Chemical Physics Letters 467 (2009) 387–392

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Chemical Physics Letters

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Theoretical studies on the bonding of Cd2+ to adenine and thymine: Tautomericequilibrium 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 i n f o a b s t r a c t

Article history:Received 10 September 2008In final form 22 November 2008Available online 3 December 2008

0009-2614/$ - see front matter � 2008 Elsevier B.V. Adoi:10.1016/j.cplett.2008.11.073

* Corresponding author. Fax: +86 591 3792932.E-mail address: wkc@fjirsm.ac.cn (K. Wu).

The influence of Cd2+ on nucleobases and base pairing has been studied systematically using high-levelDFT method. Cd2+ strongly interacts with adenine (A), changing tautomer structures and affecting thetautomer equilibrium whereas the Cd2+-thymine (T) interaction barely shifts the equilibrium of T tau-tomers. The isoenergy of metal-bridged A–Cd2+–T base pair complexes in the same binding patternreveals the absence of interaction between A and T. The effects of Cd2+ in H-bond base pairing have alsobeen discussed to further understand the possible schemes in cadmium induced DNA mutations.

� 2008 Elsevier B.V. All rights reserved.

1. Introduction

Motivated by both biological and technological concerns, therole of metal ions in DNA systems has attracted great interest[1]. Metal ions play different roles in nucleic acids system depend-ing on the type of the metals [2–4]. While alkali metals often bindto phosphate groups to steady DNA and RNA strands, transition-metal ions predominately interact directly with nucleobases. Metalbinding on nucleobases may have various consequences thatwould contribute to mutagenesis [5], including stabilizing rare tau-tomers [6–12], cross-linking between nucleobases [8,13–16], andenhancing the formation of certain non-Watson–Crick (WC) basepairs [17–20]. One representative of metal mutagenicity is plati-num, which has caught great attention since the report of anticar-cinogen cis-diamminedichloroplatinum(II) (cis-platin) in 1965 [21]and has been passionately studied through theoretical and experi-mental techniques [22].

Cadmium is accepted by the International Agency for Researchon Cancer as a Category 1 (human) carcinogen [23]. It is a soft me-tal that prone to bind to nucleobases than phosphates [23,24]. Thedirect interaction of Cd2+ with nucleobases can either stabilize theDNA strand or cause redistribution of electron density in the nucle-obase heterocyclic ring, which may diminish the phosphodiesterbonds and lead to the unwinding of the DNA strand, dependingon the concentration [3]. Although the interaction between Cd2+

and nucleobases has been widely studied, there are uncertaintiesremained on the exact mechanism of mutagenesis. It has been ob-served that Cd2+ directly interact with nucleobases, preferably withA and guanine (G) [12,25]. Hossain et al. [12] pointed out that

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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 irrevers-ible. In another related report on the interaction of Cd2+ withDNA [26], the binding nature of Cd2+ to DNA was explored throughenzyme digestion technique. The possible reason of Ssp1 digestionbeing prevented was assumed to be its disability to recognize the20-deoxyadenyl(30 ? 50)-20-deoxythymidine(AT) sites due to theCd2+ induced structural modification in A. It was also suggestedthat misparing might occur because of the possible amino–iminotautomeric equilibrium shift of A induced by Cd2+ [12], however,the possible schemes of such metalation in base paring were notdiscussed.

The purpose of this study is to investigate the interaction be-tween Cd2+ and nucleobases systems via the first-principle DFTmethod to gain insights into DNA mutation. Specifically, our studyis aimed at determining the Cd2+ binding induced tautomeric equi-librium change of nucleobases (A and T) and the impacts of theCd2+ introduced changes in base pairing. We started from explor-ing the A and T tautomers, then the Cd2+-nucleobase complexeswere extensively studied. The tautomeric equilibriums of metalat-ed bases have been discussed and the base paring based on Cd2+–Abase 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 atomsand the MWB relativistic core potential basis [30] for Cd atom wasused in the geometric optimizations and energetic characteristicscalculations. DFT results usually are well consistent with ab initioMP2 method at medium basis sets but are more computational

388 Y. Wu et al. / Chemical Physics Letters 467 (2009) 387–392

economic [4,31]. Some similar calculations on the metal ion bindingwith nucleobases system were in reasonable agreement with theexperimental data or the MP2 results at the compatible basis level[4,32,33]. The frequency calculations have also been carried out atthe same level of theory to identify the energy minima, as well asto obtain the zero point energies and thermodynamic corrections.All the energies in this study were corrected for basis set superpo-sition error (BSSE) using the standard counterpoise method [34].The relative abundance rate is calculated base on the correspondingBoltzmann distribution. The atomic charge analysis was performedby the natural bonding orbital method (NBO) of Weinhold et al.[35]. No symmetry constrains were applied in the geometricoptimizations.

The A tautomers used in this Letter are the 14 tautomers previ-ously proposed in Ref. [19], with two additional: A–1H–3H–1 andA–1H–3H–2. All A tautomers are named according to their hydro-gen positions in the heterocyclic ring (N1, N3, N7, N9) and the ori-entation of hydrogen on the enol group (1 for anti, 2 for syn). The Ttautomer T-O7HO8H is following the same nomenclature whileother tautomers of T are named by of the movement of hydrogenatoms. For instance, A–1H–3H–1 stands for the A tautomer thathave H atoms on N1 and N3 while the H on enol group stays in antiorientation and T–N1O2H stands for the T tautomer that originatedby moving hydrogen from N1 to O2 position. In the metalatedbases, the name code of Cd with its binding site prefixes the tauto-mer in order to specify each base complex. The atom numbering ofA and T (Fig. 1) is followed the IUPAC standard nomenclature fornucleobases [36]. The 16 A tautomers with all available Cd2+ bind-ing sites could originate 46 possible Cd2+–A combinations. Furthergeometric optimizations of all these combinations lead to the finalstable Cd2+–A base complexes. The Cd2+–T base complexes are ob-tained in similar way. All the calculations are performed by GAUS-

SIAN 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 tobe the second in all the 16 A tautomers, which agrees with previ-ous theoretical and experimental studies [19,38]. Canonical form Tis the most stable tautomer, with 11.17 kcal/mol lower in energythan the second stable T-N1O4H. All other T tautomers are too highin energy to exist in nature environments.

3.2. Cd2+–A base complexes

Totally 26 stable Cd2+–A base complexes are obtained from theoptimization results. In general, metal ions are feasible to deviatewhile the A molecules substantially stay within the original qua-si-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 ofthe molecular plane because of the repulsion from adjacent hydro-gen [39]. Whereas, it is only in the cases that Cd2+ binding on N1/N7 position of amino tautomers (like Cd–N7–A–9H*), the aminogroups rotate out of the heterocyclic plane as the energy couldbe 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 orderare illustrated in Fig. 2. The influence of the initial tautomers is alsoincluded in the final Nr, so the Nr is not necessarily consistent withrelative energy. However, Cd–N7/6–A–1H–9H–2, the most stablebase 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 formin experiments [40,41] instead. This high occurrence of Cd–N7/6–A–1H–9H–2 base complexes commendably confirms that Cd2+ ionscould switch amino-imino equilibrium [12] of A. The two succes-sional 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 tautomerand Cd–N7–A–9H* is originated from the canonical form but theamino group pyramidalized. These results clearly indicate thatCd2+–A binding changes the equilibriums of A tautomers and pref-erably supports certain rare tautomers.

The tautomeric equilibrium change of A is not only resultedfrom the lower energy of several Cd2+–A rare tautomer base com-plexes, but also owning to the Cd2+ induced transformation amongcertain A tautomers. For instance, during the optimization of Cd–N7–A–1H–9H–1, hydrogen atom on imino group (N6) switchesfrom 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 ofCd–N7/6–A–1H–9H–2. The switching of hydrogen is caused bythe repulsion between H atom and Cd cation, which could be bigenough to overcome the tautomer energy barriers. After the trans-formation, Cd2+ ion bonds to A bidentately. In accordance, theaffinity energy reduces for 20–30 kcal/mol comparing with themonodentate one. Such transformation did not occur in the caseof Ag+, which is strong covalently bond with nucleobases and alsostabilizes imino form of A tautomer [19], as those like Cd–N7–A–1H–9H–1 that transformed to others in Cd2+–A remain in theAg+–A base complexes.

The influence of Cd cation on electron density distribution isstronger than that of Ag+ (0.35 vs. 0.12 au positive charges areshifted away from the metal cation to A heterocyclic ring both inthe imino tautomer case). This is not only because of the morecharges that Cd2+ owns, but also due to the difference of metal ionswhich could be related with ionization energy (IE). The second IE ofCd2+ is larger than that of A (17.4 vs. 13.4 eV) while the first IE ofAg+ is close to that of A (8.1 vs. 8.0 eV), which implies stronger ten-dency of positive charge transfer from metal ions to bases in theCd2+–A base complexes. Therefore, Cd2+ is expected to have stron-ger impact in DNA systems. In fact, it has been observed [42] thatCd2+ leads to more damages than Ag+ does when interacting withDNA strand, especially in high concentration.

While in the gas phase, the abundance order of Cd2+–A com-plexes mainly depends on the ionic-electrostatic effect; in the sol-vent environment, it is also subtle to influences such as chargetransfer and polar effect due to the solvent screening. Thus, we alsoinclude the polarized continuum model (PCM) to account for theinfluence of solution environment. The abundance order of A tau-tomers undergoes no disturbing while their energy differencesare reduced with the influence of solvent effect. The energy differ-ence in Cd2+–A complexes also undergoes similar decrease, whichresults in that more complexes have considerable occurrences thanin the gas phase. The most abundant Cd2+–A complex is changed,

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 beenincluded 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.

Y. Wu et al. / Chemical Physics Letters 467 (2009) 387–392 389

Fig. 5. Metal-bridged A and T base pairs of Cd–N7/6–A–1H–9H–2 with selecteddistances (in Å), bond angles and nets charges of each part(in au). Also given are therelative 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.

390 Y. Wu et al. / Chemical Physics Letters 467 (2009) 387–392

but Cd–N7/6–A–1H–9H–2 and Cd–N3–A–7H still remain relativelyhigh 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 aminogroup wrapped by water molecules is reluctant to interact withmetal cation.

3.3. Cd2+–T base complexes

It is commonly agreed that metal binding or solvent effects donot change the tautomer equilibrium of T [43]. At the presence ofCd2+ ions, Cd–O4–T–N1O2H is the most stable complex, with2.60 kcal/mol lower in energy than the next stable one. However,canonical T originated Cd–O4–T (Nr = 99.96438%) is the one whichhas dominant occurrence in all Cd–T base complexes, in consider-ing of initial tautomer abundance rates. It is followed by anotherbase 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 differencesbetween complexes are reduced as anticipated, and the Cd–O2–Tcomplex becomes the most stable one. Taken the dominant abun-dance rate of canonical form T, the Cd–O2–T complex would beabsolutely abundant in the Cd–T base complexes. Thus, there iscoherence within the study of Cd–T considering solvent effectand the gas phase result that Cd could hardly change the tautomerequilibrium 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 toexplore the influence of Cd2+ metalation on base pairing. Thoseare typical N7 (the preferred binding site in DNA helix) and N3(the minor groove binding site) binding complexes. And accordingto the above studies, it is clear that Cd cation binding has pro-nounced effects on the bases. Thus, they could be efficient samplesin evaluating metalation effects. The Cd2+–A base complexes werecombined with the canonical form T in two different ways accord-ing to the position of Cd cation in bases.

Firstly, as experimentally revealed [44], Cd cation is supposed toform the bridge bond between bases. Only Cd–N7/6–A–1H–9H–2is the focus to study this mispairing aspect of the amino–iminoshift here. T molecules were accessed to the Cd site with O4 (orO2) in opposite orientations to A, which resulted in four differentcomplexes (as we named O4BP-1/2 and O2BP-1/2 in Fig. 5).

While the Cd–A bond stays rigid, T adapts to different geome-tries in a flexible way in the A–Cd2+–T base-pair complexes. T inboth O2 binding base pairs remains its orientation though the mol-ecule deviated out of the A plane for 33/44�, but in O4BPs (Fig. 5),

Table 1The dipole moments (in debye), energetic characteristics (in kcal/mol) and relativeabundance order of Cd2+–thymine base complexesa.

Molecular code l Er DEin

Cd–O4–T–N1O2H 2.85 0.00 �190.13Cd–O4–T–N3O2H 5.98 2.60 �183.84Cd–O2–T–N3O4H 1.76 4.61 �176.00Cd–O4–T 4.88 16.57 �152.85Cd–N1–T–O2HO4H 3.31 19.36 �163.17Cd–O4–T–N1O2H 1.21 19.51 �160.68Cd–O2–T 5.91 21.27 �148.30Cd–N3–T–O2HO4H 3.44 34.14 �149.19Cd–N1–T–N1O2H 3.81 40.63 �140.26Cd–O2 –T–N3O2H 5.63 91.36 �97.18

a l, Dipole moments; Er, relative energies; DEin, interaction energies.

the molecule tends to take in the orientation of 1. In the O4BP-2, Tundergoes a twist with 43� angle between two base planes in orderto change its orientation, which leads the complex to a local energyminimum. The electron density distribution of these ionized com-plexes indicates that Cd–T interaction is much weaker than that ofCd–A. While both A and T associate with the metal ion as electrondonors, less charge is found to transfer from T to Cd entity. Thiscould also be explained by the IE of bases. A is the favored positivecharges carrier in A–Cd2+–T base pair complexes since the com-puted 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 almostidentical in energy (so do the O2 BPs), indicating weak interactionbetween A and T. Schreiber and González [19] mentioned theisoenergy of non-planar and planar structures in such metal-bridged base pairs, which should also result from the lack of

Fig. 6. The Cd2+–A–T H-bond base pair complexes with selected distances (in Å)and net charges of each part (in au).

Y. Wu et al. / Chemical Physics Letters 467 (2009) 387–392 391

correlations between A and T bases. Thus, these metal-bridgedbase pairs could be considered as analog of two pieces of metal–nucleobase (M–NB) systems. From this point of view, the charac-ters of M-NB would imply many features of the metal-bridged base

Table 2The interaction energy (DE in kcal/mol), H-bond lengths (H1, N–H� � �O; H2, N� � �H–N in ÅA

0

)

Molecular code DE H1

Cd–N7–A–9H*–WCBP �44.91 1.5Cd–N7–A–9H*–RWCBP �43.01 1.6Cd–N7–A–9H*–N39O2BP �46.45 1.6Cd–N7–A–9H*–N39O4BP �44.74 1.6Cd–N7/6–A–1H–9H–2–N39O2BP �38.37 1.5Cd–N7/6–A–1H–9H–2–N39O4BP �38.35 1.5Cd–N3–A–7H–RWCBP �37.35 1.8Cd–N3–A–7H–WCBP �40.77 1.8

a The H-bond energy is calculated using Eq. (2) in Ref. [46].b Values in parentheses represent the differences with corresponding non-metalated

pair. Given the M–A group fixed, the difference of these A–M–Tcomplexes 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 smal-ler 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 mo-ment is enlarged (1.03 vs. 3.08 D), which implies that cooperativeinfluence could not be neglected in polar effect.

The possibility of Cd2+ binding in peripheral position is also ta-ken into account to evaluate the influence of Cd2+ in H-bond basepairs. From the aforementioned three metalated bases, eight stableCd2+–A–T base pairs were obtained (four of them are illustrated inFig. 6). As a weak interaction, the DE here is about 40 kcal/mol aswe listed in the Table 2, much less than that of the bridge bondingpattern. 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 groupof A molecule by deviating out of the original molecular plane inorder to maintain the N–H� � �O bond. Such Cd–N7–A–9H*–WCBPcould transform into the planar Cd–N7–A–9H–WCBP during pro-ton transfer processes [45].

The Cd2+–A base complexes are proton abundant owning to theextra positive charge introduced by metal ions. This has pro-nounced influence on base paring. For those sites act as proton do-nors, the H-bond binding ability is strengthened and consequentlyH-bond length is shorter, whereas the H-bond binding sites thataccommodate protons, their potentials are weaken and H-bondstend to be longer. In the Cd–N3–A–7H–WCBP complex, N–H� � �Obond is 0.09 Å shortened while N� � �H–N is elongated for 0.13 Åas shown in Table 2. The total H-bond interaction between A andT 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 evidentlyshortened for 0.34 Å, the H-bond binding ability of A is strength-ened. Accordingly, there are significance increases in H-bond en-ergy. As a result, mispairing might arise since changes in H-bondcapacity ability of A would affect its sensibility in selecting non-complementary 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 posi-tive charges are located on the counterpart T (about 0.4 au) whilein the non-metalated base pairs it almost stays neutral. It is worthnoting that the amount of charge on T is larger than that A accom-modates despite A has lower IE, as a result of that the electrostaticrepulsion between the ionized base pair and metal cation sur-passes the influence of IE [45]. Extra charges greatly shift the totalelectron density distribution as well as modify the molecule struc-ture. With more positive charge distributes in the heterocyclicring, the exocyclic methyl groups become more negative, whichreduces the bond-length between the endocyclic C and methylfunction.

and H-bond energies (EH in kcal/mol) of Cd2+ metalated A–T base pairsa,b.

H2 EH

59(�0.289) 2.187(0.260) �10.91(�6.76)17(�0.328) 2.199(0.349) �9.56(�4.59)44(�0.228) 2.244(0.395) �9.99(�5.23)10(�0.245) 2.203(0.352) �9.83(�5.07)95(�0.299) 2.205(0.351) �10.26(�5.54)70(�0.345) 2.309(0.461) �13.75(�8.90)46(�0.086) 1.980(0.142) �4.04(1.01)01(�0.095) 1.996(0.134) �4.28(0.35)

base pairs.

392 Y. Wu et al. / Chemical Physics Letters 467 (2009) 387–392

4. Conclusions

The high-level DFT calculations have been performed on theinfluence of Cd2+ on nucleobases (A and T) and base pairing. Thegas phase study agrees with the experiment that Cd2+ changesthe equilibriums of A tautomers to stable the rare tautomer com-plex Cd–N7/6–A–1H–9H–2. More Cd2+–A complexes have reason-able abundance rate due to the energy difference diminishes insolvent effect while the abundant tautomers of gas phase substan-tially remain high occurrence. Study in both gas phase and solventagrees that tautomeric equilibrium of T could be hardly affected byCd2+ binding.

The charge transfer effect plays great role in engendering fea-tures of Cd2+–A–T base pairs. In the metal-bridged base pairs, thecorrelation between A and T is weak and Cd–A interaction appealsstronger than the Cd–T interaction. With the binding of Cd2+, struc-ture of T in the H-bond metalated base pairs was deformed due tothe disturbed electron density distribution; meanwhile, H-bonds inA–T base pairs experience significant changes that might contrib-ute to mispairing. Comparing with the H-bond binding, the bridgebonding pattern is stronger but less depended on the orientation, itis also less conformationally restricted since the structure do nothave to be planar. Thus, with Cd2+ involves, the bridge bonding pat-tern should be experimentally preferred. These theoretical resultsof the Cd2+ metalated base pairing would be helpful to understand-ing 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, inthe online version, at doi:10.1016/j.cplett.2008.11.073.

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