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Theoretical studies on the bonding of Cd2+ to adenine and thymine: Tautomeric equilibrium and metalation in base pairing
Chemical Physics Letters 467 (2009) 387–392
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Theoretical studies on the bonding of Cd2+ to adenine and thymine: Tautomeric equilibrium and metalation in base pairing Yan Wu, Rongjian Sa, Qiaohong Li, Yongqin Wei, Kechen Wu * State Key Laboratory of Structural Chemistry, Fujian Institute of Research on Structure of Matter, The Chinese Academy of Sciences, 155 Yangqiao Road W., Fuzhou, Fujian 350002, People’s Republic of China
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Article history: Received 10 September 2008 In final form 22 November 2008 Available online 3 December 2008
a b s t r a c t The influence of Cd2+ on nucleobases and base pairing has been studied systematically using high-level DFT method. Cd2+ strongly interacts with adenine (A), changing tautomer structures and affecting the tautomer equilibrium whereas the Cd2+-thymine (T) interaction barely shifts the equilibrium of T tautomers. The isoenergy of metal-bridged A–Cd2+–T base pair complexes in the same binding pattern reveals the absence of interaction between A and T. The effects of Cd2+ in H-bond base pairing have also been discussed to further understand the possible schemes in cadmium induced DNA mutations. Ó 2008 Elsevier B.V. All rights reserved.
1. Introduction Motivated by both biological and technological concerns, the role of metal ions in DNA systems has attracted great interest [1]. Metal ions play different roles in nucleic acids system depending on the type of the metals [2–4]. While alkali metals often bind to phosphate groups to steady DNA and RNA strands, transitionmetal ions predominately interact directly with nucleobases. Metal binding on nucleobases may have various consequences that would contribute to mutagenesis [5], including stabilizing rare tautomers [6–12], cross-linking between nucleobases [8,13–16], and enhancing the formation of certain non-Watson–Crick (WC) base pairs [17–20]. One representative of metal mutagenicity is platinum, which has caught great attention since the report of anticarcinogen cis-diamminedichloroplatinum(II) (cis-platin) in 1965 [21] and has been passionately studied through theoretical and experimental techniques [22]. Cadmium is accepted by the International Agency for Research on Cancer as a Category 1 (human) carcinogen [23]. It is a soft metal that prone to bind to nucleobases than phosphates [23,24]. The direct interaction of Cd2+ with nucleobases can either stabilize the DNA strand or cause redistribution of electron density in the nucleobase heterocyclic ring, which may diminish the phosphodiester bonds and lead to the unwinding of the DNA strand, depending on the concentration [3]. Although the interaction between Cd2+ and nucleobases has been widely studied, there are uncertainties remained on the exact mechanism of mutagenesis. It has been observed that Cd2+ directly interact with nucleobases, preferably with A and guanine (G) [12,25]. Hossain et al. [12] pointed out that * Corresponding author. Fax: +86 591 3792932. E-mail address: [email protected] (K. Wu). 0009-2614/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.cplett.2008.11.073
unlike Ni2+ which mainly cause the structure deformation on G, Cd2+ could notably changed the structure by interacting with A. The IR measurement confirmed that the deformation is irreversible. In another related report on the interaction of Cd2+ with DNA [26], the binding nature of Cd2+ to DNA was explored through enzyme digestion technique. The possible reason of Ssp1 digestion being prevented was assumed to be its disability to recognize the 20 -deoxyadenyl(30 ? 50 )-20 -deoxythymidine(AT) sites due to the Cd2+ induced structural modification in A. It was also suggested that misparing might occur because of the possible amino–imino tautomeric equilibrium shift of A induced by Cd2+ [12], however, the possible schemes of such metalation in base paring were not discussed. The purpose of this study is to investigate the interaction between Cd2+ and nucleobases systems via the first-principle DFT method to gain insights into DNA mutation. Specifically, our study is aimed at determining the Cd2+ binding induced tautomeric equilibrium change of nucleobases (A and T) and the impacts of the Cd2+ introduced changes in base pairing. We started from exploring the A and T tautomers, then the Cd2+-nucleobase complexes were extensively studied. The tautomeric equilibriums of metalated bases have been discussed and the base paring based on Cd2+–A base complexes and canonical form T has been investigated. 2. Computational details The nonlocal three-parameter hybrid DFT method (B3LYP) [27– 29] with the basis set of 6-311++G (3df, 2pd) for N, C, O and H atoms and the MWB relativistic core potential basis [30] for Cd atom was used in the geometric optimizations and energetic characteristics calculations. DFT results usually are well consistent with ab initio MP2 method at medium basis sets but are more computational
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economic [4,31]. Some similar calculations on the metal ion binding with nucleobases system were in reasonable agreement with the experimental data or the MP2 results at the compatible basis level [4,32,33]. The frequency calculations have also been carried out at the same level of theory to identify the energy minima, as well as to obtain the zero point energies and thermodynamic corrections. All the energies in this study were corrected for basis set superposition error (BSSE) using the standard counterpoise method [34]. The relative abundance rate is calculated base on the corresponding Boltzmann distribution. The atomic charge analysis was performed by the natural bonding orbital method (NBO) of Weinhold et al. [35]. No symmetry constrains were applied in the geometric optimizations. The A tautomers used in this Letter are the 14 tautomers previously proposed in Ref. [19], with two additional: A–1H–3H–1 and A–1H–3H–2. All A tautomers are named according to their hydrogen positions in the heterocyclic ring (N1, N3, N7, N9) and the orientation of hydrogen on the enol group (1 for anti, 2 for syn). The T tautomer T-O7HO8H is following the same nomenclature while other tautomers of T are named by of the movement of hydrogen atoms. For instance, A–1H–3H–1 stands for the A tautomer that have H atoms on N1 and N3 while the H on enol group stays in anti orientation and T–N1O2H stands for the T tautomer that originated by moving hydrogen from N1 to O2 position. In the metalated bases, the name code of Cd with its binding site prefixes the tautomer in order to specify each base complex. The atom numbering of A and T (Fig. 1) is followed the IUPAC standard nomenclature for nucleobases [36]. The 16 A tautomers with all available Cd2+ binding sites could originate 46 possible Cd2+–A combinations. Further geometric optimizations of all these combinations lead to the final stable Cd2+–A base complexes. The Cd2+–T base complexes are obtained in similar way. All the calculations are performed by GAUSSIAN 03 package [37].
3. Results and discussion 3.1. A and T tautomers The amino A–9H is the most stable one and A–7H succeeds to be the second in all the 16 A tautomers, which agrees with previous theoretical and experimental studies [19,38]. Canonical form T is the most stable tautomer, with 11.17 kcal/mol lower in energy than the second stable T-N1O4H. All other T tautomers are too high in energy to exist in nature environments. 3.2. Cd2+–A base complexes Totally 26 stable Cd2+–A base complexes are obtained from the optimization results. In general, metal ions are feasible to deviate while the A molecules substantially stay within the original quasi-planar form. In seven Cd2+–A base complexes with H atoms
Fig. 1. Canonical form A and T in the numbering with selected distances (in Å).
being adjacent to the metal binding site, Cd2+ was forced out of the molecular plane because of the repulsion from adjacent hydrogen [39]. Whereas, it is only in the cases that Cd2+ binding on N1/ N7 position of amino tautomers (like Cd–N7–A–9H*), the amino groups rotate out of the heterocyclic plane as the energy could be reduced by allowing Cd2+ access to the nitrogen lone pairs. The relative energies (Er), interaction energies (DEin) of all Cd2+– A base complexes with their relative abundance rates (Nr) in order are illustrated in Fig. 2. The influence of the initial tautomers is also included in the final Nr, so the Nr is not necessarily consistent with relative energy. However, Cd–N7/6–A–1H–9H–2, the most stable base complex (Fig. 3), is also the prevailed one (Nr = 99.99991%). In other words, the dominate tautomer with the binding of Cd2+ is not the canonical form but A–1H–9H–2, the so called imino form in experiments [40,41] instead. This high occurrence of Cd–N7/6– A–1H–9H–2 base complexes commendably confirms that Cd2+ ions could switch amino-imino equilibrium [12] of A. The two successional base complexes are Cd–N3–A–7H and Cd–N7–A–9H* (Fig. 3), with 12.05 and 24.74 kcal/mol higher in energy. Cd–N3– A–7H is based on A–7H, which is the second prevailed tautomer and Cd–N7–A–9H* is originated from the canonical form but the amino group pyramidalized. These results clearly indicate that Cd2+–A binding changes the equilibriums of A tautomers and preferably supports certain rare tautomers. The tautomeric equilibrium change of A is not only resulted from the lower energy of several Cd2+–A rare tautomer base complexes, but also owning to the Cd2+ induced transformation among certain A tautomers. For instance, during the optimization of Cd– N7–A–1H–9H–1, hydrogen atom on imino group (N6) switches from the anti into the syn form (Fig. 4), which leads to the Cd– N7/6–A–1H–9H–2. Therefore, in addition to the anticipated A– 1H–9H–2, A–1H–9H–1 also contributes to the high occurrence of Cd–N7/6–A–1H–9H–2. The switching of hydrogen is caused by the repulsion between H atom and Cd cation, which could be big enough to overcome the tautomer energy barriers. After the transformation, Cd2+ ion bonds to A bidentately. In accordance, the affinity energy reduces for 20–30 kcal/mol comparing with the monodentate one. Such transformation did not occur in the case of Ag+, which is strong covalently bond with nucleobases and also stabilizes imino form of A tautomer [19], as those like Cd–N7–A– 1H–9H–1 that transformed to others in Cd2+–A remain in the Ag+–A base complexes. The influence of Cd cation on electron density distribution is stronger than that of Ag+ (0.35 vs. 0.12 au positive charges are shifted away from the metal cation to A heterocyclic ring both in the imino tautomer case). This is not only because of the more charges that Cd2+ owns, but also due to the difference of metal ions which could be related with ionization energy (IE). The second IE of Cd2+ is larger than that of A (17.4 vs. 13.4 eV) while the first IE of Ag+ is close to that of A (8.1 vs. 8.0 eV), which implies stronger tendency of positive charge transfer from metal ions to bases in the Cd2+–A base complexes. Therefore, Cd2+ is expected to have stronger impact in DNA systems. In fact, it has been observed [42] that Cd2+ leads to more damages than Ag+ does when interacting with DNA strand, especially in high concentration. While in the gas phase, the abundance order of Cd2+–A complexes mainly depends on the ionic-electrostatic effect; in the solvent environment, it is also subtle to influences such as charge transfer and polar effect due to the solvent screening. Thus, we also include the polarized continuum model (PCM) to account for the influence of solution environment. The abundance order of A tautomers undergoes no disturbing while their energy differences are reduced with the influence of solvent effect. The energy difference in Cd2+–A complexes also undergoes similar decrease, which results in that more complexes have considerable occurrences than in the gas phase. The most abundant Cd2+–A complex is changed,
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Fig. 2. The first three most abundant Cd2+–A base complexes in gas phase with selected distances in Å (* with rotated amino group).
Fig. 3. Relative energy (Er), interaction energy (DEin) and relative abundance rate (Nr) of 26 stable Cd2+–A base complexes. The influence of initial tautomers has been included in the relative abundance rates (* with rotated amino group, R with Cd cation rotated out of molecule plane).
Fig. 4. Cd2+ induced A tautomer transformation: from A–1H–9H–1 to A–1H–9H–2.
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but Cd–N7/6–A–1H–9H–2 and Cd–N3–A–7H still remain relatively high occurrences. However, while in the gas phase the Cd–N7–A– 9H* is lower in energy than the corresponding planar Cd–N7–A– 9H, the planar form shows priority in solvent since the amino group wrapped by water molecules is reluctant to interact with metal cation. 3.3. Cd2+–T base complexes It is commonly agreed that metal binding or solvent effects do not change the tautomer equilibrium of T [43]. At the presence of Cd2+ ions, Cd–O4–T–N1O2H is the most stable complex, with 2.60 kcal/mol lower in energy than the next stable one. However, canonical T originated Cd–O4–T (Nr = 99.96438%) is the one which has dominant occurrence in all Cd–T base complexes, in considering of initial tautomer abundance rates. It is followed by another base complex with the same origin, Cd–O2–T (Nr = 0.03556%), which has a larger dipole moment but smaller DEin (see Table 1). When solvent effect is included by using PCM, the differences between complexes are reduced as anticipated, and the Cd–O2–T complex becomes the most stable one. Taken the dominant abundance rate of canonical form T, the Cd–O2–T complex would be absolutely abundant in the Cd–T base complexes. Thus, there is coherence within the study of Cd–T considering solvent effect and the gas phase result that Cd could hardly change the tautomer equilibrium of T. 3.4. (Cd2+–A)–T base pair complexes Three of Cd2+–A base complexes, Cd–N7/6–A–1H–9H–2, Cd– N3–A–7H and Cd–N7–A–9H*, are selected as the building units to explore the influence of Cd2+ metalation on base pairing. Those are typical N7 (the preferred binding site in DNA helix) and N3 (the minor groove binding site) binding complexes. And according to the above studies, it is clear that Cd cation binding has pronounced effects on the bases. Thus, they could be efficient samples in evaluating metalation effects. The Cd2+–A base complexes were combined with the canonical form T in two different ways according to the position of Cd cation in bases. Firstly, as experimentally revealed [44], Cd cation is supposed to form the bridge bond between bases. Only Cd–N7/6–A–1H–9H–2 is the focus to study this mispairing aspect of the amino–imino shift here. T molecules were accessed to the Cd site with O4 (or O2) in opposite orientations to A, which resulted in four different complexes (as we named O4BP-1/2 and O2BP-1/2 in Fig. 5). While the Cd–A bond stays rigid, T adapts to different geometries in a flexible way in the A–Cd2+–T base-pair complexes. T in both O2 binding base pairs remains its orientation though the molecule deviated out of the A plane for 33/44°, but in O4BPs (Fig. 5),
Table 1 The dipole moments (in debye), energetic characteristics (in kcal/mol) and relative abundance order of Cd2+–thymine base complexesa. Molecular code
l
Er
DEin
Cd–O4–T–N1O2H Cd–O4–T–N3O2H Cd–O2–T–N3O4H Cd–O4–T Cd–N1–T–O2HO4H Cd–O4–T–N1O2H Cd–O2–T Cd–N3–T–O2HO4H Cd–N1–T–N1O2H Cd–O2 –T–N3O2H
2.85 5.98 1.76 4.88 3.31 1.21 5.91 3.44 3.81 5.63
0.00 2.60 4.61 16.57 19.36 19.51 21.27 34.14 40.63 91.36
190.13 183.84 176.00 152.85 163.17 160.68 148.30 149.19 140.26 97.18
a
l, Dipole moments; Er, relative energies; DEin, interaction energies.
Fig. 5. Metal-bridged A and T base pairs of Cd–N7/6–A–1H–9H–2 with selected distances (in Å), bond angles and nets charges of each part(in au). Also given are the relative energy (in kcal/mol), interaction energy (in kcal/mol) and dipole moment (in debye). (a) O4BP-1; (b) O4BP-2; (c) O2BP-1; and (d) O2BP-2.
the molecule tends to take in the orientation of 1. In the O4BP-2, T undergoes a twist with 43° angle between two base planes in order to change its orientation, which leads the complex to a local energy minimum. The electron density distribution of these ionized complexes indicates that Cd–T interaction is much weaker than that of Cd–A. While both A and T associate with the metal ion as electron donors, less charge is found to transfer from T to Cd entity. This could also be explained by the IE of bases. A is the favored positive charges carrier in A–Cd2+–T base pair complexes since the computed value of A (8.1 eV) is 0.7 eV lower than that of T (8.8 eV). Though T was arranged differently, the two O4BPs are almost identical in energy (so do the O2 BPs), indicating weak interaction between A and T. Schreiber and González [19] mentioned the isoenergy of non-planar and planar structures in such metalbridged base pairs, which should also result from the lack of
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pair. Given the M–A group fixed, the difference of these A–M–T complexes is mainly due to the binding patterns of the M–T part. In accordance with the Cd–O2–T and Cd–O4–T, O2BPs have a smaller dipole moment and the lower energy than O4BPs do. However, while the difference of their interaction energy is reduced (4.50 vs. 2.80 kcal/mol) as anticipated, the difference between dipole moment is enlarged (1.03 vs. 3.08 D), which implies that cooperative influence could not be neglected in polar effect. The possibility of Cd2+ binding in peripheral position is also taken into account to evaluate the influence of Cd2+ in H-bond base pairs. From the aforementioned three metalated bases, eight stable Cd2+–A–T base pairs were obtained (four of them are illustrated in Fig. 6). As a weak interaction, the DE here is about 40 kcal/mol as we listed in the Table 2, much less than that of the bridge bonding pattern. All base pairs maintain near planar structures except Cd– N7–A–9H*–WCBP and the corresponding reverse Watson–Crick (RWC) one, in which T adapts to the pyramidalized amino group of A molecule by deviating out of the original molecular plane in order to maintain the N–H O bond. Such Cd–N7–A–9H*–WCBP could transform into the planar Cd–N7–A–9H–WCBP during proton transfer processes [45]. The Cd2+–A base complexes are proton abundant owning to the extra positive charge introduced by metal ions. This has pronounced influence on base paring. For those sites act as proton donors, the H-bond binding ability is strengthened and consequently H-bond length is shorter, whereas the H-bond binding sites that accommodate protons, their potentials are weaken and H-bonds tend to be longer. In the Cd–N3–A–7H–WCBP complex, N–H O bond is 0.09 Å shortened while N H–N is elongated for 0.13 Å as shown in Table 2. The total H-bond interaction between A and T in Cd–N3–A–7H–WCBP is slightly weaker (so does the Cd–N3– A–7H–RWCBP), as its total H-bond energy reduces for 0.35 kcal/ mol. However, in the other metalated base pairs like Cd–N7/6– A–1H–9H–2–N39O2BP, of which the N–H O bonds are evidently shortened for 0.34 Å, the H-bond binding ability of A is strengthened. Accordingly, there are significance increases in H-bond energy. As a result, mispairing might arise since changes in H-bond capacity ability of A would affect its sensibility in selecting noncomplementary bases [5]. The net atomic charges of Cd2+–A–T base pair complexes on A, T and the metal ions are also shown in Fig. 6. Considerable positive charges are located on the counterpart T (about 0.4 au) while in the non-metalated base pairs it almost stays neutral. It is worth noting that the amount of charge on T is larger than that A accommodates despite A has lower IE, as a result of that the electrostatic repulsion between the ionized base pair and metal cation surpasses the influence of IE [45]. Extra charges greatly shift the total electron density distribution as well as modify the molecule structure. With more positive charge distributes in the heterocyclic ring, the exocyclic methyl groups become more negative, which reduces the bond-length between the endocyclic C and methyl function.
Fig. 6. The Cd2+–A–T H-bond base pair complexes with selected distances (in Å) and net charges of each part (in au).
correlations between A and T bases. Thus, these metal-bridged base pairs could be considered as analog of two pieces of metal– nucleobase (M–NB) systems. From this point of view, the characters of M-NB would imply many features of the metal-bridged base
Table 2 0 Å) and H-bond energies (EH in kcal/mol) of Cd2+ metalated A–T base pairsa,b. The interaction energy (DE in kcal/mol), H-bond lengths (H1, N–H O; H2, N H–N in A Molecular code *
Cd–N7–A–9H –WCBP Cd–N7–A–9H*–RWCBP Cd–N7–A–9H*–N39O2BP Cd–N7–A–9H*–N39O4BP Cd–N7/6–A–1H–9H–2–N39O2BP Cd–N7/6–A–1H–9H–2–N39O4BP Cd–N3–A–7H–RWCBP Cd–N3–A–7H–WCBP a b
DE
H1
H2
EH
44.91 43.01 46.45 44.74 38.37 38.35 37.35 40.77
1.559(0.289) 1.617(0.328) 1.644(0.228) 1.610(0.245) 1.595(0.299) 1.570(0.345) 1.846(0.086) 1.801(0.095)
2.187(0.260) 2.199(0.349) 2.244(0.395) 2.203(0.352) 2.205(0.351) 2.309(0.461) 1.980(0.142) 1.996(0.134)
10.91(6.76) 9.56(4.59) 9.99(5.23) 9.83(5.07) 10.26(5.54) 13.75(8.90) 4.04(1.01) 4.28(0.35)
The H-bond energy is calculated using Eq. (2) in Ref. [46]. Values in parentheses represent the differences with corresponding non-metalated base pairs.
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4. Conclusions The high-level DFT calculations have been performed on the influence of Cd2+ on nucleobases (A and T) and base pairing. The gas phase study agrees with the experiment that Cd2+ changes the equilibriums of A tautomers to stable the rare tautomer complex Cd–N7/6–A–1H–9H–2. More Cd2+–A complexes have reasonable abundance rate due to the energy difference diminishes in solvent effect while the abundant tautomers of gas phase substantially remain high occurrence. Study in both gas phase and solvent agrees that tautomeric equilibrium of T could be hardly affected by Cd2+ binding. The charge transfer effect plays great role in engendering features of Cd2+–A–T base pairs. In the metal-bridged base pairs, the correlation between A and T is weak and Cd–A interaction appeals stronger than the Cd–T interaction. With the binding of Cd2+, structure of T in the H-bond metalated base pairs was deformed due to the disturbed electron density distribution; meanwhile, H-bonds in A–T base pairs experience significant changes that might contribute to mispairing. Comparing with the H-bond binding, the bridge bonding pattern is stronger but less depended on the orientation, it is also less conformationally restricted since the structure do not have to be planar. Thus, with Cd2+ involves, the bridge bonding pattern should be experimentally preferred. These theoretical results of the Cd2+ metalated base pairing would be helpful to understanding the nature of cadmium-induced mutagenesis. Acknowledgement We acknowledge the financial supports from MOST Projects (2006DFA43020 and 2007CB815307), FJIRSM key Project (SZD08003) and Fujian Province Project (2006F3133). Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.cplett.2008.11.073. References [1] R.G. Endres, D.L. Cox, R.R. Singh, Rev. Mod. Phys. 76 (2004) 195. [2] J.E. Šponer, J.V. Burda, J. Leszczynki, J. Šponer, in: J. Šponer, F. Flankaš (Eds.), Interaction of Metal Cations with Nucleic Acids and their Building Units, Springer, Netherlands, 2006, p. 389. [3] B. Lippert, Coord. Chem. Rev. 200–202 (2000) 487. [4] M. Noguera, V. Branchadell, E. Constantino, J. Phys. Chem. A 111 (2007) 9823. [5] J. Muller, R.K.O. Sigel, B. Lippert, J. Inorg. Biochem. 79 (2000) 261.
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Theoretical studies on the bonding of Cd2+ to adenine and thymine: Tautomeric equilibrium and metalation in base pairing Yan Wu, Rongjian Sa, Qiaohong Li, Yongqin Wei, Kechen Wu * State Key Laboratory of Structural Chemistry, Fujian Institute of Research on Structure of Matter, The Chinese Academy of Sciences, 155 Yangqiao Road W., Fuzhou, Fujian 350002, People’s Republic of China
a r t i c l e
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Article history: Received 10 September 2008 In final form 22 November 2008 Available online 3 December 2008
a b s t r a c t The influence of Cd2+ on nucleobases and base pairing has been studied systematically using high-level DFT method. Cd2+ strongly interacts with adenine (A), changing tautomer structures and affecting the tautomer equilibrium whereas the Cd2+-thymine (T) interaction barely shifts the equilibrium of T tautomers. The isoenergy of metal-bridged A–Cd2+–T base pair complexes in the same binding pattern reveals the absence of interaction between A and T. The effects of Cd2+ in H-bond base pairing have also been discussed to further understand the possible schemes in cadmium induced DNA mutations. Ó 2008 Elsevier B.V. All rights reserved.
1. Introduction Motivated by both biological and technological concerns, the role of metal ions in DNA systems has attracted great interest [1]. Metal ions play different roles in nucleic acids system depending on the type of the metals [2–4]. While alkali metals often bind to phosphate groups to steady DNA and RNA strands, transitionmetal ions predominately interact directly with nucleobases. Metal binding on nucleobases may have various consequences that would contribute to mutagenesis [5], including stabilizing rare tautomers [6–12], cross-linking between nucleobases [8,13–16], and enhancing the formation of certain non-Watson–Crick (WC) base pairs [17–20]. One representative of metal mutagenicity is platinum, which has caught great attention since the report of anticarcinogen cis-diamminedichloroplatinum(II) (cis-platin) in 1965 [21] and has been passionately studied through theoretical and experimental techniques [22]. Cadmium is accepted by the International Agency for Research on Cancer as a Category 1 (human) carcinogen [23]. It is a soft metal that prone to bind to nucleobases than phosphates [23,24]. The direct interaction of Cd2+ with nucleobases can either stabilize the DNA strand or cause redistribution of electron density in the nucleobase heterocyclic ring, which may diminish the phosphodiester bonds and lead to the unwinding of the DNA strand, depending on the concentration [3]. Although the interaction between Cd2+ and nucleobases has been widely studied, there are uncertainties remained on the exact mechanism of mutagenesis. It has been observed that Cd2+ directly interact with nucleobases, preferably with A and guanine (G) [12,25]. Hossain et al. [12] pointed out that * Corresponding author. Fax: +86 591 3792932. E-mail address: [email protected] (K. Wu). 0009-2614/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.cplett.2008.11.073
unlike Ni2+ which mainly cause the structure deformation on G, Cd2+ could notably changed the structure by interacting with A. The IR measurement confirmed that the deformation is irreversible. In another related report on the interaction of Cd2+ with DNA [26], the binding nature of Cd2+ to DNA was explored through enzyme digestion technique. The possible reason of Ssp1 digestion being prevented was assumed to be its disability to recognize the 20 -deoxyadenyl(30 ? 50 )-20 -deoxythymidine(AT) sites due to the Cd2+ induced structural modification in A. It was also suggested that misparing might occur because of the possible amino–imino tautomeric equilibrium shift of A induced by Cd2+ [12], however, the possible schemes of such metalation in base paring were not discussed. The purpose of this study is to investigate the interaction between Cd2+ and nucleobases systems via the first-principle DFT method to gain insights into DNA mutation. Specifically, our study is aimed at determining the Cd2+ binding induced tautomeric equilibrium change of nucleobases (A and T) and the impacts of the Cd2+ introduced changes in base pairing. We started from exploring the A and T tautomers, then the Cd2+-nucleobase complexes were extensively studied. The tautomeric equilibriums of metalated bases have been discussed and the base paring based on Cd2+–A base complexes and canonical form T has been investigated. 2. Computational details The nonlocal three-parameter hybrid DFT method (B3LYP) [27– 29] with the basis set of 6-311++G (3df, 2pd) for N, C, O and H atoms and the MWB relativistic core potential basis [30] for Cd atom was used in the geometric optimizations and energetic characteristics calculations. DFT results usually are well consistent with ab initio MP2 method at medium basis sets but are more computational
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economic [4,31]. Some similar calculations on the metal ion binding with nucleobases system were in reasonable agreement with the experimental data or the MP2 results at the compatible basis level [4,32,33]. The frequency calculations have also been carried out at the same level of theory to identify the energy minima, as well as to obtain the zero point energies and thermodynamic corrections. All the energies in this study were corrected for basis set superposition error (BSSE) using the standard counterpoise method [34]. The relative abundance rate is calculated base on the corresponding Boltzmann distribution. The atomic charge analysis was performed by the natural bonding orbital method (NBO) of Weinhold et al. [35]. No symmetry constrains were applied in the geometric optimizations. The A tautomers used in this Letter are the 14 tautomers previously proposed in Ref. [19], with two additional: A–1H–3H–1 and A–1H–3H–2. All A tautomers are named according to their hydrogen positions in the heterocyclic ring (N1, N3, N7, N9) and the orientation of hydrogen on the enol group (1 for anti, 2 for syn). The T tautomer T-O7HO8H is following the same nomenclature while other tautomers of T are named by of the movement of hydrogen atoms. For instance, A–1H–3H–1 stands for the A tautomer that have H atoms on N1 and N3 while the H on enol group stays in anti orientation and T–N1O2H stands for the T tautomer that originated by moving hydrogen from N1 to O2 position. In the metalated bases, the name code of Cd with its binding site prefixes the tautomer in order to specify each base complex. The atom numbering of A and T (Fig. 1) is followed the IUPAC standard nomenclature for nucleobases [36]. The 16 A tautomers with all available Cd2+ binding sites could originate 46 possible Cd2+–A combinations. Further geometric optimizations of all these combinations lead to the final stable Cd2+–A base complexes. The Cd2+–T base complexes are obtained in similar way. All the calculations are performed by GAUSSIAN 03 package [37].
3. Results and discussion 3.1. A and T tautomers The amino A–9H is the most stable one and A–7H succeeds to be the second in all the 16 A tautomers, which agrees with previous theoretical and experimental studies [19,38]. Canonical form T is the most stable tautomer, with 11.17 kcal/mol lower in energy than the second stable T-N1O4H. All other T tautomers are too high in energy to exist in nature environments. 3.2. Cd2+–A base complexes Totally 26 stable Cd2+–A base complexes are obtained from the optimization results. In general, metal ions are feasible to deviate while the A molecules substantially stay within the original quasi-planar form. In seven Cd2+–A base complexes with H atoms
Fig. 1. Canonical form A and T in the numbering with selected distances (in Å).
being adjacent to the metal binding site, Cd2+ was forced out of the molecular plane because of the repulsion from adjacent hydrogen [39]. Whereas, it is only in the cases that Cd2+ binding on N1/ N7 position of amino tautomers (like Cd–N7–A–9H*), the amino groups rotate out of the heterocyclic plane as the energy could be reduced by allowing Cd2+ access to the nitrogen lone pairs. The relative energies (Er), interaction energies (DEin) of all Cd2+– A base complexes with their relative abundance rates (Nr) in order are illustrated in Fig. 2. The influence of the initial tautomers is also included in the final Nr, so the Nr is not necessarily consistent with relative energy. However, Cd–N7/6–A–1H–9H–2, the most stable base complex (Fig. 3), is also the prevailed one (Nr = 99.99991%). In other words, the dominate tautomer with the binding of Cd2+ is not the canonical form but A–1H–9H–2, the so called imino form in experiments [40,41] instead. This high occurrence of Cd–N7/6– A–1H–9H–2 base complexes commendably confirms that Cd2+ ions could switch amino-imino equilibrium [12] of A. The two successional base complexes are Cd–N3–A–7H and Cd–N7–A–9H* (Fig. 3), with 12.05 and 24.74 kcal/mol higher in energy. Cd–N3– A–7H is based on A–7H, which is the second prevailed tautomer and Cd–N7–A–9H* is originated from the canonical form but the amino group pyramidalized. These results clearly indicate that Cd2+–A binding changes the equilibriums of A tautomers and preferably supports certain rare tautomers. The tautomeric equilibrium change of A is not only resulted from the lower energy of several Cd2+–A rare tautomer base complexes, but also owning to the Cd2+ induced transformation among certain A tautomers. For instance, during the optimization of Cd– N7–A–1H–9H–1, hydrogen atom on imino group (N6) switches from the anti into the syn form (Fig. 4), which leads to the Cd– N7/6–A–1H–9H–2. Therefore, in addition to the anticipated A– 1H–9H–2, A–1H–9H–1 also contributes to the high occurrence of Cd–N7/6–A–1H–9H–2. The switching of hydrogen is caused by the repulsion between H atom and Cd cation, which could be big enough to overcome the tautomer energy barriers. After the transformation, Cd2+ ion bonds to A bidentately. In accordance, the affinity energy reduces for 20–30 kcal/mol comparing with the monodentate one. Such transformation did not occur in the case of Ag+, which is strong covalently bond with nucleobases and also stabilizes imino form of A tautomer [19], as those like Cd–N7–A– 1H–9H–1 that transformed to others in Cd2+–A remain in the Ag+–A base complexes. The influence of Cd cation on electron density distribution is stronger than that of Ag+ (0.35 vs. 0.12 au positive charges are shifted away from the metal cation to A heterocyclic ring both in the imino tautomer case). This is not only because of the more charges that Cd2+ owns, but also due to the difference of metal ions which could be related with ionization energy (IE). The second IE of Cd2+ is larger than that of A (17.4 vs. 13.4 eV) while the first IE of Ag+ is close to that of A (8.1 vs. 8.0 eV), which implies stronger tendency of positive charge transfer from metal ions to bases in the Cd2+–A base complexes. Therefore, Cd2+ is expected to have stronger impact in DNA systems. In fact, it has been observed [42] that Cd2+ leads to more damages than Ag+ does when interacting with DNA strand, especially in high concentration. While in the gas phase, the abundance order of Cd2+–A complexes mainly depends on the ionic-electrostatic effect; in the solvent environment, it is also subtle to influences such as charge transfer and polar effect due to the solvent screening. Thus, we also include the polarized continuum model (PCM) to account for the influence of solution environment. The abundance order of A tautomers undergoes no disturbing while their energy differences are reduced with the influence of solvent effect. The energy difference in Cd2+–A complexes also undergoes similar decrease, which results in that more complexes have considerable occurrences than in the gas phase. The most abundant Cd2+–A complex is changed,
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Fig. 2. The first three most abundant Cd2+–A base complexes in gas phase with selected distances in Å (* with rotated amino group).
Fig. 3. Relative energy (Er), interaction energy (DEin) and relative abundance rate (Nr) of 26 stable Cd2+–A base complexes. The influence of initial tautomers has been included in the relative abundance rates (* with rotated amino group, R with Cd cation rotated out of molecule plane).
Fig. 4. Cd2+ induced A tautomer transformation: from A–1H–9H–1 to A–1H–9H–2.
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but Cd–N7/6–A–1H–9H–2 and Cd–N3–A–7H still remain relatively high occurrences. However, while in the gas phase the Cd–N7–A– 9H* is lower in energy than the corresponding planar Cd–N7–A– 9H, the planar form shows priority in solvent since the amino group wrapped by water molecules is reluctant to interact with metal cation. 3.3. Cd2+–T base complexes It is commonly agreed that metal binding or solvent effects do not change the tautomer equilibrium of T [43]. At the presence of Cd2+ ions, Cd–O4–T–N1O2H is the most stable complex, with 2.60 kcal/mol lower in energy than the next stable one. However, canonical T originated Cd–O4–T (Nr = 99.96438%) is the one which has dominant occurrence in all Cd–T base complexes, in considering of initial tautomer abundance rates. It is followed by another base complex with the same origin, Cd–O2–T (Nr = 0.03556%), which has a larger dipole moment but smaller DEin (see Table 1). When solvent effect is included by using PCM, the differences between complexes are reduced as anticipated, and the Cd–O2–T complex becomes the most stable one. Taken the dominant abundance rate of canonical form T, the Cd–O2–T complex would be absolutely abundant in the Cd–T base complexes. Thus, there is coherence within the study of Cd–T considering solvent effect and the gas phase result that Cd could hardly change the tautomer equilibrium of T. 3.4. (Cd2+–A)–T base pair complexes Three of Cd2+–A base complexes, Cd–N7/6–A–1H–9H–2, Cd– N3–A–7H and Cd–N7–A–9H*, are selected as the building units to explore the influence of Cd2+ metalation on base pairing. Those are typical N7 (the preferred binding site in DNA helix) and N3 (the minor groove binding site) binding complexes. And according to the above studies, it is clear that Cd cation binding has pronounced effects on the bases. Thus, they could be efficient samples in evaluating metalation effects. The Cd2+–A base complexes were combined with the canonical form T in two different ways according to the position of Cd cation in bases. Firstly, as experimentally revealed [44], Cd cation is supposed to form the bridge bond between bases. Only Cd–N7/6–A–1H–9H–2 is the focus to study this mispairing aspect of the amino–imino shift here. T molecules were accessed to the Cd site with O4 (or O2) in opposite orientations to A, which resulted in four different complexes (as we named O4BP-1/2 and O2BP-1/2 in Fig. 5). While the Cd–A bond stays rigid, T adapts to different geometries in a flexible way in the A–Cd2+–T base-pair complexes. T in both O2 binding base pairs remains its orientation though the molecule deviated out of the A plane for 33/44°, but in O4BPs (Fig. 5),
Table 1 The dipole moments (in debye), energetic characteristics (in kcal/mol) and relative abundance order of Cd2+–thymine base complexesa. Molecular code
l
Er
DEin
Cd–O4–T–N1O2H Cd–O4–T–N3O2H Cd–O2–T–N3O4H Cd–O4–T Cd–N1–T–O2HO4H Cd–O4–T–N1O2H Cd–O2–T Cd–N3–T–O2HO4H Cd–N1–T–N1O2H Cd–O2 –T–N3O2H
2.85 5.98 1.76 4.88 3.31 1.21 5.91 3.44 3.81 5.63
0.00 2.60 4.61 16.57 19.36 19.51 21.27 34.14 40.63 91.36
190.13 183.84 176.00 152.85 163.17 160.68 148.30 149.19 140.26 97.18
a
l, Dipole moments; Er, relative energies; DEin, interaction energies.
Fig. 5. Metal-bridged A and T base pairs of Cd–N7/6–A–1H–9H–2 with selected distances (in Å), bond angles and nets charges of each part(in au). Also given are the relative energy (in kcal/mol), interaction energy (in kcal/mol) and dipole moment (in debye). (a) O4BP-1; (b) O4BP-2; (c) O2BP-1; and (d) O2BP-2.
the molecule tends to take in the orientation of 1. In the O4BP-2, T undergoes a twist with 43° angle between two base planes in order to change its orientation, which leads the complex to a local energy minimum. The electron density distribution of these ionized complexes indicates that Cd–T interaction is much weaker than that of Cd–A. While both A and T associate with the metal ion as electron donors, less charge is found to transfer from T to Cd entity. This could also be explained by the IE of bases. A is the favored positive charges carrier in A–Cd2+–T base pair complexes since the computed value of A (8.1 eV) is 0.7 eV lower than that of T (8.8 eV). Though T was arranged differently, the two O4BPs are almost identical in energy (so do the O2 BPs), indicating weak interaction between A and T. Schreiber and González [19] mentioned the isoenergy of non-planar and planar structures in such metalbridged base pairs, which should also result from the lack of
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pair. Given the M–A group fixed, the difference of these A–M–T complexes is mainly due to the binding patterns of the M–T part. In accordance with the Cd–O2–T and Cd–O4–T, O2BPs have a smaller dipole moment and the lower energy than O4BPs do. However, while the difference of their interaction energy is reduced (4.50 vs. 2.80 kcal/mol) as anticipated, the difference between dipole moment is enlarged (1.03 vs. 3.08 D), which implies that cooperative influence could not be neglected in polar effect. The possibility of Cd2+ binding in peripheral position is also taken into account to evaluate the influence of Cd2+ in H-bond base pairs. From the aforementioned three metalated bases, eight stable Cd2+–A–T base pairs were obtained (four of them are illustrated in Fig. 6). As a weak interaction, the DE here is about 40 kcal/mol as we listed in the Table 2, much less than that of the bridge bonding pattern. All base pairs maintain near planar structures except Cd– N7–A–9H*–WCBP and the corresponding reverse Watson–Crick (RWC) one, in which T adapts to the pyramidalized amino group of A molecule by deviating out of the original molecular plane in order to maintain the N–H O bond. Such Cd–N7–A–9H*–WCBP could transform into the planar Cd–N7–A–9H–WCBP during proton transfer processes [45]. The Cd2+–A base complexes are proton abundant owning to the extra positive charge introduced by metal ions. This has pronounced influence on base paring. For those sites act as proton donors, the H-bond binding ability is strengthened and consequently H-bond length is shorter, whereas the H-bond binding sites that accommodate protons, their potentials are weaken and H-bonds tend to be longer. In the Cd–N3–A–7H–WCBP complex, N–H O bond is 0.09 Å shortened while N H–N is elongated for 0.13 Å as shown in Table 2. The total H-bond interaction between A and T in Cd–N3–A–7H–WCBP is slightly weaker (so does the Cd–N3– A–7H–RWCBP), as its total H-bond energy reduces for 0.35 kcal/ mol. However, in the other metalated base pairs like Cd–N7/6– A–1H–9H–2–N39O2BP, of which the N–H O bonds are evidently shortened for 0.34 Å, the H-bond binding ability of A is strengthened. Accordingly, there are significance increases in H-bond energy. As a result, mispairing might arise since changes in H-bond capacity ability of A would affect its sensibility in selecting noncomplementary bases [5]. The net atomic charges of Cd2+–A–T base pair complexes on A, T and the metal ions are also shown in Fig. 6. Considerable positive charges are located on the counterpart T (about 0.4 au) while in the non-metalated base pairs it almost stays neutral. It is worth noting that the amount of charge on T is larger than that A accommodates despite A has lower IE, as a result of that the electrostatic repulsion between the ionized base pair and metal cation surpasses the influence of IE [45]. Extra charges greatly shift the total electron density distribution as well as modify the molecule structure. With more positive charge distributes in the heterocyclic ring, the exocyclic methyl groups become more negative, which reduces the bond-length between the endocyclic C and methyl function.
Fig. 6. The Cd2+–A–T H-bond base pair complexes with selected distances (in Å) and net charges of each part (in au).
correlations between A and T bases. Thus, these metal-bridged base pairs could be considered as analog of two pieces of metal– nucleobase (M–NB) systems. From this point of view, the characters of M-NB would imply many features of the metal-bridged base
Table 2 0 Å) and H-bond energies (EH in kcal/mol) of Cd2+ metalated A–T base pairsa,b. The interaction energy (DE in kcal/mol), H-bond lengths (H1, N–H O; H2, N H–N in A Molecular code *
Cd–N7–A–9H –WCBP Cd–N7–A–9H*–RWCBP Cd–N7–A–9H*–N39O2BP Cd–N7–A–9H*–N39O4BP Cd–N7/6–A–1H–9H–2–N39O2BP Cd–N7/6–A–1H–9H–2–N39O4BP Cd–N3–A–7H–RWCBP Cd–N3–A–7H–WCBP a b
DE
H1
H2
EH
44.91 43.01 46.45 44.74 38.37 38.35 37.35 40.77
1.559(0.289) 1.617(0.328) 1.644(0.228) 1.610(0.245) 1.595(0.299) 1.570(0.345) 1.846(0.086) 1.801(0.095)
2.187(0.260) 2.199(0.349) 2.244(0.395) 2.203(0.352) 2.205(0.351) 2.309(0.461) 1.980(0.142) 1.996(0.134)
10.91(6.76) 9.56(4.59) 9.99(5.23) 9.83(5.07) 10.26(5.54) 13.75(8.90) 4.04(1.01) 4.28(0.35)
The H-bond energy is calculated using Eq. (2) in Ref. [46]. Values in parentheses represent the differences with corresponding non-metalated base pairs.
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4. Conclusions The high-level DFT calculations have been performed on the influence of Cd2+ on nucleobases (A and T) and base pairing. The gas phase study agrees with the experiment that Cd2+ changes the equilibriums of A tautomers to stable the rare tautomer complex Cd–N7/6–A–1H–9H–2. More Cd2+–A complexes have reasonable abundance rate due to the energy difference diminishes in solvent effect while the abundant tautomers of gas phase substantially remain high occurrence. Study in both gas phase and solvent agrees that tautomeric equilibrium of T could be hardly affected by Cd2+ binding. The charge transfer effect plays great role in engendering features of Cd2+–A–T base pairs. In the metal-bridged base pairs, the correlation between A and T is weak and Cd–A interaction appeals stronger than the Cd–T interaction. With the binding of Cd2+, structure of T in the H-bond metalated base pairs was deformed due to the disturbed electron density distribution; meanwhile, H-bonds in A–T base pairs experience significant changes that might contribute to mispairing. Comparing with the H-bond binding, the bridge bonding pattern is stronger but less depended on the orientation, it is also less conformationally restricted since the structure do not have to be planar. Thus, with Cd2+ involves, the bridge bonding pattern should be experimentally preferred. These theoretical results of the Cd2+ metalated base pairing would be helpful to understanding the nature of cadmium-induced mutagenesis. Acknowledgement We acknowledge the financial supports from MOST Projects (2006DFA43020 and 2007CB815307), FJIRSM key Project (SZD08003) and Fujian Province Project (2006F3133). Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.cplett.2008.11.073. References [1] R.G. Endres, D.L. Cox, R.R. Singh, Rev. Mod. Phys. 76 (2004) 195. [2] J.E. Šponer, J.V. Burda, J. Leszczynki, J. Šponer, in: J. Šponer, F. Flankaš (Eds.), Interaction of Metal Cations with Nucleic Acids and their Building Units, Springer, Netherlands, 2006, p. 389. [3] B. Lippert, Coord. Chem. Rev. 200–202 (2000) 487. [4] M. Noguera, V. Branchadell, E. Constantino, J. Phys. Chem. A 111 (2007) 9823. [5] J. Muller, R.K.O. Sigel, B. Lippert, J. Inorg. Biochem. 79 (2000) 261.
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