J. Phys. Chem. B 2007, 111, 6571-6576
6571
Effects of OH Radical Addition on Proton Transfer in the Guanine-Cytosine Base Pair Ru bo Zhang†,‡ and Leif A. Eriksson*,‡ The Institute for Chemical Physics and School of Science, Beijing Institute of Technology, Beijing 100081, China, and Department of Natural Sciences and O ¨ rebro Life Science Center, O ¨ rebro UniVersity, 701 82 O ¨ rebro, Sweden ReceiVed: March 5, 2007; In Final Form: April 10, 2007
Double proton transfer (PT) reactions in guanine-cytosine OH radical adducts are studied by the hybrid density functional B3LYP approach. Concerted and stepwise proton-transfer processes are explored between N1(H) on guanine (G) and N3 on cytosine (C), and between N4(H) on C and O6 on G. All systems except GC6OH display a concerted mechanism. 8OHGC has the highest dissociation energy and is 1.2 kcal/mol more stable than the nonradical GC base pair. The origin of the interactions are investigated through the estimation of intrinsic acid-basic properties of the •OH-X monomer (X ) G or C). Solvent effects play a significant role in reducing the dissociation energy. The reactions including •OH-C adducts have significantly lower PT barriers than both the nonradical GC pair and the •OH-G adducts. All reactions are endothermic, with the GC6OH f GC6OHPT reaction has the lowest reaction energy (4.6 kcal/mol). In accordance with earlier results, the estimated NBO charges show that the G moiety carries a slight negative charge (and C a corresponding positive one) in each adduct. The formation of a partial ion pair may be a potential factor leading to the PT reactions being thermodynamically unfavored.
1. Introduction In natural nucleic acids (DNA/RNA), the purine and pyrimidine bases exist mostly as amino and keto tautomers. Some rare forms (imino and enol) of the bases are, however, also present in DNA and have been suggested to play an important mutagenic role, disturbing the genetic code.1 A mutation mechanism has been suggested to involve proton transfer (PT) reactions between the bases in the Guanine-Cytosine (GC) and adenine-thymine base pairs. Much experimental and theoretical attention has been given to this topic, aiming to elucidate the possible role of PT in point mutations.2,3 In the gas phase, a concerted double PT reaction mechanism of the neutral, nonradical GC base pair ground state is dominant over the stepwise pathway, and proceeds with a barrier of between 13.3 (MP2/infinite4// MP2/6-31G(d)) and 17.3 kcal/mol (B3LYP/631G(d)).3a The dramatic effects of the PT reactions in the context of nucleobase redox properties, have also been studied theoretically. Due to the facile oxidation of the GC base pair, the enhanced acidity of N1-H1 of the G radical cation results in a single proton transfer to N3 of the neutral base C in a slightly endothermic process.5 The barrier for the single PT reaction is 5.8 kcal/mol. Under the influence of an excess electron, the same proton-transfer reaction is energetically favored, with a reaction energy of -3.2 kcal/mol and a barrier of only 3.6 kcal/ mol.6 Metal ions can interact with a GC base pair through direct coordination to position N7 of the guanine. The PT reaction process is strongly associated with metal ion charge,7,8 with electrostatics as one of the factors promoting single PT between N1H(G)-N3(C). Another factor is the ability of the metal ion to oxidize G. The net PT result should be very similar to the * Corresponding author phone: 46 19 303 652; fax: 46 19 303 566; e-mail:
[email protected]. † Beijing Institute of Technology. ‡O ¨ rebro University.
case of the GC radical cation discussed above. Metal ions with charge +2 favors the stabilization of the PT product. The above studies show that charge is a main factor in mediating PT reaction between the bases. Photoinduced tautomerization of GC base pair have also been investigated theoretically.9,10 The barriers to PT of the GC base pair in the ground and low-lying singlet excited states were found to be comparable to each other, and values around 20 kcal/mol were obtained at the HF and configuration interaction including single excitations (CIS) levels of theory. Thus, the computations do not seem to support the occurrence of photoinduced PT reactions in low-lying singlet excited states. In the triplet state, however, a coupled proton (attached to N1 of G) and electron-transfer reaction was found to be exothermic with a barrier of 17 kcal/mol. It is well-known that the primary reactive species, such as free electrons, H atoms, and OH radicals, largely originate from radiolysis of the surrounding aqueous medium, and from normal cell metabolism.11,12 To date, much work has been devoted to unveil the effects and mechanisms of radiation in DNA lesion formation.13 In pyrimidines, •OH adds to the C5dC6 double bond, giving rise to the formation of base radicals. Of the radicals produced, the 5-hydroxy-6-yl radicals have reducing properties, whereas the 6-hydroxy-5-yl radicals are oxidizing.14 In purines, •OH adds to the C4, C5, and C8 positions resulting in equal amounts of oxidizing and reducing types of adduct radicals.15 The radical adducts can, in turn, undergo subsequent reactions such as unimolecular opening of the imidazole ring in the purine C8-OH adduct radicals,16 intra- or intermolecular H abstraction resulting in strand scission,17 or cross-link reactions with other biomolecules.18 The stabilities and structures of GC base pair radicals formed after addition or removal of an H atom, have been theoretically studied.19 Due to the transient nature of the radical adducts in aerobic and anaerobic cells, they are very difficult to investigate
10.1021/jp071772l CCC: $37.00 © 2007 American Chemical Society Published on Web 05/17/2007
6572 J. Phys. Chem. B, Vol. 111, No. 23, 2007
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SCHEME 1
Figure 1. SOMO level (a.u.) of •OH-X monomers (X ) G or C; dashed) and •OH-GC adducts (solid) calculated at the B3LYP/6-31+G(d,p) level.
by means of common experimental tools. Theoretical studies, therefore, can provide valuable insights by exploring the electronic interactions between the nucleobases in, e.g., radical induced tautomerization processes. Many questions regarding tautomerizations induced by radicals still remain to be solved. The potential roles of radical adducts on point mutations in DNA is also not yet clear to date. In this paper, the hydroxyl-radical induced tautomerization of the GC base pair was theoretically studied at the hybrid density functional theory level (B3LYP functional). Charge and spin distributions, proton affinities and interaction energies were explored to gain further insight into this form of radical-induced damage of DNA. 2. Methodology Atomic labeling used in the text and tables throughout refers to Scheme 1. The PT reactions considered are between N1H of G and N3 of C, and between N4H of C and O6 of G (marked in bold italics in Scheme 1). As mentioned above regarding radical additions to heterocyclic bases, only the •OH-GC base pair adducts are considered herein. The adducts are labeled MOHGC and GCNOH, where M and N are atomic numbering on G and C, respectively, according to Scheme 1. The notation MOHGCPT and GCNOHPT are used for the corresponding PT products. The geometries of the •OH-GC adducts were optimized at the hybrid density functional theory level B3LYP,20 in conjunction with the 6-31+G(d,p) basis set. For comparison, the neutral ground structure of the GC base pair and the OH-base monomeric systems were also studied at the same level. Frequency calculations were performed to confirm the correct nature of the stationary points, and to extract zero-point vibrational effects (ZPE) and estimates to the free energy at 298 K. Correction for basis set superposition errors (BSSE)21 were estimated at the same level. The charges obtained from natural population analysis were determined through natural bond orbital (NBO) theory.22 Bulk solvation effects were considered using the integral electron formalism of the polarized continuum model (IEF-PCM)21 with dielectric constant ) 78.4. All calculations were carried out using the Gaussian 03 package.23 3. Results and Discussion 3.1. Electronic Structure of GC-OH Radical Adducts. Five •OH-GC radical adducts, with •OH on C4, C5 or C8 of G, and on C5 or C6 of C, were optimized at the B3LYP/6-31+G(d,p) level. Table 1 displays the distances between the atoms connected through hydrogen bonds in the initial complexes, the transition structures, and the final proton-transferred structures of the double PT processes.
The 4OHGC and 5OHGC complexes undergo some conformational changes in that the five- and six-membered rings of the purine become folded out-of-plane (“butterfly” distortion). The dramatic torsion arises as a result of the conversion of the initial C4dC5 double bond into a single bond due to OH atom addition. The unpaired electron is found on C5 in 4OHGC and on C4 in 5OHGC, respectively. These are different from the case of 8OHGC, where the two rings remain coplanar. The O6‚‚‚N4, N1‚‚‚N3, and N2‚‚‚O2 distances are 2.83, 2.96, and 2.94 Å in 4OHGC, 2.83, 2.94, and 2.95 Å in 5OHGC, 2.81, 2.93, and 2.91 in 8OHGC, respectively. Compared with the corresponding values of the parent GC base pair, •OH addition to G has different, although minor, effects on the distance of the two bases. The OH addition slightly elongates the distance between the bases in 4OHGC and 5OHGC, and shortens it in 8OHGC. The associated low-frequency motions are 121 cm-1 for 4OHGC, 126 cm-1 for 5OHGC and 130 cm-1 for 8OHGC, which are all close to the 129 cm-1 found for the GC base pair. In addition, the N1-H1 distances are essentially unchanged in the •OH radical adducts compared to the GC base pair, which implies that the acidity of this proton should not be significantly altered. Both GC5OH and GC6OH can be formed as result of •OH addition to C. The geometry of the two radical adducts is characterized by the change of C5dC6 in cytosine into a single bond. The C5 atom deviates dramatically from the base plane in GC5OH, and the same situation is observed for C6 in GC6OH. •OH addition to C brings the two bases closer through a reduction of the O6‚‚‚N4 and N1‚‚‚N3 distances but increases the N2‚‚‚O2 distance, as seen in Table 1. The low-frequency motions are very similar to the value of the nonradical parent base pair. Both the N1-H1(G) and N4-H4(C) distances remain at almost the same value as in the GC base pair. The energetic levels of the singly occupied molecular orbital (SOMO) of the adducts are shown in Figure 1. The SOMO values of the •OH adducts to C when in the base pairs are -0.192 a.u. and -0.202 a.u. These are more negative than the values corresponding to the •OH adducts to G in the base pair, which means that the GC5OH and GC6OH adducts are more facile to capture an excess electron. Based on the same theoretical level, the SOMO values of OH-cytosine monomer adducts are -0.179 a.u. for 5OHC and -0.257 a.u. for 6OHC, which reflects the effects of guanine complementary to OH-cytosine in bringing the reducing capability of GC5OH and GC6OH to comparable levels. 5OHGC has the highest SOMO level, and should, hence, be the easiest species to ionize among the •OH adducts. The SOMOs of 4OHGC, 5OHGC, and 8OHGC are completely localized on the guanine fragment. For the adducts, including OH-cytosine, an unexpected difference in SOMO localization is observed, as presented in Figure 2. The SOMO and spin density of GC5OH are completely localized on the
Proton Transfer in the Guanine-Cytosine Base Pair
J. Phys. Chem. B, Vol. 111, No. 23, 2007 6573
Figure 2. SOMO populations (left) and spin density surfaces (right) of GC5OH (top row) and GC6OH (bottom row).
TABLE 1: Hydrogen Bond Distances (Å) at the B3LYP/6-31+G(d,p) Level GC N1(G)‚‚‚N3(C) N2(G)‚‚‚O2(C) O6(G)‚‚‚N4(C)
reactant TS product reactant TS product reactant TS product
2.947 2.616 2.899 2.935 2.852 3.005 2.798 2.485 2.696
4OH
5OH
8OH
GC5OH
GC6OH
2.964 2.662 2.875 2.944 2.950 3.006 2.830 2.479 2.675
2.942 2.654 2.877 2.954 2.927 3.022 2.832 2.481 2.688
2.926 2.649 2.883 2.912 2.888 2.984 2.806 2.479 2.694
2.930 2.604 2.888 2.955 2.840 3.010 2.785 2.528 2.726
2.936 2.635 (2.792)a 2.913 (2.920) 2.934 2.801 (2.985) 2.825 (2.990) 2.777 2.573 (2.481) 2.895 (2.753)
GC
GC
GC
a The main data are for the first H transfer (H1 to N3(C)); values in parentheses correspond to the second step in the process, H4 transfer to O6(G).
cytosine fragment, whereas in GC6OH the SOMO and spin density are localized on the guanine and on the cytosine fragments, respectively. The reason behind this is based on the fact that the highest occupied molecular orbital (HOMO) of guanine is -0.223 a.u. and the SOMO values of 5OHC and 6OHC are -0.179 and -0.257 a.u., respectively. When 5OHC and 6OHC are combined with G, for which the HOMO lies energetically midway between these, the two hydrogen bonding (HB) complexes will experience different influence from the guanine base, and hence, markedly different SOMO populations. In the PT transition state (TS), double proton transfer is observed for all the OHGC base pair adducts. As seen from Table 1 the distances of the two fragments are in the transition structures contracted to promote transfer of H1 to N3(C) and of H4 to O6(G). Unexpected differences in the TS structures are observed for TS-GC5OH and TS-GC6OH. For TS-GC5OH, the concerted double PT results in H1 leaving for N3, and at the same time H4 moving toward O6. Compared with the concerted double PT transition structures of the GC, 4OHGC, 5OHGC, and 8OHGC adducts, however, the O6‚‚‚N4 distance of GC5OH is longer, whereas its N1‚‚‚N3 distance is shorter, which shows that the reaction has a partial stepwise PT character. This is taken one step further for GC6OH, in that this displays a clear two-step PT reaction. First H1 is transferred to N3(C), giving a metastable intermediate, followed by a second PT transfer of H4 to O6(G). In the first PT step, the O6‚‚‚N4 distance is 2.573 Å, which is the longest among the TS structures. The N1‚‚‚N3 distance is smaller than those in TS-4OHGC, TS-5OHGC and
TS-8OHGC, but longer than TS-GC and TS-GC5OH. In the second step, the O6‚‚‚N4 distance is very close to the values in TS-GC, TS-4OHGC, TS-5OHGC and TS-8OHGC, but the N1‚‚‚N3 distance is extended to 2.792 Å, which is dramatically longer than that of the other TS structures. For the PT products, the distances between the two fragments are shorter than in the reactants. 3.2. Energy Profiles of GC-OH Radical Adducts. First, reaction energies of the OH radical and GC base pair were calculated at the ZPE corrected B3LYP/6-31+G(d,p) level in gas phase. The interaction between •OH and the G and C monomers were also studied at the same level for comparison. Analogously to the results for the •OH-monomer cases, the adduct with OH bonded to C8 in G is thermodynamically the most favorable of all OH-GC systems. The reaction energy is 1.2 kcal/mol more negative than that of the corresponding OH + G monomer reaction, and is exothermic by 31.4 kcal/mol; cf. Figure 3. The second most stable OH adduct is to C6 on cytosine, with a reaction energy 13 kcal/mol less exothermic than that leading to 8OHGC formation. The reaction energies for •OH addition to C of the GC pair are comparable to the cases of •OH reaction with C monomers, which in turn are slightly more stable than those of the •OH + GC f 4OHGC and •OH + GC f 5OHGC reactions. The stability ordering of all the •OH-GC adducts is 2.1
4.7
8OHGC
12.7
>
1.7
GC6OH >
GC5OH
> 4OHGC > 5OHGC. This differs slightly from the ordering of the H-GC radical adducts, where the H atom addition to C5 gives a more stable complex than H atom to C6.19b
6574 J. Phys. Chem. B, Vol. 111, No. 23, 2007
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Figure 3. ZPE-corrected energy profiles (in kcal/mol) corresponding to the double proton-transfer reaction in •OH-GC adducts computed at the B3LYP/6-31+G(d,p) level.
TABLE 2: Interaction Energies Calculated at the B3LYP/ 6-31+G(d,p) Level (in kcal/mol) system Dea Deb GC 4OH GC 5OH GC 8OH GC GC5OH GC6OH
26.2 24.3 24.8 27.3 25.9 26.0
8.3 7.3 7.8 8.9 8.7 8.7
D0c
system
24.4 (23.5) 22.6 (21.5) 22.9 (21.8) 25.7 (24.7) 24.3 (23.2) 24.5 (23.4)
GCPT 4OH GCPT 5OH GCPT 8OH GCPT GC5OHPT GC6OHPT
Dea Deb 18.8 19.6 19.5 19.9 18.1 17.3
8.5 9.0 8.8 8.6 7.5 7.2
D0c 17.9 (16.9) 18.8 (17.5) 18.6 (17.4) 18.7 (17.6) 17.1 (16.1) 16.2 (15.1)
De ) E(•OH-G) + E(C) - E(•OH-GC) for •OH addition to G; De ) E(G) + E(•OH-C) - E(•OH-GC) for •OH addition to C. b Solvent effects included. c In gas phase; Zero point energy included (BSSEcorrected values in parentheses). a ,b
To explore how the interaction between the G and C bases is affected by •OH addition, the dissociation energies (DE) were calculated at the B3LYP/6-31+G(d,p) level (Table 2). The DE value of the parent GC base pair is at the current level 26.2 kcal/mol in gas phase which after zero-point energy (ZPE) correction is reduced to 24.4 kcal/mol. This is consistent with the reported experimental value of 21.0 kcal/mol24 and previously calculated values of 25.4 kcal/mol,25 23.8 kcal/mol.3d The DE values are reduced by ca. 2.0 kcal/mol when •OH is added to the C4 and C5 sites of G. For 8OHGC, the DE value is increased by ca. 1.0 kcal/mol. These changes are consistent with the changes in intermolecular distances. For •OH addition to C the DE values are essentially unchanged. For the double PT products in gas phase, the base pairing interaction is weakened. The DE value of GCPT is 18.8 kcal/mol, which is slightly lower than the ones of 4OHGCPT, 5OHGCPT, and 8OHGCPT, but higher than those of GC5OHPT and GC6OHPT. All BSSE corrections result in a decrease in DE value by 1.0 kcal/mol. The changes in stability between the reactants and the PT-products could originate from the variation in acidity and basicity of the PTderived isomers. Furthermore, the solvent effects, estimated through the IEF-PCM calculations, considerably promote the instability of GC and its OH radical adducts, such that the DE values in aqueous solution only range from 7.0 to 9.0 kcal/ mol.
TABLE 3: B3LYP/6-31+G(d,p) +ZPE Proton Affinities (PAs) at Oxygen and Nitrogen and Deprotonation Enthalpies (DPEs) of NH (in kcal/mol) DPE (N1-H1) PA (O6)
DPE (N4-H4) PA (N3)
G
G4OH
G5OH
G8OH
338.9 216.0
338.7 213.6
336.6 214.6
331.5 214.7
C
C5OH
C6OH
354.7 228.4
347.9 226.3
343.0 228.3
The intrinsic acid-base properties that are associated with proton affinity (PA) and deprotonation enthalpy (DPE) are further estimated to investigate the intermolecular interaction. The resulting energies/enthalpies are listed in Table 3. For the •OH adducts to G in the GC base pair, the acid-base properties of C should be little affected. The DPE values of N1H1 in 4OHG, 5OHG, and 8OHG are 338.7, 336.6, and 331.5 kcal/mol, respectively, to be compared with the corresponding value 338.9 kcal/ mol for the G momomer. The results show that the acidity ordering is 8OHG > 5OHG >4OHG and that the acidity of N1H1 of 4OHGC is almost equal to that of N1H1 of GC. The basicity changes, on the other hand, are reflected in the variation of PA values. The PA values of O6 are 216.0, 213.6, 214.6, and 214.7 kcal/mol of G, 4OHG, 5OHG, and 8OHG, respectively. Hence, the basicity of O6 in the adducts are slightly weakened due to •OH addition. A series of theoretical studies have shown that the stability of the hydrogen bonded (HB) complex depends not only on the basicity of the O6 atoms, but also on the acidity of the interacting N1H1 groups, and that the effects of the latter on the hydrogen bond strengths are more pronounced.26 The most stable HB complex among the three adducts is 8OHGC, which agrees with the N1H1 site having the lowest DPE (i.e., the highest acidity). A similar analysis also applies to the GC5OH and GC6OH adducts, where the latter is slightly more stable. The barriers for proton-transfer depend on which position in the GC base pair that is attacked by •OH, as seen in Table 4 and Figure 3. For the GC base pair, the barrier height is estimated to be 10.0 kcal/mol at the B3LYP/6-31+G(d,p) level.
Proton Transfer in the Guanine-Cytosine Base Pair
J. Phys. Chem. B, Vol. 111, No. 23, 2007 6575
TABLE 4: ZPE Corrected B3LYP/6-31+G(d,p) Computed Reaction (Free) Energies and Activation Barriers (in kcal/mol) for the Different GC Proton-Transfer Reactions GC 4OH GC 5OH GC 8OH GC GC5OH GC6OH
∆E* a,b
∆E* b
∆Ec
∆G* d
∆Ge
14.9 16.8 15.3 14.2 12.8 12.6 f 3.5g
10.0 12.3 10.5 9.5 8.7 8.7 0.5
9.6 12.7 10.6 9.0 7.3 7.3 -2.7
11.0 13.2 11.0 9.7 9.5 9.4 1.1
9.8 13.0 10.8 9.1 7.3 7.4 -2.8
a Without ZPE correction. b Reaction barrier. c Reaction energy. Free energy barrier at T ) 298 K. e Reaction free energy at T ) 298 K. f First PT reaction. g Second PT reaction.
d
This can be compared with the barriers 12.4 kcal/mol for 4OHGC f 4OHGCPT, 10.6 kcal/mol for 5OHGC f 5OHGCPT, and 9.5 kcal/mol for the 8OHGC f 8OHGCPT reactions, all of which are concerted double PT reactions. The barriers are slightly higher than for the •OH adducts to C. A concerted double PT reaction is also found in GC5OH f GC5OHPT, with a barrier of 8.7 kcal/mol. For the stepwise GC6OH f GC6OHPT reaction, the first barrier (H1 f N3(C)) is almost the same as that of the GC5OH f GC5OHPT reaction. The intermediate requires another 0.5 kcal/mol to conclude the transfer of H4 to O6(G). The GC5OH f GC5OHPT and GC6OH f GC6OHPT barriers are 3-4 kcal/mol higher than the single PT reactions seen in GC+. 6 and Li-GC+.,8 emphasizing the strong dependence on the acidity of N1H1. ZPE corrections contribute to a lowering of the barrier heights by 4-5 kcal/mol. In addition, inclusion of enthalpy and entropy in the free energies of the reactions, also presented in Table 4, has very little influence with at most 1 kcal/mol higher barriers and overall energetics. All PT reactions are endothermic according to the present data. The reaction energies are between 5 and 13 kcal/mol, and again higher values are noted for the OHG adducts than the OHC ones. For two of the systems, 4OHGC and 5OHGC, the products are energetically more endothermic than their corresponding transition structures as displayed in Figure 3. The rationale for this is the effect of adding ZPE corrections to the energies; the transition structures are, however, fully characterized as true transition states. The lowest endothermicity, 4.6 kcal/mol, is seen for the stepwise GC6OH f GC6OHPT reaction, which is only slightly higher than that observed for Li-GC+.8 From the intermediate in the GC6OHPT reaction sequence the reaction is exothermic. The reason for the endothermic overall processes could stem from the stronger acidity and weaker basicity of the reactant isomers than the final PT products. We also note that the barriers toward a reversal of the PT reactions are very small: less than 2 kcal/mol for all systems except GC6OH. One approach to thermodynamically push the systems toward point mutations arising from the PT reactions, is to assemble excess positive charge on guanine. Excess positive charge (such as +2) can stabilize the G isomer from decomposition in the PT products and moreover repel protonated or positively charged cytosine as observed in the study by Sodupe et al.7 Alternatively, negative charge can be added to C in the GC base pair, caused by the higher electronegativity of C over G. The net effect is a change in acidity of the HB donor in the GC base pair.6 To explore the charge distribution in the current systems, NBO charges were calculated in the present study; the charge on the G fragment in each radical adduct is presented in Table 5. As can be seen from the table, the guanine carries a slight negative charge irrespective of whether •OH is placed on G or C. The G fragments of the PT products have higher negative charges than the corresponding reactants. We conclude that one of the reasons
TABLE 5: NBO Charges (e-) for the Guanine Fragment in GC and Its •OH Adducts GC reactant product
-0.031 -0.041
4OH
5OH
8OH
GC
GC5OH
GC6OH
-0.033 -0.046
-0.035 -0.042
-0.039 -0.043
-0.028 -0.031
-0.025 -0.100 -0.029
GC
GC
for the PT reactions being thermodynamically unfavorable can be assigned to the ion pairing formation in the Watson-Crick GC base pair and the •OH-GC adducts. 4. Conclusions In the present work, hybrid DFT methods have been employed to investigate the potential double proton-transfer processes induced by OH radical addition to the C4, C5, or C8 sites of guanine and C5 or C6 of cytosine in the GC base pair. Geometries, ZPE effects and ∆G corrections, acidity and basicity of the radical-base adducts, NBO charges, and reaction energies were obtained at the B3LYP/6-31+G(d,p) level in gas phase, followed by single point calculations performed at the same level in aqueous solution ( ) 78.4) using the IEF-PCM model. The interaction between guanine and cytosine can be slightly modified by •OH addition. The interactions in the reactants are much stronger than those of the corresponding PT products. 8OHGC has the highest dissociation energy; 1.2 kcal/mol larger than that of the GC base pair. The nature of the interaction is explored through the estimation of intrinsic acid-basic properties of the •OH-X monomer adducts (X ) G or C). In addition, solvent effects are found to play a significant role in reducing the dissociation energy. The PT reactions are for most systems found to be mediated by •OH addition. The highest barrier is 12.4 kcal, obtained for the 4OHGC f 4OHGCPT reaction, which is 2.4 kcal/mol higher than that of the neutral nonradical GC f GCPT reaction. The PT barriers for the •OH adducts to cytosine are lower than the nonradical GC and the OH-G adducts. All the reactions are endothermic, with the stepwise GC6OH f GC6OHPT having a smallest reaction energy; comparable to the value found for LiGC+.8 Apart from the GC6OH system, all other PT reactions are concerted. In GC6OH, a shallow intermediate is found in which H1(G) is transferred to N3(C), but H4(C) is not yet transferred to O6(G). Combined with the results from earlier studies by Sodupe et al.7 and Sevilla et al.,6 the NBO charges shows that the negative charge on guanine/positive charge on cytosine in the adducts can be a potential factor leading to the PT reactions not being thermodynamically favored. Acknowledgment. The Swedish Science Research Council (VR) and the National Natural Science Foundation of China (grant no. 20643007), are gratefully acknowledged for financial support. We also acknowledge generous grants of computing time at the National supercomputing facilities in Linko¨ping (NSC). Supporting Information Available: Optimized Cartesian coordinates of all structures investigated. This material is available free of charge via the Internet at http://pubs.acs.org. References and Notes (1) (a) Lowdin, P. O. AdV. Quantum Chem. 1965, 2, 213. (b) Piccirilli, J. A.; Krauch, T.; Moroney, S. E.; Benner, S. A. Nature 1990, 343, 33. (2) Benderskii, V. A.; Makarov, D. E.; Wight, C. A. Chemical Dynamics at Low Temperature. AdVances in Chemical Physics 88; Wiley & Sons: New York, 1994.
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