Ab initio Study of the Structural, Tautomeric, Pairing, and Electronic

Oct 8, 2009 - Nanophase Materials Sciences and Computer Science and Mathematics DiVision, Oak Ridge National. Laboratory, Oak Ridge, Tennessee, 37831-...
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J. Phys. Chem. B 2009, 113, 14465–14472

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Ab initio Study of the Structural, Tautomeric, Pairing, and Electronic Properties of Seleno-Derivatives of Thymine ´ lvaro Va´zquez-Mayagoitia,*,† Oscar Huertas,‡ Giorgia Brancolini,§ Agostino Migliore,| A Bobby G. Sumpter,⊥ Modesto Orozco,# F. Javier Luque,‡ Rosa Di Felice,§ and Miguel Fuentes-Cabrera*,∇ Chemistry Department, UniVersity of Tennessee, 1416 Circle DriVe, 552 Dabney-Buehler Hall, KnoxVille, Tennessee 37996-1600, Departament de Fisicoquı´mica and Institut de Biomedicina (IBUB), Facultat de Farma`cia, UniVersitat de Barcelona, AVgda Diagonal 643, Barcelona, 08028, Spain, National Center on nanoStructures and bioSystems at Surfaces (S3) of INFM-CNR, Via Campi 213/A, 41125 Modena, Italy, Center for Molecular Modeling and Department of Chemistry, UniVersity of PennsylVania, 231 South 34th Street, Philadelphia, PennsylVania 19104-6323, Center for Nanophase Materials Sciences and Computer Science and Mathematics DiVision, Oak Ridge National Laboratory, Oak Ridge, Tennessee, 37831-6494, Molecular Modeling and Bioinformatics Unit, Institut de Recerca Biome`dica, Barcelona Scientific Park, Josep Samitier 1-6, 08028 Barcelona, Spain, Department of Life Sciences, Barcelona Supercomputing Centre, Jordi Girona 29, 08034 Barcelona, Spain, Departament de Bioquı´mica, Facultat de Biologia, AVgda Diagonal 647, Barcelona 08028, Spain, Joint Institute for Computational Sciences, UniVersity of Tennessee, Center for Nanophase Materials Sciences and Computer Science and Mathematics DiVision, Oak Ridge National Laboratory, Oak Ridge, Tennessee, 37831-6494 ReceiVed: June 17, 2009; ReVised Manuscript ReceiVed: September 14, 2009

The structural, tautomeric, hydrogen-bonding, stacking, and electronic properties of a seleno-derivative of thymine (T), denoted here as 4SeT and created by replacing O4 in T with Se, are investigated by means of ab initio computational techniques. The structural properties of T and 4SeT are very similar, and the geometrical differences are mainly limited to the adjacent environment of the C-Se bond. The canonical “keto” form is the most stable tautomer, in the gas phase and in aqueous solution, for both T and 4SeT. It is argued that the competition between two opposite trends, i.e., a decrease in the basepairing ability and an increase of the stacking interaction upon incorporation of 4SeT into a duplex, likely explains the similar experimental melting points of a seleno-derivative duplex (Se-DNA) and its native counterpart. Interestingly, the underlying electronic structure shows that replacement of O4 with Se promotes a reduction in the HOMO-LUMO gap and an increase in interplane coupling, which suggests that Se-DNA could be potentially useful for nanodevice applications. This finding is further supported by the fact that transfer integrals between 4SeT · · · A stacked base pairs are larger than those determined for similarly stacked natural T · · · A pairs. Introduction Charge mobility in DNA continues to be a subject of intense research effort due to its potential impact in biomedicine and biotechnology. Although theoretical and experimental techniques have improved our understanding on how fluctuations, nanocontacts, and interactions with the environment affect the conductivity of DNA, the precise nature of the mechanisms that underlie the transfer of charges between DNA sites is still controversial.1-4 While this debate rages, different authors have explored synthetic DNA polymers that contain modified nucleo* To whom correspondence should be addressed. E-mail: avazque1@ utk.edu (A.V.-M.); [email protected] (M.F.-C.). † Chemistry Department, University of Tennessee. ‡ Universitat de Barcelona. § National Center on nanoStructures and bioSystems at Surfaces (S3) of INFM-CNR. | University of Pennsylvania. ⊥ Center for Nanophase Materials Sciences and Computer Science and Mathematics Division, Oak Ridge National Laboratory. # Institut de Recerca Biome`dica, Barcelona Supercomputing Centre, and Departament de Bioquı´mica. ∇ Joint Institute for Computational Sciences, University of Tennessee, Center for Nanophase Materials Sciences and Computer Science and Mathematics Division, Oak Ridge National Laboratory.

sides as potential nanowires. Those modified DNAs not only preserve the self-assembling property of natural DNAs but also have other attractive features that can improve the charge mobility in DNA.5-17 In this context, our groups have investigated size-expanded DNAs, generated by the introduction of size-expanded nucleosides,18-27 and metalated DNAs (M-DNA),28-30 which contain metal ions inside the helix. Both size-expanded and metalated DNAs constitute promising alternatives to natural DNA for nanotechnological applications. In this paper, we continue this line of research by focusing on a selenium(Se)-modified DNA (Se-DNA). Recently, Salon et al.31 have replaced the oxygen denoted as O4 in thymine (T; Figure 1a) with a Se atom, and used the resultant Se-modified T base (denoted here as 4SeT; Figure 1b) to build a duplex. Strikingly, the Se-modified duplexes showed considerable stability in spite of the structural distortion and loss of hydrogenbond ability that one can reasonably expect upon replacing O4 by Se. Here, we carry out a detailed ab initio study of the structural, tautomeric, base-pairing ability, stacking, and electronic properties of the base 4SeT. Although we do not investigate a complete Se-DNA duplex, the results give valuable

10.1021/jp9057077 CCC: $40.75  2009 American Chemical Society Published on Web 10/08/2009

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Va´zquez-Mayagoitia et al. TABLE 1: Structural Properties of 4SeT and T in the Geometries Optimized at the MP2/6-31G** (BHLYP/ cc-pVTZ) Level bond length (Å) bond N1-C2 C2-N3 N3-C4 C4-C5

Figure 1. Optimized structure for (left) thymine and (right) 4SeT. C5-C6

insight into the stability, electronic properties, and charge transfer of DNA duplexes containing 4SeT.

C6-N1 C2-O2

Methodology

C5-Cme

Geometry optimizations were carried out in the gas phase without imposing geometrical restrictions using the NWChem suite of programs.32 Both T and 4SeT were optimized at the MP2/6-31G** and BHLYP/cc-pVTZ levels. The hydrogenbonded base pair formed between 4SeT and adenine (A) was optimized at the MP2 level using the LANL2DZ pseudopotential for Se and the 6-31G** basis set for the rest of the atoms. Here, this methodology is referred to as MP2/6-31G**-LANL2DZ(Se). The basis-set superposition error (BSSE) was corrected using the counterpoise method.33 In all cases, the local minimum energy of the optimized structures was verified by the lack of imaginary vibrational frequencies. The influence of solvation on the tautomeric preferences of T and 4SeT was examined by computing the relative stability in aqueous solution (∆Gaq; eq 1), which is determined by combining the gas-phase tautomerization free energies (∆Ggas) and the relative solvation free energies (∆∆Gsol) between tautomers. Relative hydration free energies were obtained with Gaussian 0334 using our HF/6-31G* and B3LYP/6-31G* MST versions35,36 of the PCM method within the IEF formalism.37,38

∆Gaq ) ∆Ggas + ∆∆Gsol

(1)

An electron density topological analysis was carried out using the theory of atoms-in-molecules,39 which has been successfully used to characterize hydrogen bonds in a variety of molecular complexes (see, for instance, refs 40 and 41). In particular, calculations were performed to determine the properties of the bond (3,-1) critical points using the molecular geometry optimized at the MP2 level and the PROAIM program.42 The effect of replacing O4 by Se on the ability to form hydrogenbond interactions was also examined from the analysis of the minima in the electrostatic potential,43 as determined with the MOPETE program.44 The optimized structures of T and 4SeT were used for studying the HOMO, LUMO, and HOMO-LUMO gap using Hartree-Fock (HF) and density functional theory (DFT). For the latter, the exchange-correlation energy was approximated with the LDA(SVWN5),45,46 GGA(BLYP),47,48 and B3LYP49 functionals. The electronic properties of model periodic stacks were calculated within the plane-wave pseudopotential DFT framework as implemented in the PWSCF software.50 We adopted the PBE exchange-correlation functional,51 ultrasoft pseudopotentials,52 and a plane-wave kinetic-energy cutoff of 25 (200) Ry for the electron wave functions (charge density).

C4-X4 (X: Se, O)

bond angle (deg)

4SeT

T

angle

4SeT

T

1.383 (1.368) 1.387 (1.372) 1.381 (1.364) 1.443 (1.438) 1.359 (1.341) 1.373 (1.362) 1.223 (1.199) 1.494 (1.491) 1.782 (1.798)

1.384 (1.368) 1.384 (1.368) 1.401 (1.387) 1.461 (1.459) 1.352 (1.332) 1.378 (1.369) 1.223 (1.197) 1.494 (1.489) 1.229 (1.201)

N1-C2-N3

112.0 (112.8) 128.8 (128.0) 114.8 (115.7) 118.4 (117.5) 122.1 (122.9) 123.8 (123.5)

112.2 (113.1) 128.6 (127.7) 114.3 (114.9) 118.4 (117.8) 122.4 (122.9) 124.1 (123.5)

C2-N3-C4 N3-C4-C5 C4-C5-C6 C5-C6-N1 C6-N1-C2

The supercell unit was 6.8 Å in the stacking direction and contained two bases. More details about the structure of the periodic stacks are given below. Even though the PBE functional does not reproduce satisfactorily long-range interactions when they are dominated by dispersion, it seems that the description of the electron density is little affected upon explicit inclusion of dispersion terms on the mean field procedure at frozen geometries.53,54 Accordingly, these findings would support the use of PBE, which in fact has been successfully used in previous studies of electronic properties of DNA, for our purposes here.55-57 Stacking interactions were evaluated for geometries generated by superimposing the bases optimized at the MP2/6-31G** level over the experimental structure of relevant duplexes (these duplexes are labeled as 1DNS and 2NSK in the Protein Data Bank crystallographic database). A similar procedure was used for creating the stacked dimers (T · · · A)2 and (4SeT · · · A)2, and transfer integrals for these systems were computed using the Becke half-and-half exchange-correlation functional (BHLYP)58 and a variety of basis sets, by means of a novel method27,59 that holds beyond the two-state approximation and does not require the knowledge of the exact transition state coordinate. This method yields directly the effective electronic coupling that enters the Marcus formula for the electron transfer rate, without the need for any additional transformation that makes use of the overlap matrix. Results and Discussion A. Structural Properties. Table 1 enumerates the optimized bond lengths and bond angles for T and 4SeT. The lengths of the bonds in both bases are very similar, except for the bonds C4-O4 and C4-Se (see Figure 1). The latter is larger than the former by 0.55 Å at the MP2/6-31G** level and by 0.59 Å at the BHLYP/cc-pVTZ level. This is expected on the basis of the larger size of Se relative to O, as noted by the van der Waals radii of O (1.4 Å) and Se (2.0 Å).60 The change in the length of the C4-X (X: O, Se) bond is accompanied by consequent changes in the adjacent bonds N3-C4 and C4-C5, which in the case of 4SeT are shortened by ∼0.02 Å with respect to T. The rest of the bonds are mainly unaltered. Replacement of O4 with Se changes the bond angles only slightly, these changes

Seleno-Derivatives of Thymine

J. Phys. Chem. B, Vol. 113, No. 43, 2009 14467 TABLE 3: Free Energy Differences in the Gas Phase (∆Ggas), Relative Hydration Free Energies (∆∆Gsol), and Relative Stabilities in Aqueous Solution (∆Gaq) of 4SeT and Its Tautomers (All Values in kcal/mol) tautomer 4SeT 4SeT-O

Figure 2. (a) Canonical 4SeT and two representative tautomers (b) 4SeT-O and (c) 4SeT-E.

4SeT-E

TABLE 2: Relative Energies (kcal/mol) and Zero-PointEnergy-Corrected Energies (in Parentheses) for 4SeT and Its Tautomers 4SeT-O and 4SeT-E, at Different Computational Levels method MP2/6-31G** MP2/6-31G**-LANL2DZ(Se) BHLYP/cc-pVTZ CCSD(T)/6-31G**-LANL2DZ(Se)a a

4SeT

4SeT-O

4SeT-E

0.0 (0.0) 0.0 (0.0) 0.0 (0.0) 0.0 (0.0)

15.0 (11.9) 17.0 (13.7) 16.5 (13.3) 19.4 (16.3)

19.7 (19.0) 19.7 (18.8) 19.1 (18.4) 20.6 (19.9)

4SeT 4SeT-O 4SeT-E

∆Ggas

∆∆Gsola

MP2/6-31G** 0.0 0.3 11.7 (0.5, 0.1) -4.5 19.1 (-4.6, -4.3) 0.0

BHLYP/cc-pVTZ 0.0 0.0 1.0 12.9 (1.4, 0.6) -4.9 18.5 (-5.1, -4.7)

∆Gaq 0.0 12.0 14.6 0.0 13.9 13.6

a

Averaged values of relative hydration free energies determined at the IEF-MST/HF-6-31G* and IEF-MST/B3LYP-6-31G* levels (the corresponding ∆∆Gsol values are given in parentheses).

In the MP2/6-31G** geometry.

being in general lower than 0.3°, except for N3-C4-C5, which increases by 0.5° (0.8°) at the MP2/6-31G** (BHLYP/cc-pVTZ) level. B. Tautomerism. The tautomerism of 4SeT has been examined by analyzing the relative stability of the canonical diketo-like (Figure 2a), the keto(O)-enol(Se) (4SeT-O; Figure 2b), and the enol(O)-keto(Se) (4SeT-E; Figure 2c) tautomers in gas phase and aqueous solution. The relative energies in the gas phase were computed at the MP2/6-31G**, MP2/6-31G**LANL2DZ(Se), and BHLYP/cc-pVTZ levels (see Table 2). All three methods give similar trends for the differences in stability between tautomers. The canonical form is the most stable species, followed by 4SeT-O and 4SeT-E, which are destabilized by more than 15 kcal/mol. The difference in energy between 4SeT and 4SeT-O is large enough to consider that, at least in the gas phase, the population of the enol forms is negligible. These findings were further validated by computations at the CCSD(T)/6-31G**-LANL2DZ(Se)//MP2/6-31G** level (see last row in Table 1), which revealed a modest destabilization of 4SeT-O and 4SeT-E tautomers compared to the MP2/631G**-LANL2DZ(Se) values. These trends are consistent with the tautomerism of 2,4-diselenouracil, where the difference between the two most stable tautomers amounts to around 8 kcal/mol at the MP4(SDQ) level.61 On the other hand, these findings mimic the trends observed for the corresponding tautomers of T, where the canonical tautomer is predicted to be the preferred species by an energy difference close to 13 and 19 kcal/mol relative to the enol forms 4T-O and 4T-E, respectively (4T-O: 2-enol, 4-keto; 4T-E: 2-keto, 4-enol).62,63 The tautomeric preferences in aqueous solution have been examined by adding the relative hydration free energies to the free energy differences in the gas phase (see eq 1 in the Methodology section and Table 3). Whereas the tautomer 4SeT-O is slightly disfavored upon hydration, the 4SeT-E form is stabilized by nearly 5 kcal/mol. The hydration preferences of the tautomers mostly reflect the differences in the dipole moment, which is similar for 4SeT and 4SeT-O and much larger for 4SeT-E (4.7, 5.4, and 6.8 D, respectively, at the MP2/631G** level). Nevertheless, the stabilization of 4SeT-E in aqueous solution is small compared with the large difference

Figure 3. H-bonds in (a) T-A and (b) 4SeT · · · A (as suggested by Salon et al.31).

in the intrinsic tautomerization free energy, and accordingly, the tautomeric equilibria in water favor the canonical diketolike form, 4SeT. This finding mimics once again the trend found for T, which is also predicted to populate the canonical tautomer in aqueous solution.62,63 C. Hydrogen-Bonding Interaction. Recently, Salon et al.31 synthesized two duplexes containing Se atoms. One of these duplexes has the sequence 5′-A-T-G-G-SeT-G-C-T-C-3′, where Se T corresponds to the base denoted here as 4SeT. The other duplex, denoted as 2NSK and with sequence 5′-G-dUSe-G-SeTA-C-A-C-3′, has two Se atoms: one inserted into T yielding 4SeT and the other attached to the C2′ carbon atom of the sugar in the uracil nucleotide. Salon et al. found that the melting point of 5′-A-T-G-G-SeT-G-C-T-C-3′ is only 0.6° smaller than that of its native counterpart. Moreover, an X-ray crystallographic study of 5′-G-dUSe-G-SeT-A-C-A-C-3′ revealed that the 4SeT · · · A base pair, as the T · · · A pair, adopts an arrangement that permits the formation of two hydrogen bonds (H-bonds; see Figure 3). These two facts led them to conclude that replacing O4 with Se had little impact on both the structure and stability of the duplex, which is somehow surprising considering that Se is expected to be a weaker hydrogen-bond acceptor than O and accordingly should destabilize the duplex. To clarify this point, we performed a detailed analysis of the hydrogen-bonding and stacking properties of 4SeT. Table 4 contains information on the structural properties of the base pairs 4SeT · · · A and T · · · A. We have found that 4SeT · · · A has a weaker binding energy than T · · · A, i.e., -8.1 kcal/mol versus -12.0 kcal/mol, which reflects the fact that the H-bonds in 4SeT · · · A are larger and weaker than those in

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Va´zquez-Mayagoitia et al.

TABLE 4: Selected Structural Parameters of the Theoretical (Determined at the MP2/6-31G**-LANL2DZ(Se) and BHLYP/ cc-pVTZ levels) and Experimental Base Pairs 4SeT · · · A and T · · · A, and Electron Density Topological Descriptors of the Interaction between Bases 4SeT · · · A parameter

a

N1(A)-N3(X) N1(A)-H3(X) N6(A)-Y H6(A)-Y C2(A)-O2(X) H2(A)-O2(X) C6(A)-N1-N3-C4(T)

MP2 BHLYP 2.92 2.97 1.89 1.96 3.51 3.59 2.50 2.60 3.22 3.23 2.33 2.33 -10.0 -7.5

Exp.

b

T· · ·A F(rc)

c

∇ F(rc) 2

c

3.02 0.034

0.0861

3.35 0.016

0.0426

MP2

Exp.

d

2.83

2.78

1.79 2.97

2.87

1.95

F(rc)c

∇2F(rc)c

0.043

0.1058

0.026

0.0737

0.006

0.0211

3.56 0.014

0.0384

-5.7

2.72 0.7

-2.4

Distances are given in Å and angles in degrees. X ) 4SeT; T. Y ) Se(4SeT); O4(T). Data taken from the X-ray crystallographic structure of the duplex 5′-G-dUSe-G-SeT-A-C-A-C-3′ (PDB entry 2NSK). c The electron density F(rc) and its Laplacian ∇2F(rc) are evaluated at the bond critical point; the values are given in atomic units, au. d From ref 69. a

T · · · A. This change can be ascribed to the larger van der Waals radius of Se as compared to that of O. In fact, as seen in Table 4,for4SeT · · · A,thebondsN1(A)-N3(4SeT)andN6(A)-Se(4SeT) are approximately 0.1 and 0.5 Å larger than the corresponding bonds in T · · · A (N1(A)-N3(T) and N6(A)-O4(T), respectively). The opposite trend, nevertheless, is seen for the bond between C2 and O2, which is about 0.4 Å larger in the T · · · A base pair, though the interaction between these two atoms has been found to be very weak in comparison with canonical hydrogen bonds.64 Accordingly, our results support the chemical intuition that replacing O4 by Se weakens the H-bonding interaction. Additional evidence about the weakened H-bond interaction for 4SeT · · · A can be obtained from the topological analysis of the H-bonds in the base pairs and from the analysis of the electrostatic potential created by 4SeT and T. The topological properties of the bond (3,-1) critical points in 4SeT · · · A and T · · · A were determined according to Bader’s theory of atomsin-molecules.39 The results are shown in Table 4. For the H-bonds in both base pairs, the Laplacian of the electron density is positive, indicating a depletion of the electron density from the interatomic surface toward the interacting nuclei, as expected for closed-shell interactions. For 4SeT · · · A (T · · · A), the electron density at the (3,-1) critical point for N1(A)-N3(4SeT) (N1(A)-N3(T)) and N6(A)-Se(4SeT) (N6(A)-O4(T)) is 0.034 (0.043) and 0.016 (0.026) au, respectively. Thus, the electron density diminishes when Se replaces O4. Even though the opposite trend is found for the electron density at the bond critical point of C2(A)-O2(T) and C2-O2(4SeT), which reflects the fact that these two atoms are closer in 4SeT · · · A than in T · · · A, the small value of the electron density is indicative of a very weak interaction in the two cases. Overall, it can be said that the topological analysis confirms a weakening of the H-bonding interaction when Se replaces O4. Figure 4 shows the electrostatic potential around the bases T and 4SeT. Clearly, substituting O4 with Se unbalances the electrostatic potential: whereas in T the electrostatic potential is alike around the oxygen atoms O2 and O4, in 4SeT, the electrostatic potential around Se is very different compared to that around O2. This difference is quantitatively reflected in Table 5, which contains the depth of the minima of the electrostatic potential around the atoms O2 and O4 in T, and

b

Figure 4. Representation of the electrostatic potential created for the canonical-like tautomers of T (left) and 4SeT (right). The isocontour corresponding to -20 kcal/mol is shown.

TABLE 5: Depth of the Minima in the Electrostatic Potential for Canonical Tautomers of T and 4SeT (All Values in kcal/mol) minimaa

4SeT

T

Se/O4 (N3) Se/O4 (C5) O2 (N3) O2 (N1)

-29.2 -29.1 -41.7 -39.6

-46.2 -47.8 -46.1 -43.2

a The orientation of the minimum energy well is designated by the name of the atom given in parentheses.

O2 and Se in 4SeT. It can be seen that replacing O4 with Se reduces the depth of the minima by about 40% (from -47 to -29 kcal/mol), and that this replacement has a minor effect on the minima at O2. In summary, all of the above analysis indicates that the larger size of Se as compared to that of O and a decrease in the electrostatic potential around Se make the hydrogen binding of 4SeT to A weaker than the hydrogen binding of T to A, in agreement with chemical intuition, but in apparent contradiction with experimental findings. We therefore inspected also the stacking energetics, to address the issue of whether more favorable stacking properties counterbalance the loss of stability due to weakening of the H-bonds in selenated thymine-adenine pairs. D. Stacking Properties. To examine the stacking properties of 4SeT relative to T, we extracted from the native duplex 1DNS

Seleno-Derivatives of Thymine

J. Phys. Chem. B, Vol. 113, No. 43, 2009 14469

TABLE 6: Stacking Energies for G-T-A and G-4SeT-A Stacks Obtained from MP2 Calculations (All Values in kcal/mol)a system

6-31G(d: 0.25)

6-31+G*

G-4SeT-A

-31.9 (-12.6) -28.3 (-10.7)

-24.1 (-9.2) -19.9 (-7.3)

G-T-A a

BSSE-corrected energies are given in parentheses.

and the Se-modified duplex 2NSK stacks of three consecutive bases (G-T-A from 1DNS and G-4SeT-A from 2NSK). These stacks were then used as model systems for investigating stacking interactions. To avoid a bias into the energy calculations due to possible uncertainties in X-ray crystallographic data, the experimental geometries of the bases were replaced by the corresponding geometries optimized at the MP2/6-31G** level. Single-point calculations were performed at the MP2 level using the 6-31G(d: 0.25) and 6-31+G* basis sets. In the 6-31G(d: 0.25) basis set, the exponent of the d orbital is reduced from 0.80 to 0.25 for heavy elements.65,66 It is worth noting that the MP2/6-31G(d: 0.25) method has recently been shown to provide reliable estimates of the stacking energies for nucleic base pairs at a reasonable computational cost.67 The stacking interaction energies determined for the two stacks are reported in Table 6. The results clearly indicate that the Se-modified stack, G-4SeTA, is more stable than its natural counterpart, G-T-A, the energy difference being ca. 4 kcal/mol at both levels of theory (near 2 kcal/mol after BSSE correction). In summary, replacing O4 by Se reduces the intrinsic H-bonding interaction of 4SeT · · · A relative to T · · · A (see above), but the reduction in the H-bond pairing is partially compensated by the increase in the stacking interaction of the former. Moreover, as expected from the differences in the electrostatic potential of the canonical-like tautomers (see Figure 4), the H-bond pairing of T should be penalized by the larger desolvation cost compared to 4SeT (-14.3 vs -13.2 kcal/mol, respectively, as determined by averaging IEF-MST/HF-6-31G* and IEF-MST/B3LYP-6-31G* hydration free energies). The balance between these opposite trends is likely to be the reason why Se-DNA is only slightly less stable than its native counterpart. E. Electronic Properties. It is reasonable to expect that the electronic properties of Se-DNA will be quite different from those of DNA. Now, the main question that we wish to address is whether those differences make Se-DNA a better candidate than DNA for nanotechnological applications. In particular, note, for instance, that the ability of manipulating the fundamental gap and the strength of the π-π coupling may be in principle exploited to improve the charge mobility throughout DNA, to insert local nonlinearities at specific locations, and also to resolve the electrical signals of individual base pairs. Therefore, one wonders whether modifying DNA with Se allows for any of these advantages. To gain insight into this question, we have investigated the electronic properties of isolated 4SeT, the H-bonded pair 4SeT · · · A, periodic stacks of 4SeT’s, as well as the transfer integrals of a (4SeT · · · A)2 stacked dimer. The results were compared to those for the analogous systems with natural T. Table 7 reports the DFT HOMO and LUMO energy levels and HOMO-LUMO gap of the 4SeT and T bases from LDA(SVWN5)/6-31G**//MP2/6-31G** computations. Clearly, the transformation of T into 4SeT raises the HOMO level and lowers the LUMO level, leading to a dramatic shrink of the

TABLE 7: Energies of HOMO, LUMO, and HOMO-LUMO Gap for Isolated Bases and Base Pairs Determined from LDA(SVWN5)/6-31G**//MP2/6-31G** Computations (All Values in eV) system

HOMO

LUMO

GAP

4SeT T T· · ·A 4SeT · · · A

-4.84 -5.82 -5.21 -4.90

-2.74 -1.96 -1.82 -2.68

2.10 3.87 3.39 2.22

HOMO-LUMO gap by 1.8 eV. An analogous effect takes place in the base pairs: the HOMO-LUMO gap of 4SeT · · · A is 1.2 eV smaller than that of T · · · A. As shown in Figure 5, in T · · · A, the HOMO is localized in A and the LUMO in T, while in 4SeT · · · A both the HOMO and LUMO are localized in 4SeT. Similar trends are seen in the results derived from BLYP and B3LYP computations (see the Supporting Information). On the basis of these results, replacement of O4 by Se in a native duplex is expected to reduce the HOMO-LUMO gap of the duplex. To account for polymer effects, we have considered model stacks of both T and 4SeT that form infinite one-dimensional chains and are similar to those already used to investigate the role of the twist angle in the electronic structure of guaninerich DNA motifs.68 The construction of periodic systems allows us to discuss the results in terms of the band structure concept; namely, it allows us to explore the formation of delocalized electron states upon the stacking interaction: the higher the bandwidth, the higher is the delocalization due to π-π coupling.68 The investigated model stacks are illustrated in Figure 6, along with isosurface densities of the computed HOMO at the Γ point. Γ is the center of the Brillouin zone (BZ) associated with the periodic direction, the size of which is 2π/a ) 0.92 Å-1 (a ) 6.8 Å for our supercell). Each system shown in Figure 6 contains two stacked bases per unit cell. The stacking separation is 3.4 Å. In Figure 6a (c), the two stacked T (4SeT) bases are eclipsed, whereas, in Figure 6b (d), the two stacked T (4SeT) bases are rotated by 36° relative to each other around an axis that passes through the center of mass and is parallel to the stacking direction in the unit cell. In what follows, eclipsed and rotated stacks are denoted as X(0°) and X(36°), respectively, where X ) T; 4SeT. In all cases, the planar conformations of the canonical tautomers of T and 4SeT were considered. Periodic replicas were separated from each other by including a thickness of vacuum of at least 20 Å in the directions perpendicular to the stacking direction. BZ sums were performed using 4 k points in the one-dimensional BZ along the stacking direction. The results for the band structures of the four stacks are shown in Figure 7, where the red solid lines indicate the bands that are derived from the HOMO and LUMO of the single base. Significant parameters are summarized in Table 8. In this table, ∆Egap is the fundamental gap, i.e., the difference between the HOMO- and LUMO-derived bands at the Γ point. ∆EHOMO is the width of the HOMO-derived band, i.e., the difference between the eigenvalues of the highest occupied electron states at the center and at the edge of the BZ in the X(360) stacks. In the X(00) stacks, due to BZ folding, ∆EHOMO is indeed the difference between the highest occupied eigenvalue at the Γ point and its folded companion again at the Γ point.68 Roughly, ∆EHOMO of the X(360) stacks should be compared to 1/2∆EHOMO of the X(00) stacks. From the results shown in Table 8 and Figure 7, it is seen that the shrinking of the fundamental gap, discussed above for

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Figure 5. LDA/6-31G**//MP2/6-31G** contour plot of electron density (isodensity at 0.02 au) of HOMO (blue) and LUMO (red): (a) T · · · A; (b) 4SeT · · · A.

Figure 6. Structures and charge density isosurface plots of the HOMO at the Γ point for (a) T2(0°), (b) T2(36°), (c) 4SeT2 (0°), and (d) 4SeT2 (36°).

the single 4SeT relative to the natural T, is maintained also for stacked systems. Although the stacks computed here are simple models that do not effectively simulate the real Watson-Crick helices, we believe that they reliably convey qualitative messages due to the stacking interaction. Therefore, we are confident

that the gap modulation should be feasible also in real DNA samples where T is substituted by 4SeT, at least in sequences with T-rich portions. In addition to the gap shrinking, we find another feature that was already discussed for guanine-rich duplexes:68 X(00) stacks are characterized by dispersive bands

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Figure 7. DFT-computed band structure for the periodic stacked systems illustrated in Figure 6. Γ is the BZ origin and A the BZ edge.

TABLE 8: Band Gaps and Band Widths, as Defined in the Text, for the Computed Periodic Stacks Illustrated in Figure 6 (All Values in eV) system

∆Egap

∆EHOMO

∆ELUMO

T2 (0°) T2 (36°) 4SeT2 (0°) 4SeT2 (36°)

2.43 3.09 0.36 1.57

1.24 0.30 2.61 0.01

1.44 0.18 2.03 0.27

TABLE 9: Transfer Integrals for Hole Transfer Rates (VIF) and Normalization of the Ground-State Wave Function (N) (T · · · A)2 method27,53 BHLYP

6-311G* cc-pVTZ 6-311++G(3df,3pd) aug-cc-pVTZ

(4SeT · · · A)2

VIF (eV)

Na

VIF (eV)

Na

0.079 0.059 0.054 0.053

0.998 0.997 0.998 0.998

0.260 0.223

0.960 0.959

a N ) 〈ψ|ψ〉1/2, where ψ is the ground-state wave function. This quantity is very close to unity for T · · · A, thus stating a strict fulfillment of the two-state approximation. The latter is less well satisfied in the 4SeT · · · A system, though still acceptable for the method employed to calculate the transfer integrals.59

with a large bandwidth, which underlie the existence of delocalized bonding-like states. However, the bands become flat for X(360) stacks with a rotation angle typical of B-DNA, indicating the probable presence of interplane nodes and no semiconductor-like states in real DNA sequences. Table 9 summarizes the values of the transfer integrals (VIF) calculated for stacked (T · · · A)2 and (4SeT · · · A)2 dimers with the different methods described in the computational section. The comparison between the cc-pVTZ values obtained for the (T · · · A)2 and (4SeT · · · A)2 stacks reveals a marked increase of the transfer integral upon thymine selenation, by a factor of almost 4. The same trend is obtained using the 6-311G* basis set, although the latter does not appear accurate enough for quantitative evaluations. In fact, to gain confidence in our results, we also studied the dependence of the VIF value on the size of

the employed basis set for the (T · · · A)2 system. As shown in Table 7, the calculation using the 6-311G* basis set overestimates the electronic coupling, while the VIF value obtained at the cc-PVTZ level is similar to those obtained using the larger, and computationally more expensive, 6-311++G(3df,3pd) and aug-cc-pVTZ basis sets. Hence, our results embody the hypothesis that T-selenation could be a viable strategy toward electrical applications of synthetic DNA derivatives.2 Conclusions The ab initio results presented above show that replacing the O4 atom of T with Se, so as to generate a seleno-derivative of T denoted here as 4SeT, should affect neither the structural properties nor the tautomeric equilibrium. In contrast, the H-bonding with A and the stacking interactions are affected by the substitution of O4 with Se, but the changes roughly cancel each other. This overall compensation is probably the reason why incorporating 4SeT into a duplex reduces the melting point only slightly. The electronic structure changes induced by the selenium substitution at the O4 location of T are quite remarkable. Indeed, when considering isolated bases, base pairs, or periodic stacks of bases, those containing 4SeT have smaller HOMO-LUMO gaps than those containing T. This trend is reinforced by the enhancement of the charge transfer integral in selenated (4SeT · · · A)2 stacks relative to the natural (T · · · A)2 ones. Overall, these results suggest that incorporating 4SeT into duplexes might offer a valid alternative to natural DNA for nanotechnological applications, because Se-DNA duplexes should preserve the self-assembling property of natural DNA while conducting and/or modulating charge more favorably. 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) and used resources of the National Center for Computational Sciences, ORNL, supported by the Office of Science, USDOE. This research used

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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. DEAC02-05CH11231, and also used resources at the UT/ORNL National Institute for Computational Sciences. R.D.F. and G.B. acknowledge financial support by the European Commission through project DNANANODEVICES, contract FP6-029192. F.J.L. and M.O. acknowledge the financial support received from the Spanish Ministerio de Ciencia e Innovacio´n (SAF2008-05595, BIO200601602, CONSOLIDER Project in Supercomputation) and the computational facilities from the Centre de Supercomputacio´ de Catalunya (CESCA). O.H. acknowledges a fellowship from the Spanish Ministerio de Ciencia e Innovacio´n. A.V.-M. acknowledges the support provided by the USDOE, offices of Basic Energy Science and Advanced Scientific Computing Research as part of the SciDac program. A.M. acknowledges funding from NIH (Grant No. GM067689) and Mike Klein for helpful discussions and support at CMM (UPenn, Philadelphia). Supporting Information Available: Atomic coordinates, energetic terms (as computed with different methodologies), and complete references (NWChem and Gaussian). This material is available free of charge via the Internet at http://pubs.acs.org. References and Notes (1) Endres, R. G.; Cox, D. L.; Singh, R. R. P. ReV. Mod. Phys. 2004, 76, 195. (2) Porath, D.; Cuniberti, G.; Di Felice, R. Top. Curr. Chem. 2004, 237, 183. (3) Genereux, J. C.; Augustyn, K. E.; Davis, M. L.; Shao, F. W.; Barton, J. K. J. Am. Chem. Soc. 2008, 130, 15150. (4) Voityuk, A. A.; Siriwong, K.; Rosch, N. Angew. Chem., Int. Ed. 2004, 43, 624. (5) Aich, P.; Labiuk, S. L.; Tari, L. W.; Delbaere, L. J. T.; Roesler, W. J.; Falk, K. J.; Steer, R. P.; Lee, J. S. J. Mol. Biol. 1999, 294, 477. (6) Lee, J. S.; Latimer, L. J. P.; Reid, R. S. Biochem. Cell Biol. 1993, 71, 162. (7) Rakitin, A.; Aich, P.; Papadopoulos, C.; Kobzar, Y.; Vedeneev, A.; Lee, J.; Xu, J. Phys. ReV. Lett. 2001, 86, 3670. (8) Di Felice, R.; Calzolari, A.; Zhang, H. Nanotechnology 2004, 15, 1256. (9) Gao, J. M.; Liu, H. B.; Kool, E. T. J. Am. Chem. Soc. 2004, 126, 11826. (10) Liu, H. B.; Gao, J. M.; Maynard, L.; Saito, Y. D.; Kool, E. T. J. Am. Chem. Soc. 2004, 126, 1102. (11) Liu, H. B.; Gao, J. M.; Kool, E. T. J. Am. Chem. Soc. 2005, 127, 1396. (12) Liu, H. B.; Lynch, S. R.; Kool, E. T. J. Am. Chem. Soc. 2004, 126, 6900. (13) Gao, J. M.; Liu, H. B.; Kool, E. T. Angew. Chem., Int. Ed. 2005, 44, 3118. (14) Lu, H. G.; He, K. Z.; Kool, E. T. Angew. Chem., Int. Ed. 2004, 43, 5834. (15) Lee, A. H. F.; Kool, E. T. J. Am. Chem. Soc. 2005, 127, 3332. (16) Lee, A. H. F.; Kool, E. T. J. Org. Chem. 2005, 70, 132. (17) Liu, H. B.; Gao, J. M.; Lynch, S. R.; Saito, Y. D.; Maynard, L.; Kool, E. T. Science 2003, 302, 868. (18) Fuentes-Cabrera, M.; Meunier, V.; Sumpter, B. Nanotechnology 2007, 18, 424019. (19) Fuentes-Cabrera, M.; Lipkowski, P.; Huertas, O.; Sumpter, B.; Orozco, M.; Luque, F.; Wells, J.; Leszczynski, J. Int. J. Quantum Chem. 2006, 106, 2339. (20) Fuentes-Cabrera, M.; Sumpter, B. G.; Lipkowski, P.; Wells, J. C. J. Phys. Chem. B 2006, 110, 6379. (21) Fuentes-Cabrera, M.; Sumpter, B. G.; Wells, J. C. J. Phys. Chem. B 2005, 109, 21135. (22) Fuentes-Cabrera, M.; Zhao, X.; Kent, P. R. C.; Sumpter, B. G. J. Phys. Chem. B 2007, 111, 9057. (23) Huertas, O.; Poater, J.; Fuentes-Cabrera, M.; Orozco, M.; Sola, M.; Luque, F. J. J. Phys. Chem. A 2006, 110, 12249.

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