Cation Coordination to Adenine−Thymine Base Pair. Effects on

J. Phys. Chem. B 2008, 112, 4817-4825

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Cu2+/+ Cation Coordination to Adenine-Thymine Base Pair. Effects on Intermolecular Proton-Transfer Processes Marc Noguera, Juan Bertra´ n, and Mariona Sodupe* Departament de Quı´mica, UniVersitat Auto´ noma de Barcelona, Bellaterra 08193, Spain ReceiVed: December 21, 2007; In Final Form: February 6, 2008

Intermolecular proton-transfer processes in the Watson & Crick adenine-thymine Cu+ and Cu2+ cationized base pairs have been studied using the density functional theory (DFT) methods. Cationized systems subject to study are those resulting from cation coordination to the main basic sites of the base pair, N7 and N3 of adenine and O2 of thymine. For Cu+ coordinated to N7 or N3 of adenine, only the double proton-transferred product is found to be stable, similarly to the neutral system. However, when Cu+ interacts with thymine, through the O2 carbonyl atom, the single proton transfer from thymine to adenine becomes thermodynamically spontaneous, and thus rare forms of the DNA bases may spontaneously appear. For Cu2+ cation, important effects on proton-transfer processes appear due to oxidation of the base pair, which stabilizes the different single proton-transfer products. Results for hydrated systems show that the presence of the water molecules interacting with the metal cation (and their mode of coordination) can strongly influence the ability of Cu2+ to induce oxidation on the base pair.

Introduction DNA interacts with metals in two clearly distinguished manners.1 The first one consists of having metal cations interacting with the DNA backbone’s phosphate groups through nonspecific interactions. These interactions are electrostatic in nature and are mainly found with alkaline and alkaline-earth metals, which can be found in cell media (i.e., Na+, K+, and Ca2+ are responsible for osmothic equilibrium in cells). These cations arrange around DNA following the external part of the double helix. Screening of phosphate’s negative charge diminishes electrostatic repulsion between phosphate backbones and thus favors DNA stability.2 On the other hand, at the nucleobase level, we can find metal cations interacting with nitrogenated bases directly in an inner-shell coordination manner, or indirectly through water molecules. Metal cations that prefer this mode of interaction are usually found to be transition metals, and, in this case, the interaction is usually not solely electrostatic. Although the second type of interaction is quantitatively inferior, it may modify DNA in an irreversible way. One illustrative case for this kind of metal-DNA interaction is the cis-Pt2+(NH3)2Cl2 molecule, which links two consecutive bases together and is used as an anticarcinogenic drug. cis-Pt2+(NH3)2Cl2 was discovered by Rosenberg3 and has been one of the main subjects of research on the metal-DNA field due to its significance in the pharmacological world. Therefore, although cationphosphate interactions are predominant, the binding of metal ions to the bases is not negligible, especially at high concentrations, and can modify the hydrogen bonding and the stacking interactions that stabilize the double helix.4 It is well known that the N7 position of guanine, which is readily accessible in the major groove of duplex DNA, and is not involved in Watson-Crick base pairing, is the preferred metal binding site.1,2,5,6 Many studies have analyzed the interaction of different metal cations to guanine6-16 and their influence on base pairing17,18 and on the helical strength.19 Moreover, a * Corresponding author. E-mail: [email protected].

few theoretical results have shown that the presence of metal cations interacting at the N7 position of guanine promotes the proton transfer from N1 of guanine to the N3 acceptor site of cytosine.16,20 However, the screening of the metal charge by the environment (water molecules and phosphate) reduces significantly the probability of such mutagenic process.21 Adenine’s N7 center also interacts with cations, although to a lesser extent.1,22,23 Moreover, it has been suggested in the bibliography that regions of DNA that are rich in AT pairs are involved in the organization of solvated cations inside the minor groove of DNA. This kind of organization occurs all along the minor groove of DNA through the N3 and O2 basic sites of adenine and thymine, respectively. Hydration spine24-28 may lead to a highly organized cation chain along the minor groove where the metal cation could stay for relatively long periods of time. Most of the theoretical studies performed on the interaction of metal cations with guanine, adenine, or adenine-thymine (AT) and guanine-cytosine (GC) base pairs have dealt with alkali, alkaline earth, or closed-shell transition metal cations.6,11,15,16,20,29-36 Fewer studies have focused on open-shell metal cations interacting with nucleobases.23,37-40 To the best of our knowledge, only a few studies have analyzed the interaction of Cu2+, a d9 open-shell cation, with guanine,39,40 or other nucleobases,41,42 but its influence on base pairing or intermolecular proton-transfer processes has only been considered for GC base pair.21 Moreover, due to the oxidant character of Cu2+,21,39,41,42 its interaction with the base pair might lead to the formation of electron holes on the base pair, which has been shown to favor the proton transfer from N1 of guanine to the N3 of cytosine.43 The aim of this work is to analyze the influence of both bare and hydrated metal cations interacting with different basic sites of AT on the intermolecular proton-transfer processes and compare it to that found for GC.21 Computational Details Full geometry optimizations, without any symmetry constraints, have been carried out using the Gaussian 0344 program

10.1021/jp711982g CCC: $40.75 © 2008 American Chemical Society Published on Web 03/22/2008

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SCHEME 1: Proton-Transfer Processes and Metal Coordination Sites

package and the three-parameter B3LYP45,46 hybrid density functional. Previous theoretical calculations have shown that B3LYP approach is a cost-effective method for studying transition metal ligand systems, particularly Cu+-L systems.47,48 However, for open-shell Cu2+-ligand systems, recent studies carried out in our group49,50 have shown that functionals with a larger percentage of exact exchange such as BHLYP provide better results than B3LYP, when comparing to the highly correlated CCSD(T) method. Thus, for Cu2+-AT systems, in addition to B3LYP, we have also carried out calculations with the hybrid BHLYP functional.51 For non-solvated systems, we have used a 6-31++G(d,p) basis set for H, C, N, and O atoms both for optimization and for final energy evaluation, while for solvated system, due to the larger computational cost, optimizations have been carried out using the 6-31G(d,p) basis set for the same atoms, while energy evaluation has been carried out using the same 6-31++G(d,p) basis. In all cases, the Cu basis set is based on the (14s9p5d) primitive set of Wachters52 supplemented with one s, two p, and one d diffuse functions53 as well as one f polarization function,54 the final contracted basis set being [10s7p4d1f]. The nature of the stationary points has been checked by vibrational frequency calculations. Thermodynamic corrections have been obtained assuming an ideal gas, unscaled harmonic vibrational frequencies, and the rigid rotor approximation by standard statistical methods.55 Net atomic charges have been obtained using the natural population analysis of Weinhold et al.56 Results and Discussion First, we will present the results obtained for the bare metal cations coordinated to the AT base pair. Next, the results for the water solvated systems will be discussed. A. Bare Metal Cations. Scheme 1 shows the metal coordination sites (N7, N3, and O2) and the single proton-transfer (SPT) and double proton-transfer (DPT) processes considered in the present work. In contrast to GC system, for which the observed trends on proton-transfer processes upon Cu+ and Cu2+ binding were found to be similar for both cations, for AT base pair the binding of Cu+ or Cu2+ induces a completely different behavior depending on the oxidation state of the metal. That is, for Cu+AN3T and Cu+AN7T base pairs only the canonical reactant

and the double proton-transferred products were found to be stable on the potential energy surface. However, for Cu2+ adenine coordinated systems only the reactant and the products arising from the single proton-transferred processes could be located. Metal binding at the O2 site of adenine also results in a very different behavior depending on whether the metal cation is Cu+ or Cu2+. That is, for Cu+ATO2 system only the SPT1 product is found to be stable, similarly to the protonated system,57 whereas Cu2+ binding to thymine’s O2 causes the base pair disruption. As expected, the nature of the interaction of Cu+ and Cu2+ with AT is different, not only due to the fact that we have one monovalent and one divalent cation but also due to the oxidative character of Cu2+. The different proton-transfer processes observed for each metal cation point out the importance of the oxidative effects of Cu2+. Energy profiles of the different proton-transfer processes obtained upon Cu+ and Cu2+ binding of AT are shown in Figures 1 and 2, respectively. Metal-ligand and hydrogen-bond distances of the minima involved in these processes are also shown in these figures. First, it can be observed in Figure 1 that the larger Cu+ affinity occurs at the N7 basic center, in agreement with the fact that in this situation the metal shows a bidentate coordination through N7 and N6.23 Monodentate coordination at the N3 sites is 3.7 kcal/mol less favorable, whereas cation affinity for thymine’s O2 is about 13 kcal/mol lower, in agreement with the preference of Cu+ cation for softer basic centers. For Cu2+ metal cation, however, both bidentate N7,N6 and monodentate N3 coordination show similar metal cation affinities, the B3LYP(BHLYP) relative energies between the bidentate N7,N6 and the monodentate N3 being 0.7(-1.2) kcal mol-1 (see Figure 2). Coordination of bare Cu+/2+ to N7 results in a pyramidalization of adenine’s amino group to maximize the interaction between the metal cation and the amino group lone electron pair. Thymine moiety adapts perfectly to the nonplanarity of the amino group by undergoing an out of plane motion of about 40° for Cu+AN7T and 20° for Cu2+AN7T. However, upon proton transfer the planarity is recovered and the metal cation coordination evolves from bidentate to monodentate (see Figures 1 and 2). Optimized N6-O4 and N1-N3 hydrogen-bond distances of neutral AT are 2.95 and 2.89 Å, respectively. Therefore, effects

Cu2+/+ Cation Coordination to AT Base Pair

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Figure 1. B3LYP energy profiles (in kcal mol-1) and main geometry parameters (distances in Å) of the minima corresponding to the considered proton-transfer processes in Cu+AT. Relative energies are given with respect to the canonical form of Cu+AN7T.

Figure 2. B3LYP energy profiles (in kcal mol-1) and main geometry parameters (distances in Å) of the minima corresponding to the considered proton-transfer processes in Cu2+AT. BHLYP values are shown in italics. Energies are given with respect to each cation complexed canonical form.

of Cu+ coordination on the hydrogen-bonding distances are significant and expected. That is, the moiety holding the charge of the cation is acidified and the hydrogen bond in which it

acts as proton donor is shortened, whereas that in which it acts as proton acceptor is lengthened. This happens for the three coordinated systems (see Figure 1). For instance, N1-N3

4820 J. Phys. Chem. B, Vol. 112, No. 15, 2008

Figure 3. Singly occupied molecular orbital for Cu2+AN3T and Cu2+AN7T.

hydrogen-bond distance in the Cu+ATO2 system is shortened 0.16 Å as a consequence of thymine acidification by the binding of the cation to thymine’s O2 center. On the other hand, coordination at adenine basic centers elongates the N1-N3 hydrogen bond and shortens the N6-O4 one. This is more significant upon N7 coordination as the pyramidalization strongly acidifies the hydrogen-bonded proton. As expected, hydrogen-bonding changes upon proton transfer are different for SPT1 and for DPT. For SPT1, which is only found for Cu+ATO2, the proton charge is transferred from thymine to adenine in such a way that the SPT1 complex can be viewed as an ion-pair A(+H+)+-T(-H+)- species interacting with Cu+ through O2. As a consequence, the N6-O4 hydrogen bond is shortened, whereas the N1-N3 one is elongated. This SPT1 process is exothermic, the minima corresponding to reactants being extremely shallow. In fact, this minimum disappears when Gibbs free energies are considered, very much resembling the energy profile observed for H+ATO2.57 For the DPT processes, which are found for the N7 and N3 adenine cationized base pair, electroneutrality in the base pair is maintained, and the resulting hydrogen bonds arise from a compromise between the acid/base properties of the basic centers involved in the transfer. Thus, as for the neutral base pair, the hydrogen-bond distances for DPT products are shorter than those of the reactants. Also, similarly to the neutral systems, the reaction is endothermic and the minimum of the DPT products is very shallow. Nevertheless, the DPT products are higher in energy than for the neutral or protonated base pairs, for which the reaction energy of the double proton-transferred process was computed to be 13.6 (H+AN7T) and 17.2 (H+AN3T) kcal mol-1, respectively.57 For Cu2+ coordinated AT base pair, the situation is completely different due to the nature of the metal cation. Similarly to Cu2+GC base pair,21 oxidant effects of the Cu2+ cation on the cationized base pair structures are significant and are observed for both adenine coordination sites, in such a way that Cu2+ANXT is better described as Cu+[ANXT]+• with the unpaired electron located on the base pair. This is in agreement with the open-shell orbital shown in Figure 3, which is mainly localized at the pyrimidine moiety. This is different from what was observed for Cu2+GC, for which oxidation was produced at the purine moiety; that is, the system could be viewed as Cu+G+•C. However, for Cu2+AT the obtained complex is better described as Cu+AT+•. This can be related to the ionization energies of the different bases. The experimental value for isolated adenine (8.3 eV) is only 0.6 eV lower than that of isolated thymine (8.9 eV).58 Therefore, despite the IE of adenine is lower than that of thymine, in the cationized base pair the preferred situation is to have the positive charge at the pyrimidine moiety because this reduces the electrostatic repulsion between the ionized base pair and the metal cation. However, the IE of guanine (8.0 eV) is 1 eV lower than that of cytosine (9.0 eV),58 and thus the radical is invariably located at guanine in the Cu2+GC case. Because the B3LYP computed ionization energies for adenine and thymine (8.1 and 8.7 eV, respectively) are in good

Noguera et al. agreement with the experimental values, we expect the observed trends to be reliable. With respect to metal-ligand distances, it can be observed that they are slightly larger for the open-shell systems (Cu2+) than for the closed-shell ones (Cu+), due to base pair oxidation. However, differences are considerably smaller than those found for cationized GC given that in Cu2+AT base pair the oxidation is located at the pyrimidine moiety, which is far from the cation, and thus the electrostatic repulsion is smaller. Effects of Cu2+ cationization on hydrogen bonding respond to the fact that the charge is distributed on both moieties. That is, thymine and adenine are both holding a positive charge. The charge on adenine part is highly localized as it mainly remains on the bound metal cation, whereas the one on thymine is delocalized on the π system of thymine. This distribution of charge results in a general, although small, elongation of both hydrogen bonds. This elongation arises from a subtle balance between the acidification of both moieties on those bonds in which they act as hydrogen-bond donors and the loss of basicity of the respective proton-acceptor counterparts. However, as hydrogen bonds, in general, slightly elongate, the decrease of basicity on the proton-acceptor atoms appears to be more important than the increase of acidity. When analyzing proton-transfer processes on Cu2+ANXT, we have not only to consider the influence of the metal cation binding but also the oxidative effects of Cu2+, which, in the present case, lead to the formation of a radical cation at the thymine monomer. Thus, in contrast to Cu2+GC for which both metal cation binding and oxidation occur at the purine moiety, in Cu2+AT, metal cation binding acts on adenine, while oxidation occurs on the pyrimidine monomer. Consequently, electrostatic and oxidative effects reinforce each other in Cu2+GC, but act in opposite direction in Cu2+AT. In the SPT1 process, the reaction simply displaces a positive charge from thymine to adenine, which corresponds to the proton being transferred. Because NPA analysis reveals that spin is located on thymine, the net charge of deprotonated thymine becomes equals to zero after the transfer, whereas that of Cu+A(+H+)+ fragment becomes approximately equal to 2 au. Therefore, both hydrogen bonds of the base pair where now adenine acts as proton donor are drastically reinforced. However, in the SPT2 process, the transfer of the proton from adenine to thymine is accompanied by a π electron transfer from adenine to thymine, and thus in the SPT2 product the radical character lies on adenine (see Table 1). In this way, the distribution of charge in the product remains equivalent to that of the reactant, the net charge of the Cu+A and T both being about 1 au. Energy profiles presented in Figure 2 show that the SPT1 products are largely stabilized as compared to the neutral system.57 This is in agreement with the fact that the radical species easily undergoes single proton-transfer processes,43 due to the increased acidity of the oxidized moiety. Although to a lesser extent than in the SPT1 case, both N7 and N3 SPT2 products are also significantly stabilized with respect to the neutral base pair. This process is less favorable than SPT1 for both coordinated systems due to the poorer basicity of O4 atom as compared to N1 and to the fact that the SPT2 proton transfer implies an electron transfer from adenine to thymine. B. Hydrated Metal Cations. The presence of water molecules screens electrostatic interactions and modifies the oxidative effects in such a way that gas-phase results on protontransfer processes can be largely modified by the solvent. Cation’s first solvation shell plays a critical role in these modifications, and thus considering the first sphere of solvent

Cu2+/+ Cation Coordination to AT Base Pair

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TABLE 1: Charge and Spin Density (in Parentheses) Values from Natural Population Analysis A T Mn+ A T Mn+ A T

AT

[AT]+‚a

0.03 -0.03

0.79(0.86) 0.21(0.14)

Cu+ATO2

Cu+ATO2SPT1

0.92 0.10 -0.02

0.87 0.84 -0.71

Cu+AN7T

Cu+AN7TSPT1

Cu+ATO2DPT

Cu+AN7TSPT1

Cu+AN7TDPT

0.86 0.10 0.04 Cu+AN3T

Mn+ A T

Cu+ATO2SPT2

0.85 0.11 0.04 Cu+AN3TSPT1

Cu+AN3TSPT2

0.84 0.15 0.01

Cu+AN3TDPT 0.84 0.06 0.10

Cu2+AN7T Cu2+AN7TSPT1 Cu2+AN7TSPT2 Cu2+AN7TDPT Mn+ A T

0.89(0.00) 0.17(0.00) 0.94(1.00)

0.89(0.00) 0.91(0.00) 0.20(1.00)

0.89(0.00) 0.22(1.00) 0.89(0.00)

Cu2+AN3T Cu2+AN3TSPT1 Cu2+AN3TSPT2 Cu2+AN3TDPT Mn+ 0.87(0.00) A 0.29(0.00) T 0.84(1.00) a

0.89(0.00) 0.89(0.00) 0.22(1.00)

0.90(0.01) 0.22(0.99) 0.88(0.00)

Taken from ref 43.

molecules around the cation is mandatory. Because the influence of solvation is more important in divalent cations, we have only considered Cu2+ for this part of the study. Similarly to GC base pair21 and Mg2+AU,16,20 we have considered five water molecules distributed around the metal cation interacting with N7 of adenine in an octahedric disposition. In addition, we have considered the coordination of the hydrated metal in the minor groove of the base pair through the N3 and O2 basic centers. Similarly to Cu2+GN7C, the octahedral coordination is not maintained around Cu2+ cation, one water molecule moving from the first hydration shell to the second one. This mode of coordination is denoted as (4,1) to indicate that four water molecules directly interact with Cu2+, whereas the fifth one lies in the second solvation shell. It can be observed in Figure 4 that this structure has Cu2+ coordinating to adenine in a monodentate manner through N7. The metal interaction with the N6 amino group is now outer shell through hydrogen-bond interactions, which induces a slight pyramidalization of the amino group. A deep exploration of the potential energy surface indicates that for this metal coordination only the DPT product is stable, the single proton-transferred SPT1 or SPT2 products not being located as minima. Thus, pentasolvated Cu2+ shows a behavior similar to that found for Cu+AT system, although now the reaction energy of the DPT process (10.0 kcal/mol) is significantly smaller than that of Cu+AT (18.9 kcal/mol). This similarity is not surprising considering that in (4,1)Cu2+AN7T electrostatic effects of Cu2+ are largely screened by the water molecules. In addition, NPA analysis shows that the spin density lies now at the metal cation and not on the nucleobases (thymine), which shows the importance of having a complete coordination sphere to stabilize Cu2+ and avoid oxidative effects. On the other hand, it should be noted that the double proton transfer in (4,1)Cu2+AN7T is energetically more favorable than the same process for the neutral system, for which the reaction energy is 13.6 kcal/mol,57 which points out the stabilization of the adenine rare tautomer by the solvated cation.

As mentioned, the coordination environment of Cu2+ determines the magnitude of electrostatic effects and whether or not the base pair is oxidized. Because of that, and to analyze the influence of water coordination on these effects, we have also performed calculations for Cu2+AN7T using four water molecules with different coordination modes. These configurations have been denoted as (m,n)Mn+AN7T, where m is the number of molecules interacting with the cation in the first shell and n equals the number of water molecules in the second solvation shell. Figure 5 only shows the canonical base pairs, although all minima arising from both SPT and DPT processes have been found with the sole exception of (4,0)Cu2+AN7T, for which only the DPT product has been located. It can be observed that the (4,0)Cu2+AN7T structure presents a square pyramid coordination, with adenine’s N7 and three water molecules in the same plane. The fourth water molecule is situated in the axial position with a longer metal-ligand distance. (3,1)Cu2+AN7T shows a tetragonal coordination around the cation, while (2,2)Cu2+AN7T presents a trigonal planar disposition involving two inner-sphere water molecules and adenine’s N7 basic site. Finally, (1,3) coordination mode shows a linear structure, involving adenine’s N7 and one water molecule. The other three water molecules are disposed in the outer sphere, and only one of them interacts with the nucleobases through one hydrogen bond with adenine’s amino group. It is important to mention that these coordination modes are maintained along the different proton-transfer processes. That is, no water molecule is found to move from or to the inner shell, so that no novel interactions involving hydrogen bonds appear along proton-transfer processes within the same solvation mode. This is an energetically important fact as it allows us to relate energy differences to the different electrostatic and oxidative effects of the metal cation and not to the different water-water or water-nucleobase interactions arising along the protontransfer processes. Table 2 shows that charge and spin distribution strongly depend on the coordination mode of the metal cation. That is, the smaller the coordination number of the metal cation is, the larger are the oxidative effects of Cu2+; that is, the spin density values on the base pair increase. Note that the largest values of spin density at the metal cation appear for (4,1) and (4,0) complexes, whereas for (3,1), (2,2), and (1,3) coordination modes the spin density mainly lies at the thymine moiety as for the non-solvated system. A comparison between B3LYP and BHLYP methods indicates that B3LYP provides a more delocalized picture of the electron hole. This is especially important for the (3,1) complex for which the spin density at the B3LYP level is distributed all over the system, whereas at the BHLYP level it is localized at the thymine moitey. However, trends with both methods are the same: the larger is the coordination number of Cu2+, the larger is the spin density at metal cation. Table 3 shows the relative energies of each proton-transferred product relative to the corresponding canonical structure. One of the most relevant trends is that double proton-transferred products are high in energy in all cases. In the DPT products, the electronic distribution is the same as in the corresponding reactants, and thus their energetic is determined by the intrinsic basicity of the atoms involved in the double proton-transfer process. On the other hand, as mentioned, SPT1 and SPT2 products are not found for the (4,1) and (4,0) coordination modes. Nevertheless, they might be stabilized by the presence of the radical character on the base pair. That is, they can be characterized as minima on the potential energy surface for the

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Figure 4. B3LYP energy profile and main geometry parameters of the stationary points found for the double proton-transfer reaction in the (4,1) Cu2+AN7T system. BHLYP values are shown in italics.

Figure 5. B3LYP optimized geometries for the four different coordination modes of (4H2O)‚Cu2+AN7T. Distances are in angstroms.

(1,3), (2,2), and (3,1) solvation modes, for which oxidation of the base pair becomes more significant (see above). Similarly to bare Cu2+AT, the SPT1 product corresponds to a [(H2O)4‚ Cu+-A(+H+)+-T(-H+)•], whereas SPT2 product can be described as [(H2O)4‚Cu+A(-H+)•-T(+H+)+], where the radical has moved from thymine to adenine due to the adenine f thymine electron transfer that accompanies the SPT2 proton transfer. Therefore, the presence of the radical at the base pair appears to be crucial for the single proton-transfer processes to exist. Surprisingly, the relative energy of proton-transferred products is very similar in all cases. In this way, the electrostatic effects of the copper cation are similar regardless of whether

one, two, or three water molecules are directly coordinated to the metal cation. On the other hand, SPT2 products are always less stable than the SPT1 ones. This is due to the lower basicity of the O4 atom as compared to that of N1. The trends observed are similar with both DFT methods, although with BHLYP the SPT species become more stabilized due the larger localization of the radical character at the base pair. For Cu2+ coordination in the minor groove, the metal cation is not found to be directly coordinated to one of the basic centers of the nucleobases, either thymine’s O2 or adenine’s N3. Optimization calculations with five water molecules and the specified basic center of the base pair (N3 or O2) interacting

Cu2+/+ Cation Coordination to AT Base Pair

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TABLE 2: Charge and Spin Densities (in Parentheses) for Pentasolvated and Tetrasolvated Systems from Natural Population Analysis (4,1)

B3LYP BHLYP (4,0) B3LYP BHLYP (3,1) B3LYP BHLYP (2,2) B3LYP BHLYP (1,3) B3LYP BHLYP (2,2,1) B3LYP BHLYP

metal

adenine

thymine

(m+n)‚H2O

1.38(0.63) 1.60(0.84) 1.22(0.43) 1.60(0.84) 0.99(0.19) 0.86(0.00) 0.95(0.16) 0.85(0.00) 0.76(0.00) 0.80(0.00) 0.79(0.00) 0.85(0.00)

0.25(0.11) 0.19(0.06) 0.20(0.07) 0.21(0.06) 0.34(0.24) 0.14(0.00) 0.34(0.22) 0.15(0.00) 0.44(0.30) 0.18(0.00) 0.88(0.94) 0.94(1.00)

0.14(0.11) 0.03(0.00) 0.42(0.43) 0.03(.00) 0.52(0.55) 0.91(1.00) 0.57(0.60) 0.91(1.00) 0.66(0.70) 0.91(1.00) 0.15(0.06) 0.08(0.00)

0.23(0.15) 0.18(0.10) 0.17(0.07) 0.15(0.09) 0.15(0.02) 0.09(0.00) 0.14(0.02) 0.09(0.00) 0.14(0.00) 0.11(0.00) 0.18(0.00) 0.13(0.00)

TABLE 3: B3LYP(BHLYP) Relative Energies (kcal mol-1) of Each Proton-Transfer Product Relative to the Corresponding Canonical Structure for the Cu2+AN7T Systems (m,n)

(m,n)AT

(4,1) (4,0) (3,1) (2,2) (1,3) (0,0) (2,2,1)

0.0 0.0 0.0 0.0 0.0 0.0 0.0

(m,n)SPT1

-0.2(-3.9) -0.5(-3.9) -1.4(-2.9) 4.5(4.6) 5.5(5.3)

(m,n)SPT2

4.2(-1.7) 3.3(-0.6) 4.1(0.6) 8.2(5.4) 3.1(2.5)

(m,n)DPT 10.0(14.9) 14.0(14.6) 11.9(-) 11.0(-) 11.9(-) 8.9(8.0)

with the metal cation in an octahedral disposition as the starting point lead to an outer-shell simultaneous coordination with the basic centers of both nucleobases (see Figure 6). The water molecules evolve to a linear disposition with two water

molecules around the metal cation, whereas the remaining water molecules are disposed in outer solvation shells. That is, water molecules belonging to the solvation sphere act as a bridge between basic centers of the two monomers. This is in agreement with the concept of hydration spine of DNA found in the literature,28 which postulates a highly structured disposition of solvated cations in the minor groove of DNA. This system is referred as (2,2,1)Cu2+AHydT and allows the interaction of the solvated metal cation with the nucleobase with a very slight deformation of the base pair. Coordination to the minor groove by the metal cations is more stable than coordination to the major groove through the N7 basic center. That is, (2,2,1)Cu2+AHydT is 4.3(13.6) kcal mol-1 more stable than (4,1)Cu2+AN7T at the B3LYP(BHLYP) levels of theory. Charge and spin distribution show that for (2,2,1)Cu2+AHydT there is an electron transfer from adenine to the metal cation in such a way that the spin is almost entirely located at this nucleobase (see Table 2). This behavior is closely related to the type of coordination in which water molecules are disposed. Linear coordination strongly stabilizes a d10 closed-shell electronic configuration for copper; that is, it favors the Cu+ oxidation state. Contrarily, square pyramid coordination around the cation, which is found for (4,1)Cu2+AN7T (see above), favors an open-shell, d9, electronic configuration for the cation, that is, a Cu2+ oxidation state, due to the ligand field created by the water molecules. In this latter case, the orbital lying in the coordination plane strongly interacts with the electron pair of water molecules, and thus the full occupation of this orbital is extremely unstabilizing. However, the splitting of d orbitals experienced by the metal cation due to the ligand field is much

Figure 6. B3LYP energy profile and main geometry parameters of the minima located for the proton-transfer processes in minor groove (2,2,1)penta-hydrated Cu2+AN7T system. BHLYP values are shown in italics.

4824 J. Phys. Chem. B, Vol. 112, No. 15, 2008 smaller when the metal is linearly coordinated by only two water molecules. Moreover, the dz2 orbital pointing to the lone pair of water molecules can minimize repulsion by sd hybridization. Thus, oxidation preferably takes place at the base pair, particularly at adenine, which is the nucleobase with a lower ionization energy. Consequently, for this open-shell (2,2,1)Cu2+AHydT system, the N6-O4 hydrogen bond is drastically strengthened and the N1-N3 hydrogen bond is weakened. For this Cu2+ coordination, all SPT1, SPT2, and DPT products have been found to be stable at the B3LYP level of theory. Energy profiles and optimized structures are shown in Figure 6. It can be observed that all of these proton-transfer reactions are endothermic, the SPT2 one being the most favorable process. This is in agreement with the fact that the radical character lies at adenine, which significantly enhances the N6 acidity. After the proton transfer, the radical character remains at adenine. However, in the SPT1 reaction, the proton transfer from thymine to adenine is accompanied by an electron transfer, the final product having the radical character at thymine. This reaction is somewhat more endothermic than SPT2 and significantly less favorable than the same reaction for the (3,1), (2,2), and (1,3) (H2O)4Cu2+AN7T coordinated system for which this proton-transfer reaction is found to be exothermic. This is related to the fact that in these particular (H2O)4Cu2+AN7T species the radical is mainly located on thymine, whereas in (2,2,1)Cu2+AHydT the radical character is on the adenine moiety. Finally, the double proton-transfer reaction is the process that is found to be less favorable. Overall, the results obtained for the hydrated systems indicate that the ability of Cu2+ to induce oxidation is highly dependent on the solvation sphere of the metal cation and the basic site that is interacting with. At this point, it is worth mentioning that whereas the changes on the oxidative character of Cu2+ with its coordination environment are expected to be well described with the models adopted in the present study, the changes on the electrostatic interactions induced by the solvent are only partially introduced, the screening by long-range interactions not being taken into account. The influence of these interactions on the proton-transfer energy profiles, however, is expected to be minor as compared to that provided by oxidative effects. Conclusions Gas-phase results indicate that coordination of Cu+ cation to adenine, either N7 or N3, does not produce any significant qualitative changes with respect to the neutral system. The double proton-transfer tautomer is the only stable product found, its relative energy with respect to the canonical form being somewhat higher in energy than that for the neutral system. However, when Cu+ interacts with thymine, through the O2 carbonyl atom, the single proton-transfer SPT1 process becomes spontaneous, and thus rare forms of the DNA bases may appear. It must be mentioned, however, that Cu+ affinity for this site is the lowest of the three considered basic centers. For Cu2+ cation coordinated to N7 and N3 of adenine, however, important effects on proton-transfer processes appear due to oxidation of the base pair, in particular of the pyrimidine moiety. As a consequence, both thymine to adenine (SPT1) and adenine to thymine (SPT2) single proton-transfer processes are found to be possible and more favorable than for the neutral system. The first one involves the transfer of a proton, whereas in the second one, SPT2, the proton transfer is accompanied by a π electron transfer from adenine to thymine. Finally, results for hydrated Cu2+ show that the presence of water molecules coordinated to the metal cation can strongly

Noguera et al. influence its ability to induce oxidation on the base pair. For pentacoordinated Cu2+ interacting with N7 of adenine, only the DPT process is found to be possible as found for the analogous bare Cu+ system. However, coordination of hydrated Cu2+ to N3 of adenine or O2 of thymine leads to a structure in which water molecules belonging to the solvation sphere act as a bridge between basic centers of the two monomers in agreement with the postulated highly structured disposition of solvated cations in the minor groove of DNA. In this environment, the metal cation oxidizes adenine, and single proton-transfer reactions become more favorable than the double proton-transfer one. In a general perspective, we can say that the chemistry of proton-transfer processes in AT base pair when coordinated to a metal cation through N7 or N3 is not qualitatively modified if the interaction of the metal cation with the nucleobases is solely electrostatic. However, when oxidative effects appear and a positive charge is driven from the metal center to the base pair, single proton-transfer products become energetically accessible as the charge distribution on the base pair is totally different. Nevertheless, the ability of Cu2+ to induce oxidation is highly dependent on the solvation sphere of the metal cation and the basic site that it is interacting with. Acknowledgment. Financial support from MCYT and DURSI, through the CTQ2005-08797-C02-02/BQU and SGR2005-00244 projects, and allowance of computer resources from the CESCA supercomputing center are gratefully acknowledged. References and Notes (1) Lippert, B. Coord. Chem. ReV. 2000, 200-202, 487. (2) Sigel, A.; Sigel, H. Metal Ions in biological systems: Interactions of metal ions with nucleotides, nucleic acids, and their constituents; Marcel Dekker: New York, 1996; Vol. 32. (3) Rosenberg, B.; VanCamp, L.; Trosko, J. E.; Mansour, V. H. Nature 1969, 222, 385. (4) Bregadze, V. G. Met. Ions Biol. Syst. 1996, 32, 419. (5) Martin, R. B. Acc. Chem. Res. 1985, 18, 32. (6) Burda, J. V.; Sponer, J.; Hobza, P. J. Phys. Chem. 1996, 100, 7250. (7) Song, B.; Zhao, J.; Griesser, R.; Meiser, C.; Sigel, H.; Lippert, B. Chem.-Eur. J. 1999, 5, 2374. (8) Russo, N.; Toscano, M.; Grand, A.; Jolibois, F. J. Comput. Chem. 1998, 19, 989. (9) Cerda, B. A.; Wesdemiotis, C. J. Am. Chem. Soc. 1996, 118, 11884. (10) Petrov, A. S.; Lamm, G.; Pack, G. P. J. Phys. Chem. B 2002, 106, 3294. (11) Petrov, A. S.; Pack, G. P.; Lamm, G. J. Phys. Chem. B 2004, 108, 6072. (12) Fonseca Guerra, C.; Bickelhaupt, F. M.; Snijders, J. G.; Baerends, E. J. J. Am. Chem. Soc. 2999, 122, 4117. (13) Fonseca Guerra, C.; Bickelhaupt, F. M. Angew. Chem., Int. Ed. 1999, 38, 2942. (14) Gadre, S. R.; Pundlik, S. S.; Limaye, A. C.; Rendell, A. P. Chem. Commun. 1998, 573. (15) Gresh, N.; Sponer, J. J. Phys. Chem. B 1999, 103, 11415. (16) Sponer, J.; Sabat, M.; Gorb, L.; Leszczynski, J.; Lippert, B.; Hobza, P. J. Phys. Chem. B 2000, 104, 7535. (17) Sigel, R. K. O.; Lippert, B. Chem. Commun. 1999, 2167. (18) Burda, J. V.; Sponer, J.; Hraba´kova´, J.; Zeizinger, M.; Leszczynski, J. J. Phys. Chem. B 2003, 107, 5349. (19) Eichorn, G. L.; Shin, Y. A. J. Am. Chem. Soc. 1968, 90, 73237328. (20) Mun˜oz, J.; Sponer, J.; Hobza, P.; Orozco, M.; Luque, F. J. J. Phys. Chem. B 2001, 105, 6051. (21) Noguera, M.; Bertran, J.; Sodupe, M. J. Phys. Chem. A 2004, 108, 333. (22) Rodgers, M. T.; Armentrout, P. B. Acc. Chem. Res. 2004, 37, 989. (23) Noguera, M.; Branchadell, V.; Constantino, E.; Rios-Font, R.; Sodupe, M.; Rodriguez-Santiago, L. J. Phys. Chem. A 2007, 111, 9823. (24) Tereshko, V.; Minasov, G.; Egli, M. J. Am. Chem. Soc. 1999, 121, 3590. (25) Mocci, F.; Saba, G. Biopolymers 2003, 68, 471. (26) Rueda, M.; Cubero, E.; Laughton, C. A.; Orozco, M. Biophys. J. 2004, 87, 800.

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