Ab Initio Study of Naphtho-Homologated DNA Bases - The Journal of

J. Phys. Chem. B 2008, 112, 2179-2186

2179

Ab Initio Study of Naphtho-Homologated DNA Bases A Ä lvaro Vazquez-Mayagoita,†,§ Oscar Huertas,§,‡ Miguel Fuentes-Cabrera,*,⊥ Bobby G. Sumpter,⊥ Modesto Orozco,| and F. Javier Luque*,‡ UniVersidad Auto´ noma Metropolitana Iztapalapa, Department Quı´m., DiV. Ciencias Ba´ sicas and Ingn., San Rafael Atlixco 186, Col. Vincetina, Iztapalapa, Mexico City, DF 09340 Mexico, Departament de Fisicoquı´mica and Institut de Biomedicina (IBUB), Facultat de Farma` cia, UniVersitat de Barcelona, AVgda Diagonal 643, Barcelona, 08028, Spain, Center for Nanophase Materials Sciences and Computer Science and Mathematics DiVision, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831-6493, Unitat de Modelitzacio´ Molecular Bioinforma´ tica, Institut de Recerca Biome´ dica, Parc Cientı´fic de Barcelona, Josep Samitier 1-5, Barcelona 08028, Spain, Departament de Bioquı´mica i Biologia Molecular, Facultat de Biologia Departament de Bioquı´mica, Facultat de Biologıá, UniVersitat de Barcelona, AVgda Diagonal 647, Barcelona 08028, Spain, and Computacional Biology Program, Barcelona Supercomputer Center, Jordi Girona 31, Edifici Torre Girona, Barcelona 08034, Spain ReceiVed: October 1, 2007; In Final Form: NoVember 20, 2007

Naphtho-homologated DNA bases have been recently used to build a new type of size-expanded DNA known as yyDNA. We have used theoretical techniques to investigate the structure, tautomeric preferences, basepairing ability, stacking interactions, and HOMO-LUMO gaps of the naphtho-bases. The structure of these bases is found to be similar to that of the benzo-fused predecessors (y-bases) with respect to the planarity of the aromatic rings and amino groups. Tautomeric studies reveal that the canonical-like forms of naphthothymine (yyT) and naphtho-adenine (yyA) are the most stable tautomers, leading to hydrogen-bonded dimers with the corresponding natural nucleobases that mimic the Watson-Crick pairing. However, the canonicallike species of naphtho-guanine (yyG) and naphtho-cytosine (yyC) are not the most stable tautomers, and the most favorable hydrogen-bonded dimers involve wobble-like pairings. The expanded size of the naphthobases leads to stacking interactions notably larger than those found for the natural bases, and they should presumably play a dominant contribution in modulating the structure of yyDNA duplexes. Finally, the HOMOLUMO gap of the naphtho-bases is smaller than that of their benzo-base counterparts, indicating that sizeexpansion of DNA bases is an efficient way of reducing their HOMO-LUMO gap. These results are examined in light of the available experimental evidence reported for yyT and yyC.

Introduction Size-expanded DNA bases constitute a promising strategy to expand the genetic alphabet and to develop non-natural duplexes with potential biotechnological applications. Two types of size-expanded bases, denoted as x-1 and y-bases,2 can be seen as non-natural bases formed upon insertion or addition of a benzene ring to the natural DNA base. The viability of a new modification consisting of the fusion between a naphthalene ring and the natural base, leading to the so-called yy-bases (see Figure 1), recently has been explored for the derivatives of thymine and cytosine.3 In contrast to x- and y-bases, which are about 2.4 Å wider than the natural counterparts, yy-bases are about 4.8 Å larger. Base pairs formed by a natural base and a size-expanded one make up size-expanded DNAs. Specifically, the duplexes known as xDNA, yDNA, and yyDNA are made of base-pairs containing x-, y-, and yy-bases, respectively. Figure 2 shows the base-pairs between a natural nucleobase and its * Address correspondence to this author. E-mail: [email protected] (M.F.C.) or [email protected] (F.J.L.). † Universidad Auto ´ noma Metropolitana Iztapalapa. ‡ Universitat de Barcelona. § Both authors contributed equally to this work. ⊥ Oak Ridge National Laboratory. | Institut de Recerca Biome ´ dica; Departament de Bioquı´mica i Biologia Molecular, Facultat de Biologia Departament de Bioquı´mica, Facultat de Biologıá, Universitat de Barcelona; and Barcelona Supercomputer Center.

complementary canonical-like yy-base (note that the term canonical for yy-bases is used here to designate those tautomers that enable the Watson-Crick hydrogen-bonded pairing with the natural nucleobases). Size-expanded bases have many properties that make them of biotechnological interest. For example, since x-, y-, and yybases are fluorescent they might be valuable to develop sequence-selective assays for detecting natural nucleic acids. Other potential applications of size-expanded DNA duplexes are related to the large aromatic surface, which gives rise to enhanced π-π stacking interactions and hydrophobicity.4,5 In turn, these properties contribute to explain the increased stability of xDNA and yDNA, which is reflected in the larger melting points of these size-expanded duplexes compared to those of the corresponding pure DNA ones.1,2 Moreover, since the π-π stacking interactions are believed to play a prominent role in the conductivity of DNA, duplexes containing size-expanded nucleobases could also be valuable as molecular nanowires due to improved conductivity properties relative to the natural duplexes. This rationale is supported by previous results reported for G4-wires6 and from the fact that the HOMO-LUMO gap of x- and y-bases is lower (between 0.3 and 1.0 eV) than that of their natural counterparts.7-9 Furthermore, the HOMOLUMO gap might be tuned by suitable chemical modifications of the benzene ring.9,10 Finally, we have previously shown that

10.1021/jp7095746 CCC: $40.75 © 2008 American Chemical Society Published on Web 01/29/2008

2180 J. Phys. Chem. B, Vol. 112, No. 7, 2008

Figure 1. Representation and atom numbering of yy-bases: (a) yyA; (b) yyC; (c) yyG; (d) yyT. Color code: oxygen, red; carbon, black; nitrogen, blue; hydrogen, brown.

for analogous sequences of xDNA and DNA, the π-π* gap of xDNA is about 1.3 eV smaller than that of DNA.11 Because the yy-bases contain one extra benzene ring as compared to x- and y-bases, one might hypothesize that the former will lead to stronger π-π stacking interactions and lower HOMO-LUMO gaps, thus making the yyDNA a promising candidate as a molecular nanowire. To this end, nevertheless, the yy-bases should be able to meet the requirements needed for a proper recognition with their natural counterparts to form a stable yyDNA duplex. The aim of the present study is to perform a detailed ab initio study of the structural and electronic properties, tautomeric stability, stacking interactions, and basepairing ability of yyA, yyG, yyC, and yyT. The results are discussed in light of the experimental data available for the pyridimidine-like naphtho-bases.3 Methods Gas-Phase Calculations. The geometrical features of the canonical-like tautomers of yy-bases were determined from the molecular geometries optimized at the MP2/6-31G** level without imposing symmetry restraints. The relative stabilities between tautomers was determined from BHandHLYP calculations (this method combines Becke’s “half-and-half” functional for exchange as implemented in Gaussian and the Lee-YangParr functional for correlation) by using the cc-pVTZ calculations. Choice of this computational procedure was motivated by the large size of the naphtho-bases and by the reliable performance of BHandHLYP computations to predict the relative stabilities between tautomers of natural nucleobases and size-expanded x-bases.4,12 In particular, we have found an excellent correlation (r ) 0.99) between the relative energies predicted for tautomers of natural and x-bases determined from BHandHLYP/cc-pVTZ computations and those obtained with high-level ab initio computations.4 In all cases, the minimum nature of the optimized geometries was verified by the lack of imaginary vibrational frequencies. Zero-point energies and

Vazquez-Mayagoita et al. enthalpy and entropy corrections were evaluated by using the standard harmonic oscillator-rigid rotor model at 1 atm and 298 K. Dimerization energies of selected tautomers were determined from BHandHLYP/c-pVTZ computations. The starting structures of the dimers were chosen to mimic Watson-Crick pairing and to maximize the hydrogen bond interactions. Due to the large size of the dimers, only the intermolecular parameters were optimized, whereas the internal geometries of the monomers were kept fixed in their monomer equilibrium values. The basis set superposition error (BSSE) was corrected by using the Boys and Bernardi counterpoise method.13 The electronic properties of the ground state of each base were obtained with Density Functional Theory (DFT) computations, using the 6-31G** and 6-31G basis sets. Different functionals were used for the exchange-correlation potential, including the local-density LDA14 and the hybrid B3LYP.15 Computations were performed with the NWChem suite of programs16 and Gaussian0317 programs. Solvation Calculations. To estimate the influence of hydration on the relative stability between tautomers, quantum mechanical Self-Consistent Reaction Field continuum calculations were performed by using the HF/6-31G(d)-optimized version of the Miertus-Scrocco-Tomasi (MST) model.18 This method yields accurate hydration free energies for a large variety of neutral organic solutes and has proven to be very powerful in describing the influence of hydration on the tautomeric equilibrium of different nucleobases.19 It is worth noting that the relative hydration free energies determined from MST and Monte Carlo-Free Energy Perturbation calculations for a total set of 68 tautomers of both natural bases and their benzobase derivatives (x-bases) showed a close agreement,4 thus giving confidence to the relative stabilities in aqueous solution determined here for the yy-bases. As described elsewhere, the MST model is a derivation of the Polarizable Continuum Model method,20 which exploits a solvent-adapted definition of the cavity and atomic surface tensions determined by fitting to the experimental solvation free energies.21 Following the standard procedure in the MST model, the free energy of solvation was computed by using the gas-phase optimized geometries. The relative stability of the tautomers in solution (eq 1) was estimated by adding the gas-phase tautomerization free energies (∆Ggas) and the relative solvation free energies (∆∆Gsol). MST calculations were performed with a locally modified version of Monstergauss.22

∆Gaq ) ∆Ggas + ∆∆Gsol

(1)

Results Structural Properties. The yy-bases can be seen as the lateral extension of the y-bases, since the former contain an extra benzene ring. Thus it is convenient to compare the structural properties of yy- and y-bases to understand how the lateral extension affects the planarity of the amino groups and aromatic rings. The results given in Table 1 show that the amino groups in y- and yy-bases have a similar degree of pyramidalization, as expected from the resemblance of the local environment around the amino groups in y- and yy-bases. To estimate the planarity of the aromatic rings in y- and yy-bases, the torsional angles in each ring were added and compared. Comparisons between torsional angles of equivalent rings of yy- and y-bases are given in Table 1, where the rings are ordered as first, second, third, and fourth from the left to the right of each base as shown in Figure 1 for the yy-bases (see Figure S1 of the Supporting

Naphtho-Homologated DNA Bases

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Figure 2. Representation of the Watson-Crick hydrogen bonding of yy-bases with their natural counterparts.

TABLE 1: Nonplanarity (deg) of the Amino Groups and Aromatic Rings Determined from the MP2/6-31G** Optimized Structures, and Differences in Energy (∆E in kcal/mol) between Planar and Nonplanar Amino-Group Configurations of the yy-Bases (Data for the y-Bases from Ref 7) Amino Groups base

torsion

angle

torsion

angle

∆E

yyA yA yyC yC yyG yG

H61-N6-C6-N1 H61-N6-C6-N1 H42-N4-C4-N3 H42-N4-C4-N3 H22-N2-C2-N1 H22-N2-C2-N1

24.0 23.4 10.0 9.5 34.6 23.4

H62-N6-C6-C5 H62-N6-C6-C5 H41-N4-C4-C5 H41-N4-C4-C5 H21-N2-C2-C5b H21-N2-C2-N3

19.9 21.4 41.5 43.2 12.3 25.7

0.7 0.7 1.4 1.6a 0.6 0.8

Aromatic Ringsb,c yy-base

first

second

third

fourth

yyA yA yyC yC yyG yG yyT yT

0.0/9.1 0.2/7.5 0.1/24.5 -0.1/23.2 -0.5/18.5 -0.4/18.0 0.1/12.3 0.0/0.0

0.0/23.8 0.0/13.7 0.0/23.9

0.0/27.5

0.0/5.8 0.0/3.0

0.0/27.0 0.0/20.6 0.0/21.5

6.0/14.6 0.0/11.4 0.0/27.0

0.0/5.7 0.0/3.9

2.6/14.0 0.0/0.0

a This energy is likely to be overestimated since yC in planar configuration was obtained by imposing geometrical restrictions.7 b Values corresponding to the unsigned and signed sum of torsional angles of the rings are given in roman and italics, respectively. c The extra rings in the yy-bases relative to the y-bases correspond to the third and second rings in yy-purines and yy-pyrimidines, respectively (see Figure 1 for yy-bases, and Figure S1 in the Supporting Information for y-bases).

Information for the representation of the y-bases). These comparisons show that the lateral extension of the y-bases to make the yy-counterparts has little impact on the planarity of the aromatic rings and the pyramidalization of the amino groups. This is better appreciated by examining the term ∆E in Table 1, which gives the difference in energy between a base that has its amino group nonplanar and planar. Tautomerism. As the natural nucleobases, the yy-bases can display different tautomeric forms. On the basis of previous studies of the tautomeric preference of x- and y-bases,4,8,10 the tautomerism of yyA and yyT has been examined considering the canonical-like amino (yyA-A) and diketo (yyT-OO) forms, four imino (yyA-Ic1, yyA-Ic3, yyA-It1, and yyA-It3) and four enol (yyT-OEc1, yyT-EcO3, yyT-EtO1, and yyT-EtO3) tautomers (see Figure 3). With regard to yyG and yyC (see Figure 4), in addition to the canonical-like amino-oxo (yyG-AO1 and yyC-AO1) species, five and four other tautomers have been

Figure 3. Schematic representation and numbering of the different tautomers of yyA and yyT.

examined for yyG (the amino-oxo yyG-AO3, the amino-enol yyG-AEc and yyG-AEt, and the imino-oxo yyG-ItO13 and yyGIcO13 forms) and yyC (the amino-oxo yyC-AO3, the aminoenol yyC-AEc and the imino-oxo tautomers yyC-IcO13 and yyC-ItO13). The free energy differences in the gas phase (∆Ggas) associated with the corresponding tautomeric processes of yy-bases are given in Table 2. For yyA, the canonical amino form (yyAA) is predicted to be the most populated tautomer in the gas phase, and the population of the imino forms is negligible, as


Vazquez-Mayagoita et al. TABLE 2: Free Energy Differences in the Gas Phase (∆Ggas), Relative Hydration Free Energies (∆∆Gsolv), and Relative Stabilities in Aqueous Solution (∆Gaq) of Tautomeric Species of the yy-Basesa tautomer

∆Ggas

∆∆Gsolv

∆Gaq

0.0 -15.7 -2.2 -9.0 -7.1

0.0 20.0 8.3 18.6 9.3

0.0 -2.0 1.1 -3.4 -5.0

0.0 13.4 13.7 15.5 15.0

0.0 10.3 13.8 14.8 14.2 14.4

0.0 -7.1 2.2 2.2 -4.0 -4.2

0.0 6.0 9.8 5.5 6.4

0.0 -0.9 8.1 3.1 3.5

yyA A Ic1 Ic3 It1 It3

0.0 35.7 10.5 27.6 16.4

OO OEc1 EcO3 EtO1 EtO3

0.0 15.4 12.6 18.9 20.0

AO1 AO3 AEc AEt IcO13 ItO13

0.0 -17.4 -11.6 -12.6 -18.2 -18.6

AO1 AO3 AEc IcO13 ItO13

0.0 -6.9 -1.7 -2.4 -2.9

yyT

yyG

yyC

a

Figure 4. Schematic representation and numbering of the different tautomers of yyG and yyC.

the first minor tautomer (yyA-Ic3) is destabilized by around 10 kcal/mol. A similar conclusion can be formulated for yyT, since the canonical-like diketo tautomer (yyT-OO) is predicted to be more stable than the first minor tautomer (the enol-oxo form yyT-EcO3) by around 12 kcal/mol. The tautomeric space of expanded guanine is richer, since there are three tautomers of yyG with similar stability (differing by around 1 kcal/mol) in the gas phase: the imino-enol yyG-ItO13 and yyG-IcO13 forms and the amino-oxo yyG-AO3 species. The rest of the tautomers are largely disfavored, and particularly the canonical-like yyGAO1 is destabilized by about 18 kcal/mol, thus mimicking the findings already reported for the tautomeric preferences of yG.8 With regard to yyC, the tautomerism in the gas phase is dominated by the amino-oxo yyC-AO3, since the imino-oxo and amino-enol forms are destabilized by more than 4 kcal/ mol and the canonical-like amino-oxo yyC-AO1 is disfavored by nearly 7 kcal/mol. Due to the different polarity of tautomers, hydration leads in some cases to significant alterations in the relative tautomerization free energy (see Table 2). The canonical-like tautomers of yyA and yyT (yyA-A and yyT-OO) are the least favorably hydrated species, but this destabilizing effect is not large enough to revert to the gas-phase preference. Accordingly, these tautomers are expected to be the dominant ones of yyA and

All values are given in kcal/mol.

yyT in water. Hydration partly compensates the intrinsic destabilization of yyG-AO1, which is nevertheless destabilized by around 7 kcal/mol relative to the main tautomeric species (yyG-AO3), whereas the imino tautomers are disfavored by only 3 kcal/mol. Finally, hydration influences the tautomerism of yyC by stabilizing the yyC-AO1 form, which was undetectable in the gas phase (see Table 2), and the tautomers yyC-AO3 and yyC-AO1 are predicted to coexist in aqueous solution in a ratio as their relative difference amounts to only 1 kcal/mol. On the basis of the preceding results, we can conclude that naphtho-homologated yyA and yyT are present in tautomeric forms that allow them to retain the Watson-Crick (WC) hydrogen-bonded pairing of the natural A and T bases, and that yyDNAs formed by combination of yyA and yyT with the corresponding natural nucleobases should preserve the specific recognition between the strands in the duplex. In contrast, both in the gas phase and in aqueous solution the main tautomeric forms of yyG and yyC do not correspond to the canonical-like species. These findings, therefore, raise the question of whether yyG and yyC can form canonical-like hydrogen-bond pairings in yyDNA. Base-Pairing Properties. The capability of yyA and yyT to recognize T and A in the gas phase, respectively, was examined by BHandHLYP/cc-pVTZ computations performed for the corresponding yyA‚‚‚T and yyT‚‚‚A dimers, which retain the WC hydrogen-bond pairing (see Figure S2 in the Supporting Information). The BSSE-corrected interaction energies for yyA‚ ‚‚T and yyT‚‚‚A are very favorable, as they amount to -12.4 and -12.9 kcal/mol, respectively (the corresponding interaction energy determined from AMBER computations amounts to -12.5 and -13.0 kcal/mol). Moreover, they mimic the value obtained for the WC pairing between adenine and thymine (-12.1 kcal/mol at the BHandHLYP/cc-pVTZ level). For the yyG‚‚‚C pair, four dimers involving the canonicallike tautomer, yyG-AO1, and the three most stable tautomeric



Figure 6. Optimized geometries of the hydrogen-bonded pairing geometries of yyC (from top to bottom: yyC-AO1 and yyC-AO3) and G (distances in Å).

Figure 5. Optimized geometries of the hydrogen-bonded pairing geometries of selected tautomers of yyG (from top to bottom: yyGAO1, yyG-AO3, yyG-IcO13, and yyG-ItO13) and C (distances in Å).

species, yyG-AO3, yyG-IcO13, and yyG-ItO13, were considered. The optimized geometries (see Figure 5) reveal that yyGAO1 and yyG-IcO13 retain the standard WC geometry. However, even though yyG-ItO13 also reflects the WC interaction, the optimized geometry shows a highly nonplanar arrangement of the bases due to the repulsion between lone pairs on the imino (yyG-ItO13) and oxo (C) groups. Finally, the yyG-AO3 pair corresponds to a wobble interaction. As expected, the most stable pairing corresponds to yyG-AO1 (-34.8 kcal/mol), while the interaction energies of the other pairings are notably lower (yyG-AO3: -20.0 kcal/mol; yyGIcO13: -18.8kcal/mol; yyG-ItO13: -10.7 kcal/mol). Similar interaction energies are obtained from AMBER computations (yyG-AO1: -32.0; yyG-AO3: -19.4; yyG-IcO13: -19.9; yyG-ItO13: -11.7 kcal/mol). However, when the intrinsic difference in stability of the tautomers is taken into account, the wobble pairings yyG-AO3‚‚‚C and yyG-IcO13‚‚‚C are the most favorable ones in the gas phase: the ordering of stability is yyG-AO3‚‚‚C (-20.0 kcal/mol) ≈ yyG-IcO13‚‚‚C (-19.6 kcal/mol) < yyG-AO1‚‚‚C (-17.4 kcal/mol) < yyGItO13‚‚‚C (-11.9 kcal/mol). It is worth noting that the gas phase interaction energy of the best yyG‚‚‚C pairing is nearly 6 kcal/mol disfavored relative to that of the canonical WC G‚‚‚C dimer (-25.7 kcal/mol at the BHandHLYP/cc-pVTZ level). With regard to yyC, only two pairings, which involve yyCAO1 and yyC-AO3, were examined. The optimized geometry of the yyC-AO1‚‚‚G pair (-30.9 kcal/mol) retains the WC hydrogen bonding, whereas the yyC-AO3‚‚‚G pair (-25.3 kcal/ mol) corresponds to a wobble geometry (Figure 6; the interaction energies determined from AMBER computations are -29.6 and -24.0 kcal/mol, respectively). By taking into account the intrinsic stability of the two amino-oxo tautomers, the interaction energy of the yyC-AO3‚‚‚G pair in the gas phase is 1.3 kcal/ mol larger than that of the yyC-AO1‚‚‚G (-24.0 kcal/mol) one. The lack of detailed structural information about the putative yyDNA duplexes makes it difficult to assess the impact of the yyDNA environment on the pairing of yyG and yyC.23 Nevertheless, the present results indicate that one should be

cautious about the assumption that the canonical-like yyG-AO1 and yyC-AO1 species are the only tautomers involved in yyDNA duplexes. Stacking Properties. Besides hydrogen bonding, the stacking between bases is one of the main stabilizing forces in a DNA duplex. To estimate qualitatively the influence of the naphthalene unit on the stacking between bases, we built up pairs of hydrogen-bonded naphthoderivative‚‚‚natural bases, (yyA-A‚‚ ‚T)2, (yyT-OO‚‚‚A)2, (yyG-AO3‚‚‚G)2, and (yyC-AO3‚‚‚G)2, with their planes separated at 3.4 Å and determined the torsional dependence of the stacking energy on the rotation of one pair through the axis normal to the center of the hydrogen-bonded bases in the other dimer. To this end, calculations were performed with the AMBER99 force field,24 using RESP/HF6-31G* charges25 for the atoms in the yy-bases and van der Waals parameters taken from similar atom types in the force field. This choice was motivated by the fact that this computational scheme reflects the main trends of the interaction energies obtained for stacked complexes of nucleic acid bases determined from high-quality ab initio results, thus avoiding the shortcomings of density functional methods to estimate accurately the energetics of stacking complexes.26 The energy profiles for the interaction between stacked pairs (Figure 7) show that there is larger orientational dependence for the mixed yy-base‚‚‚natural dimers compared to the fully natural ones. In fact, the shift in the total interaction energy between the stacked pairs for the hybrid yy-base‚‚‚natural dimers relative to their fully natural counterparts can be as large as 9 kcal/mol, which mainly arises from the stabilizing contribution due to the van der Waals component (data not shown). This finding agrees with the experimentally determined melting temperatures of self-complementary duplexes containing a 5′dangling yy-base,3 which indicate that the stabilization for a dangling yyT and yyC base is 2-3 kcal/mol larger than that for T and C. Clearly, a quantitative energetic comparison is not feasible, as the experimental values include other enthalpic and entropic terms besides the stacking energy. Nevertheless, present results point out that from a qualitative point of view the larger magnitude of the dispersion forces that mediate stacking between naphtho-fused bases must contribute to the enhanced stabilization of the yyDNA duplexes. Electronic Properties. The lack of detailed structural information of yyDNAs makes it difficult to calculate their electronic and conductivity properties. Accordingly, following our previous studies on the electronic properties of x- and y-bases,7,8 we examine here the electronic properties of yy-bases to gain qualitative insight into the electronic properties of size-expanded yyDNAs.


Vazquez-Mayagoita et al.

Figure 8. HOMO-LUMO gap versus number of extra benzene rings for A, C, G, T, and their benzo- and naphtho-homologated analogues. Figure 7. Dependence of the stacking interaction energy (kcal/mol) on the torsional rotation (degrees) between pairs of fully natural and mixed yy-base‚‚‚natural dimers (top: (A‚‚‚T)2, (yyA-A‚‚‚T)2, and (yyTOO‚‚‚A)2; bottom: (G‚‚‚C)2, (yyC-AO3‚‚‚G)2, and (yyC-AO3‚‚‚G)2). The ideal twist angle for canonical B-DNA is close to 36°.

TABLE 3: HOMO and LUMO Orbital Energies and HOMO-LUMO Gap (in eV) for the yy-Bases Calculated at the LDA/6-31G** Levela base

HOMO

LUMO

gap

A xA yA yyA

Adenine 0.56 0.72 1.21 1.35

4.44 3.62 4.09 3.52

3.88 2.90 2.89 2.17

T xT yT yyT

Thymine 0.10 0.22 0.00 0.37

3.97 3.62 3.55 3.15

3.87 3.40 3.55 2.78

G xG yG yyG yyG-AO3

Guanine 0.81 0.89 1.46 1.62 1.04

4.81 4.05 3.95 3.38 3.55

4.00 3.16 2.50 1.76 2.51

C xC yC yyC yyC-AO3

Cytosine 0.50 0.58 0.90 0.81 0.88

4.14 3.62 4.10 3.48 3.53

3.63 3.04 3.19 2.67 2.65

a The energies are given relative to the HOMO of yT (-5.92 eV). For comparison purposes, we also show the HOMO and LUMO orbital energies and HOMO-LUMO gap for the natural bases and their xand y-derivatives determined at the same level of theory in previous studies.7,8

Table 3 contains the HOMO and LUMO energies, and the HOMO-LUMO gap (as computed with LDA/6-31G**) of the natural nucleobases and their canonical-like x-, y-, and yy-bases, as well as those of the most stable tautomers of yyC and yyG (yyC-AO3 and yyG-AO3, respectively). The HOMO-LUMO gap of yyW is smaller than those of W, xW, and yW (where W

Figure 9. HOMA index27 of aromaticity for (a) yyG (yyG-AO1) and (b) the tautomer yyG-AO3. The HOMA is one of the most widely used indexes to quantify the aromaticity of molecules. It varies between 0 and 1, which are the values for a model nonaromatic and fully aromatic system. In the figure, each number indicates the HOMA index of the corresponding ring. As can be seen, in going from yyG-AO1 to yyGAO3, the HOMA of the naphtho motif is the one that changes the most.

) A, C, G, and T; see also Figure 8). Noteworthy, there is a sharp drop in the HOMO-LUMO gap value when yG and yyG are considered (Figure 8c). Compared to xG, the smaller HOMO-LUMO gap of yG was found to stem from the low aromaticity of the benzene ring.8,10 A similar situation occurs for yyG, where the HOMO-LUMO gap of the canonicallike form yyG-AO1 is 0.75 eV smaller than that of yyG-AO3. Thus the low aromaticity of yyG’s naphthalene motif accounts for its instability and small HOMO-LUMO gap, as noted by the HOMA aromaticity index27 of the different rings (see Figure 9). In a previous study11 we investigated the electronic properties of an xDNA duplex made of T-xA nucleotide pairs and compared its π-π* gap to that of the corresponding natural B-DNA duplex (by nucleotide-pairs we mean a system composed of a WC base-pairs plus the sugar and phosphate motifs of each base). The π-π* gaps of the T‚‚‚xA and T‚‚‚A pairs (3.93 and 4.75 eV, respectively, at the B3LYP/6-31G level) were 0.87 and 0.41 eV larger than the π-π* gaps of the corresponding duplexes (3.06 and 4.34 eV for xDNA and B-DNA, respectively). The larger reduction in the π-π* gap observed in going from nucleotide pairs to duplexes for xDNA (by near



Figure 10. HOMO and LUMO orbitals for the base-pair yyA-T: (a) HOMO and (b) LUMO. The naphtho mofif contributes to both the HOMO and LUMO orbitals.

TABLE 4: π-π* Gap for the Base-Pair yyA-T and the Nucleotide-Pairs xA-T and A-T As Computed at the B3LYP/6-31G Levela base-pair or nucleotide-pair

π-π* gap

yyA-T xA-T A-T

3.48 3.93 4.75

a

The results for the nucleotide-pairs were taken from ref 11, where the same level of theory was used to determine the π-π* gap.

0.5 eV) was attributed to the stronger π-π stacking interactions compared to the natural B-DNA duplex. Since yyDNAs have stronger stacking interactions than xDNA (see above and ref 3), an even larger reduction in the π-π* gap can be expected for yyDNA. To verify the preceding suggestion, we extended those computations to the π-π* gap of the base-pair yyA‚‚‚T. Both HOMO and LUMO orbitals reside on yyA (see Figure 10). The π-π* gap of yyA‚‚‚T is 3.48 eV, which is 0.45 and 1.27 eV smaller than those of xA‚‚‚T and A‚‚‚T, respectively (see Table 4). Assuming that the difference between the π-π* gap of a yyDNA duplex made of yyA‚‚‚T base-pairs and the π-π* gap of yyA‚‚‚T is comparable to that found between xDNA and xA‚‚‚T, the B3LYP/6-31G π-π* gap of yyDNA is estimated to be 2.61 eV (this is probably an upper limit since the stacking interactions in yyDNAs are stronger than those in xDNA). This finding suggests that the π-π* gap of yyDNA could be at least 1.73 eV smaller than that of an analogous DNA, reinforcing the hypothesis that yy-DNA might have improved electric conductivity properties. Functional Implications. The preceding results are encouraging, as they point out that yyDNA might be well suited to design nanowire devices with improved conductivity properties. However, the structural stability of yyDNAs is not firmly established, as is suggested by the available experimental data3 measured for yyDNAs containing yyT and yyC paired to adenine and guanine, respectively. Whereas fluorescence resonance energy transfer measurements, fluorescence quenching experiments, and hybridizations on beads suggest self-assembly between complementary strands, thermal denaturation plots and CD spectra are less conclusive. On the basis of the results presented here, two main factors can affect the structural stability of yyDNAs. First, the predominance of tautomeric forms other than the canonical-like ones for yyC and yyG would lead to the formation of wobble pairings instead of the WC hydrogenbonded dimers shown in Figure 2. This is of particular relevance for yyG, as the intrinsic stability of the most favorable yyG ...C dimer is nearly 6 kcal/mol lower relative to the canonical G...C one. In contrast, yyT and yyA are expected to maintain the WC pairing with A and T, and the intrinsic stability of the yyA...T and yyT...A pairs is similar to that found for A‚‚‚T. Second, the stacking propensity of yy-bases is exceptionally strong, as noted by the increase in the melting temperature of complementary duplexes containing a 5′ dangling yyT or yyC base (melting

temperature enhanced by around 15 deg relative to the same duplexes with dangling T or C). It is unclear how the enhanced stacking and hydrophobicity can affect not only the structure of the yyDNA duplex, but also the single naphtho-homologated containing strands, thus affecting the plasticity required for the formation of a self-complementary duplex. At this point, it is worth noting that the magnitude of chromicity changes observed in UV-monitored mixing experiments is very small, which is consistent with strong stacking in the single strands,3 and that for certain sequences no observable differences are observed in the CD spectra of yyDNA strands and putative duplexes. Accordingly, even though the experimental data3 suggest the formation of 1:1 strand complexation, caution must be taken when assuming the formation of a stable structure that resembles the canonical B-DNA duplex. Conclusions Naphtho-homologated DNA bases represent an attempt to expand the genetic alphabet by exploiting the limits of sizeexpanded nucleobases. Though the structure of these bases do not differ much from those of their structurally related predecessors, i.e., y-bases, the tautomeric preferences of yyC and yyG are expected to give rise to hydrogen-bonded dimers that might not retain the WC interaction pattern. In addition, the large contribution of stacking forces and hydrophobicity could be detrimental for the plasticity required to assemble selfcomplementary strands. The lack of detailed structural information about the putative yyDNA duplexes precludes a rigorous assessment of the contribution of these factors on the stability of the complexes. Nevertheless, the available experimental data support the suitability of exploring the limits of size-expanded bases and pave the way to investigating the use of naphthohomologated analogues, including suitable chemical modifications in the naphthalene unit to stabilize the canonical-like tautomers and to modulate both stacking and hydrophobicity. Moreover, those modifications could serve to tune the HOMOLUMO gap,8,9,28 and eventually lead to molecular devices with good conductor properties. Acknowledgment. Work at Oak Ridge National Laboratory (ORNL) was supported by the Center for Nanophase Materials Sciences, sponsored by the Division of Scientific User Facilities, U.S. Department of Energy (USDOE) (MFC, BGS), and used resources of the National Center for Computational Sciences, ORNL, supported by the Office of Science, USDOE. This research also used resources of the National Energy Research Scientific Computing Center, which is supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231. Financial support for A.V.M. was provided by CONACYT, Mexico, through the scholarship 179850, and partially by the ASTRO program of ORAU. This work was supported by the Spanish Ministerio de Ciencia y Tecnologıá (CTQ2005-08797-C02-01/BQU), the Centre de Supercomputacio´ de Catalunya, and the Barcelona Supercomputer Center. Supporting Information Available: Complete ref 17, representation of x- and y-bases, and graphical display of the optimized geometries of yyA‚‚‚T and yyT‚‚‚A hydrogen-bonded pairings. This material is available free of charge via the Internet at http://pubs.acs.org. References and Notes (1) (a) Liu, H.; Gao, J.; Maynard, L.; Saito, D. Y.; Kool, E. T. J. Am. Chem. Soc. 2004, 126, 1102. (b) Gao, J.; Liu, H.; Kool, E. T. J. Am. Chem.

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