Dehydrogenated Guanine Radical-Lysine Complexes complexes

∆E

∆H

[G(-H1)•-Lys]

0.00 -0.33 -0.15 17.36 -8.96

0.00 -0.52 -0.29 17.31 -9.18

[G(-H2a)•-Lys] [G(-H2b)•-Lys] [G(-H8)•-Lys] [G(-H9)•-Lys]

TABLE 3: Relative ZPE-Corrected Total Energies (∆E) and the Thermal Energy-Corrected Enthalpy Changes (∆H) (kcal/mol) (T ) 298.15 K) and Adiabatic Electron Affinities (AEAs) (eV) of Different Deprotonated Guanine Anion-Lysine Complexesa

a

Figure 3. Optimized geometries of complexes obtained at the B3LYP/ 6-31G** level of theory: G-Lys (a), [G(-H1)-]-Lys (b), [G(-H2a)-]Lys (c), [G(-H2b)-]-Lys (d), [G(-H8)-]-Lys (e), and [G(-H9)-]-Lys (f). Some interatomic distances including hydrogen bond distances (Å) are shown.

(Lys)-H1(G), and O1a(Lys)-H2a(G), the interatomic distances being 1.946, 1.870, and 2.034 Å respectively (Figure 3a). Relative ZPE-corrected total energies and the thermal energycorrected enthalpy changes for five different optimized complexes between the dehydrogenated guanine radical and lysine are presented in Table 2. From this table, it is clear that among the five complexes, the H9-abstracted guanine radical makes the most stable complex with lysine. The stabilities of different complexes follow the order G(-H9)•-Lys > G(-H2a)•-Lys > G(-H2b)•-Lys > G(-H1)•-Lys > G(-H8)•-Lys (Table 2). This result shows that the N9-H bond of isolated guanine that will be replaced by the N9-sugar bond in DNA can be dissociated most easily. This is in agreement with the previous results.14,17

complexes

∆E

∆H

AEAs

[G(-H1)-]-Lys [G(-H2a)-]-Lys [G(-H2b)-]-Lys [G(-H8)-]-Lys [G(-H9)-]-Lys

0.00 8.51 10.94 48.53 2.47

0.00 8.49 11.06 48.85 2.60

2.83 2.44 2.35 1.48 2.33

Optimized structures are shown in Figure 3.

3.3.B. Deprotonated Guanine Anion and Neutral Lysine. Optimized structures of the five different complexes between the deprotonated guanine anion and the neutral lysine are shown in Figures 3b-f. In all these cases, hydrogen bonds involve the atoms or groups attached to the six-membered ring of the deprotonated guanine. Relative ZPE-corrected total energies, the thermal energy-corrected enthalpy changes, and AEAs of these complexes are presented in Table 3. Stabilities of these complexes follow the order [G(-H1)-]-Lys > [G(-H9)-]-Lys > [G(-H2a)-]-Lys > [G(-H2b)-]-Lys > [G(-H8)-]-Lys (Table 3). Thus, deprotonation of guanine from the N1 position produces a more stable complex with lysine by ∼2.5 kcal/mol than that in which the N9 position of guanine is deprotonated. The calculated AEAs of different deprotonated guanine-lysine complexes lie between 1.48 and 2.83 eV (Table 3), the minimum and maximum values corresponding to [G(-H8)-]-Lys and [G(H1)-]-Lys, respectively. These results show that the N1 position of guanine is more easily deprotonated than any other position of the molecule when it makes a complex with lysine. 3.3.C. Dehydrogenated Guanine Radical and Lysine Radical Cation. Optimized structures of the guanine-lysine radical cation complex (G-Lys•+) and different dehydrogenated guanine radical-lysine radical cation complexes are shown in Figure 4. In the most stable optimized G-Lys•+ complex, Lys•+ is in the zwitterionic form, which is quite different from its isolated most stable zwitterionic form (Figure 2d). This complex is stabilized by three strong hydrogen bonds, i.e., H7a(Lys•+)O6(G), O1b(Lys•+)-H1(G), and O1a(Lys•+)-H2a(G), the hydrogen-bonding distances being 2.142, 1.511, and 1.644 Å, respectively (Figures 1 and 4a). The first hydrogen bond is quite weak while the latter two hydrogen bonds involving the COO and NH3+ groups of zwitterionic lysine are very strong. Large amounts of positive charge (∼1) and spin (∼0.8) densities are transferred from the lysine radical cation to guanine in the complex (Figure 4a). Thus, in this complex, guanine is in its radical cation form (Figure 4a). The complex of the lysine radical cation and the dehydrogenated guanine radical at the N1 position has four possible structures S1, S2, S3, and S4 (Figures 4b-e). In structure S1, most of the positive charge resides on the lysine moiety (Figure 4b). In each of the structures S2-S4, a CO2 fragment is formed

5422 J. Phys. Chem. B, Vol. 111, No. 19, 2007

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Figure 4. Optimized geometries of complexes obtained at the B3LYP/6-31G** level of theory: G-Lys•+ (a), [G(-H1)·]-(Lys)•+ (b-e), [G(-H2a)•](Lys)•+ (f), [G(-H2b)•]-(Lys).+ (g), [G(-H8)•]-(Lys)•+ (h), and [G(-H9)•]-(Lys).+ (i). Some interatomic distances including hydrogen bond distances (Å) and total CHelpG charges (in brackets) on lysine and guanine moieties are shown.

due to dissociation of the lysine cation and it is followed by a strong structural rearrangement in the complexes (Figures 4c-e). Dissociation of CO2 from the metal-induced lysine radical cation and the protonated lysine cation was also previously observed experimentally.31 Liberation of CO2 from the isolated deprotonated lysine cation has also been observed experimentally.46 In structure S2, a proton is transferred from the terminal NH3+ group of lysine to the O6 atom of guanine (Figure 4c). Thus, guanine is converted from the keto to the enol form. This enol form of guanine has also been observed experimentally.47,48 Most of the positive charges still reside on the remaining part of the lysine radical cation (Figure 4c). In structure S3, a proton is transferred from the side-chain NH2 group to the N1 position of guanine (Figure 4d). In this case, ∼0.6 positive charge resides on the guanine moiety, i.e., guanine would behave like its cation (Figure 4d). After a proton is transferred from the O6 site of guanine (Figure 4d) to the terminal NH2 group in structure S4, a strong movement of the remaining fragment of lysine occurred (Figure 4e). In this case, guanine is almost in the neutral, normal

form while lysine is in the radical cation form (Figure 4e). In biological systems, the liberation of CO2 from lysine would lead to protein fragmentation and genome instability. There are three hydrogen bonds in all other complexes between the dehydrogenated guanine radical and the lysine radical cation (Figures 4f-i). In these cases, no fragmentation of the lysine moiety takes place (Figure 4). In the G(-H2b)•Lys•+, G(-H8)•-Lys•+, and G(-H9)•-Lys•+ complexes (Figure 4g-i), guanine is in the cationic form. ZPE-corrected total energies, the thermal energy-corrected enthalpy changes, and APAs of the different complexes between dehydrogenated guanine radicals and the lysine radical cation are presented in Table 4. Among these complexes, S4 is most stable. The stabilities of the different complexes follow the order G(-H1)•-Lys•+ (S4) > G(-H1)•-Lys•+ (S3) > G(-H1)•-Lys•+ (S2) > G(-H9)•-Lys•+ > G(-H2a)•-Lys•+ > G(-H2b)•-Lys•+ > G(-H1)•-Lys•+ (S1) > G(-H8)•-Lys•+ (Table 4). The highest stability of S4 shows that dissociation of CO2 and proton transfer from the lysine radical cation due to its interaction with

Guanine-Lysine Interaction

J. Phys. Chem. B, Vol. 111, No. 19, 2007 5423

TABLE 4: Relative ZPE-Corrected Total Energies (∆E) and the Thermal Energy-Corrected Enthalpy Changes (∆H) (kcal/mol) (T ) 298.15 K) and Adiabatic Proton Affinities (APAs) (eV) of Different Dehydrogenated Guanine Radical-Lysine Radical Cation Complexesa complexes

∆E

∆H

APAs

[G(-H1)·]-Lys•+ (S1)b [G(-H1)·]-Lys•+ (S2)b [G(-H1)·]-Lys•+ (S3)b [G(-H1)·]-Lys•+ (S4)b [G(-H2a)·]-Lys•+ [G(-H2b)·]-Lys•+ [G(-H8)·]-Lys•+ [G(-H9)·]-Lys•+

0.00 -69.89 -81.53 -100.76 -4.22 -3.91 9.03 -27.04

0.00 -68.87 -79.98 -99.18 -4.09 -3.85 9.15 -26.93

-7.48 -4.45 -3.95 -3.75 -7.31 -7.32 -7.12 -6.70

a Optimized structures of dehydrogenated guanine radical-lysine radical cation complexes are shown in Figure 4. b Optimized structures S1, S2, S3, and S4 are shown in Figure 4, parts b, c, d, and e, respectively.

TABLE 5: Relative ZPE-Corrected Total Energies (∆E) and the Thermal Energy-Corrected Enthalpy Changes (∆H) (kcal/mol) (T ) 298.15 K) and Adiabatic Proton Affinities (APAs) (eV) of Different Dehydrogenated Guanine Radical-Protonated Lysine Cation Complexesa complexes

∆E

∆H

APA

[G(-H1)·]-LysH+ [G(-H2a)·]-LysH+ [G(-H2b)·]-LysH+ [G(-H8)·]-LysH+ [G(-H9)·]-LysH+

0.00 -0.75 4.94 22.27 0.62

0.00 -0.95 4.78 22.59 -0.07

11.12 11.13 10.89 10.90 10.69

a Optimized structures of dehydrogenated guanine radical-protonated lysine cation complexes are shown in Figure 5.

dehydrogenated guanine radical would be a highly probable event. The APAs of the different complexes given above lie in the range -3.73 to -7.48 eV (Table 4). The least APA value is obtained for structure S4 (Table 4, Figure 4e). 3.3.D. Dehydrogenated Guanine Radical and Protonated Lysine Cation. Optimized structures of complexes of guanine and five different dehydrogenated guanine radicals with protonated lysine cation (LysH+) are shown in Figures 5a-f. In the most stable optimized structure of the G-LysH+ complex, the protonated amino group (NH3+) makes two strong hydrogen bonds, one each with the O6 and N7 atoms of guanine (Figure 5a). This is in agreement with both previous experimental and theoretical studies.3,35,49 A significant structural modification of the lysine molecule occurs in going from isolation (Figure 2e) to its complex with guanine (Figure 5a). Radicals of guanine with abstracted hydrogen atoms from N1, N2, and N9 positions of the molecule make three strong hydrogen bonds with LysH+ each (Figures 5b,c,d,f). However, in the G(-H8)•-LysH+ complex only two hydrogen bonds are formed (Figure 5e). Relative ZPE-corrected total energies, the thermal energycorrected enthalpy changes, and adiabatic proton affinities of the dehydrogenated guanine-protonated lysine cation complexes are presented in Table 5. Among the different complexes, the one in which the H2a-hydrogen abstracted guanine makes a complex with the protonated lysine cation is found to be most stable. The stabilities of the different complexes follow the order [G(-H2a)•]-LysH+ > [G(-H1)•]-LysH+ > [G(-H9)•]-LysH+ > [G(-H2b)•]-LysH+ > [G(-H8)•]-LysH+ (Table 5). Broadly speaking, the APAs of these complexes are comparable (Table 5). However, the APAs of the H1- and H2a-abstracted guanine are quite close together and significantly larger than those involving hydrogen abstraction from the other sites of guanine (Table 5).

Figure 5. Optimized geometries of complexes obtained at the B3LYP/ 6-31G** level of theory: G-LysH+ (a), [G(-H1)•]-LysH+ (b), [G(H2a)•]-LysH+ (c), [G(-H2b)•]-LysH+ (d), [G(-H8)•]-LysH+ (e), and [G(H9)•]-LysH+ (f). Some interatomic distances including hydrogen bond distances (Å) are shown.

4. Conclusions The present study leads us to the following conclusions: (i) Abstraction of the H2a atom among the various hydrogen atoms and deprotonation of the N9 site among the various nitrogen sites of guanine are most probable. (ii) In neutral lysine, no zwitterionic structure exists in the gas phase. The non-zwitterionic structures of the lysine radical cation and the protonated lysine cation are appreciably more stable than the corresponding zwitterionic structures in the gas phase as obtained at all the levels of theory employed here.

5424 J. Phys. Chem. B, Vol. 111, No. 19, 2007 (iii) The guanine-lysine and guanine-lysine radical cation complexes are stabilized by three strong hydrogen bonds each. These hydrogen bonds involve the face of guanine that is involved in the GC base pair and the COOH and NH2 groups of lysine. Large amounts of positive charge and spin density get transferred from the lysine radical cation to guanine in the guanine-lysine radical cation complex, due to which guanine is converted from its normal, neutral form to the radical cationic form. Occurrence of this complex in DNA would affect the DNA structure and function severely. (iv) The complexation of the lysine radical cation with the H1-hydrogen-abstracted guanine radical leads to fragmentation of lysine liberating CO2 and a proton from lysine. This complex is much more stable than those in which the lysine radical cation is unfragmented. In biological systems, the liberation of CO2 would lead to protein fragmentation and genome instability. (v) Complexation of guanine with the protonated lysine cation is stabilized by two strong hydrogen bonds involving O6 and N7 positions of guanine and the terminal NH3+ group of the protonated lysine cation. This structure is in agreement with the experimentally observed hydrogen-bonded complex between the two species. Acknowledgment. The authors are thankful to the Council of Scientific and Industrial Research (New Delhi) and the University Grants Commission (New Delhi) for financial support. References and Notes (1) Vigneault, F.; Guerin, S. L. Expert ReV. Proteomics 2005, 2, 705. (2) Echols, H. Science 1986, 233, 1050. (3) Cheng, A. C.; Chen, W. W.; Fuhrmann, C. N.; Frankel, A. D. J. Mol. Biol. 2003, 327, 781. (4) Kim, J.; Bhinge, A. A.; Morgan, X. C.; Iyer, V. R. Nat. Methods 2005, 2, 47. (5) Von Sonntag, C. The Chemical Basis of Radiation Biology; Taylor & Francis: London, UK, 1987; p 221. (6) Becker, D.; Sevilla, M. D. AdV. Radiat. Biol. 1993, 17, 121. (7) Steenken, S. Chem. ReV. 1989, 503. (8) Bernhard, W. A.; Close, D. M. In Charged Particle and Photon Interactions with Matter Chemical, Physicochemical and Biological Consequences with Applications; Mozumdar, A., Hatano, Y., Eds.; Marcel Dekker, Inc.: New York, 2004; p 431. (9) Milligan, J. R.; Aguilera, J. A.; Ly, A.; Tran, N. Q.; Hoang, O.; Ward, J. F. Nucleic Acids Res. 2003, 31, 6258. (10) Adhikary, A.; Kumar, A.; Sevilla, M. D. Radiat. Res. 2006, 165, 479. (11) Sevilla, M. D.; Becker, D.; Yan, M.; Summerfield, S. R. J. Phys. Chem. 1991, 95, 3409. (12) Abdoul-Carime, H.; Gohlke, S.; Illenberger, E. Phys. ReV. Lett. 2004, 92, 168103. (13) Pan, X.; Sanche, L. Chem. Phys. Lett. 2006, 421, 404. (14) Wesolowski, S. S.; Leininger, M. L.; Pentchev, P. N.; Schaefer, H. F., III J. Am. Chem. Soc. 2001, 123, 4023. (15) Chen, E. S. D.; Chen, E. C. M.; Sane, N. Biochem. Biophys. Res. Commun. 1998, 246, 228. (16) Russo, N.; Toscano, M.; Grand, A. J. Comput. Chem. 2000, 21, 1243. (17) Bera, P. P.; Schaefer, H. F., III Proc. Natl. Acad. Sci. 2005, 102, 6698. (18) Lind, M. C.; Bera, P. P.; Richardson, N. A.; Wheeler, S. E.; Schaefer, H. F., III Proc. Natl. Acad. Sci. 2006, 103, 7554. (19) Reynisson, J.; Steenken, S. Phys. Chem. Chem. Phys. 2002, 4, 5346. (20) Messer, B. M.; Cappa, C. D.; Smith, J. D.; Drisdell, W. S.; Schwartz, C. P.; Cohen, R. C.; Saykally, R. J. J. Phys. Chem. B 2005, 109, 21640. (21) Schroeder, O. E.; Andriole, E. J.; Carver, K. L.; Colyer, K. E.; Poutsma, J. C. J. Phys. Chem. A 2004, 108, 326.

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