DNA Bases on the

Jun 8, 2009 - Pierre Mignon,† Piero Ugliengo,‡ and Mariona Sodupe*,†. UniVersitat Auto`noma de Barcelona, Dep. Quimica, 08193 Bellaterra, Spain,...
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J. Phys. Chem. C 2009, 113, 13741–13749

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Theoretical Study of the Adsorption of RNA/DNA Bases on the External Surfaces of Na+-Montmorillonite Pierre Mignon,† Piero Ugliengo,‡ and Mariona Sodupe*,† UniVersitat Auto`noma de Barcelona, Dep. Quimica, 08193 Bellaterra, Spain, and UniVersity of Torino, Dip. Chimica IFM and NIS Centre of Excellence, Via P. Giuria, 7. I-10125 Torino, Italy ReceiVed: February 24, 2009; ReVised Manuscript ReceiVed: April 23, 2009

This work analyzes the adsorption of RNA/DNA nucleobases on the external surfaces of Na+-montmorillonite by using periodic plane wave calculations based on the PBE functional. The adsorption energies were corrected by a posteriori added empirical term to account for purely dispersive interactions. Adsorption has been considered either on the side comprising the Na+ counterion or on the opposite side, where only siloxane bonds are present. Different orientations of the nucleobases (parallel and orthogonal to the surface plane) have been considered. The results show that guanine and cytosine, for which the metal cation interacts with two basic centers (N and O), are the ones with larger adsorption energies (-27.6 kcal mol-1 for GO6N7 and -27.0 kcal mol-1 for CO2N3). The remaining three bases present smaller adsorption energies (-21.7 for Tπ(O4), -21.2 for Uπ(O4) and -20.2 kcal mol-1 for AN3). On the other hand, adsorption of the nucleobase on the surface free from Na+, either in a face-to-face or orthogonal orientation, was found to be sizable for all bases (from -3.7 to -11.3 kcal mol-1), due to the stabilizing effect of dispersion interactions. Introduction In the last few years the adsorption of biomolecules on the surface of solid materials has attracted a lot of attention from both fundamental and applied research points of views. This is due to the fact that an increasing number of applications1,2 such as biomedical sensors,3,4 solid phase peptide synthesis,5 or medical implants6 are based on such processes. Furthermore, the adsorption of biomolecules on the surface of oxide materials such as clays is important in the field of prebiotic chemistry, since, as suggested by D. Bernal as early as 1949,7 clays are ubiquitous materials that may have played a crucial role in the selection, concentration, and protection of the monomer building blocks of biological macromolecules. Moreover, clays may have provided the proper active sites to activate the monomers, allowing for an easier polymerization. In the genetic-first viewpoint of the origin of life, the RNA molecule is proposed to play the role of protein and DNA; that is, it catalyzes reactions and stores the genetic information essential for life to begin the long path to cellular evolution. However, the mechanism of RNA prebiotic synthesis remains unknown. For several years, Ferris et al.8 have experimentally studied the role of clays, in particular, montmorillonite largely found in volcanic ash, on the catalysis of RNA polymerization.9 These studies have suggested that the reaction proceeds at approximate sites in the interlayer between the clay platelets.10,11 The first studies on the binding of nucleobases, nucleotides, and polynucleotides on montmorillonite clays postulated that adenine and cytosine may be protonated at the basal plane and edges, known to be acidic.12,13 This would improve the binding between the nucleobase (positively charged) and the clay surface (negatively charged). Later on, a face-to-face binding mode between the nucleobase and the clay surface that maximizes the stabilizing interaction Via dispersive forces, instead of * Corresponding author. E-mail: [email protected]. † Universitat Auto`noma de Barcelona. ‡ University of Torino.

electrostatics, was proposed.14 Indeed, purine bases were observed to bind more strongly than pyrimidines to montmorillonite, in line with the greater stacking (dispersive) interactions of purines compared to pyrimidines. In addition, it was observed that the activated inosine nucleotide, which has a nonbasic hypoxanthine purine ring, binds to montmorillonite as strongly as nucleotides containing the basic adenine ring, thus excluding the protonation of nucleobases. In this case, however, one may expect a repulsive interaction in the face-to-face orientation between the π system of the neutral base and the negatively charged surface. Therefore, many uncertainties remain on the binding mode of nucleobases on a Na+-montmorillonite surface and on the influence of electrostatic or dispersive forces upon the adsorption process. In this context, theoretical calculations can provide very useful information at a molecular level which, to the best of our knowledge, has not been addressed before. The present study aims to analyze the adsorption of purine (guanine and adenine) and pyrimidine (cytosine, thymine, and uracil) nucleobases on the surface of Na+-montmorillonite by means of periodic DFT calculations. The study is limited to the adsorption of DNA/RNA bases on the external surface of dry montmorillonite. Simulations in the absence of water solvent are particularly interesting because they allow understanding of the intrinsic contact features between nucleobases and montmorillonite. Once this step is complete, we will be able to determine how solvent molecules alter the interactions between nucleobases and montmorillonite. Nucleobases are taken in their neutral form according to experimental findings.15 Various adsorption configurations are considered according to the direct interaction of the nucleobase with the surface or with the sodium cation, in either an orthogonal or parallel orientation. Dispersion contributions are taken into account in a posteriori fashion by adding an empirical term to the DFT energy. This allows us to separate the effect of dispersive and electrostatic interactions on the adsorption energy as well as to discuss the possibility of finding a face-to-face stacking orientation in a stable configuration as proposed from experimental results.

10.1021/jp901699q CCC: $40.75  2009 American Chemical Society Published on Web 06/08/2009

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Figure 1. Left: cell used for Na+-montmorillonite in the ab plane. Right: view of the slabs from the ac plane. Atoms’ color code: H, gray; O, red; Na, green; Mg, cyan; Al, magenta; Si, yellow.

Computational Details Model. Montmorillonite belongs to the smectite class of clay minerals with a layer structure. In montmorillonite, each layer is composed of two tetrahedral (T) silica sheets sandwiching one octahedral (O) alumina sheet and is referred to a TOT 2:1 layer type clay mineral. Isomorphic substitution in the octahedral or tetrahedral layers creates a negative charge which is balanced by metal cations such as sodium. Montmorillonite with substitution only in the octahedral layer is known as “Otay-type” montmorillonite, whereas that with substitution on both octahedral and tetrahedral sites is referred to as Wyoming-type montmorillonite. In the present study we only consider the former Otay-type. Montmorillonite is naturally disordered in the planes of the clay layers because of isomorphic substitutions. Therefore, little structural data is available in X-ray crystallographic databases. A common way to build up a model cell of montmorillonite is to start from the unit cell of pyrophyllite, which has identical aluminosilicate layers to montmorillonite but exhibits no substitution. The unit cell formula of pyrophyllite is [Al4(OH)4(Si4O10)2]. We started from the experimental cell parameters of pyrophyllite (CIF code 26742), adopted a double cell (b increased 2-fold), and optimized (cell and atoms) with periodic conditions, as described below. Subsequently, an aluminum atom was substituted by a magnesium atom, with the induced negative charge being compensated by a Na+ cation placed in the center of the silicate six-member ring above the Mg2+ (Figure 1). The fully optimized cell, [Na+,MgAl7(OH)8(Si4O10)4], exhibits the following lattice parameters: a ) 8.90 Å; b ) 10.28 Å, c ) 20.00 Å. It should be mentioned that the interlayer distance, regulated by the unit cell c parameter, was set to a large enough value (20.0 Å) to model the external surface of montmorillonite. For the orthogonal interaction of nucleobases with the surface side not comprising Na+, this value was increased to 30 Å to diminish the long-range electrostatic interactions between the Na+ cation of the above layer and the adsorbed nucleobase. That is, the present study simulates the adsorption of RNA/DNA bases at the external surface, and not within the interlayer, of dry montmorillonite. RNA/DNA bases were placed considering two possibilities: (i) direct interaction with the oxygen atoms of the montmorillonite surface and (ii) direct interaction with the Na+ cation. In each case, both planar and orthogonal orientations were considered. For the interaction with Na+, we considered all orientations involving interactions via the heteroatoms of the purines and pyrimidines, as well as cation-π type adducts. All starting structures were set up with the Moldraw package,16 and then the positions of ions were optimized. Methods. Periodic DFT calculations, as implemented in the Vienna Ab Initio Simulation Package, VASP,17,18 were carried

Mignon et al. out to compute equilibrium structures and energies. All calculations were performed by using the projected augmented wave (PAW)19,20 method to describe the ionic cores and a plane wave basis set for the valence electrons. The PerdewBurke-Ernzerhof (PBE)21 form of the generalized gradient approximation for the exchange and correlation functional was used. The kinetic energy cutoff was fixed at 400 eV. Convergence and accuracy was tested with respect to the number of k-points for the adenine N3 adsorbed complex. The MonkhorstPack22 sampling of the Brillouin zone was used for the following meshes: (1,1,1); (2,1,1); (2,2,1); (2,2,2); (2,2,4); (4,4,4); (8,4,4), which correspond to 1, 1, 2, 4, 8, 32, 64 k-points per unit cell, respectively. In all cases, no geometrical differences were observed after the optimization procedure. However, significant energy differences, ∆E ) 4.67 kcal mol-1, were determined for the (1,1,1) mesh as compared to the most accurate (8,4,4) one. Since from the (2,2,1) mesh the difference in energy became less than 0.12 kcal mol-1, which is reasonably accurate, all subsequent calculations were carried out using the (2,2,1) mesh. With this methodology, full geometry optimizations were performed for all complexes by using a conjugate gradient algorithm. Structures were assumed to be converged when forces on each atom were below 0.05 eV/Å. Adsorption energies of the RNA/DNA bases were calculated as ∆EADS ) ECPLX - E0BASE - E0MNT; ECPLX is the energy of the complex of the adsorbed base on the clay surface, E0BASE is the energy of the isolated base, and E0MNT is the energy of the isolated surface, with each one optimized separately. For the calculation of the isolated base, an orthorhombic cell of 20 × 20 × 17 Å3 was used. Due to the size of the unit cell, lateral interactions between DNA bases of adjacent cells (either attractive or repulsive) may occur, thereby contributing to the final adsorption energies of the different complexes. In order to mimic situations with lower coverages in which interactions between nucleobases are absent and to determine the intrinsic preferred mode of adsorption of a nucleobase in a Na+montmorillonite surface, a correction to the adsorption energy for the lateral interactions between the DNA bases of adjacent cells was computed as follows: ∆EL ) EBASEa,b,c - EBASE20,20,17, where EBASE20,20,17 is the energy of the base in a cell of dimension 20 × 20 × 17 Å3 and EBASEa,b,c is the energy of the base in the same a,b,c cell of the complex. For each, we considered the geometry and orientation of the base as the one found in the adsorbed optimized complex with the clay. In this way, we evaluate the lateral interactions between the bases of adjacent cells present in the cell of a,b,c dimension (EBASEa,b,c), which are not present in a cell of dimension 20 × 20 × 17 Å3. If ∆EL is negative, the lateral interactions are attractive and overstabilize the complex, and Vice Versa. One drawback of classical DFT methods is that dispersion interactions are not taken into account. However, several recent studies have shown that they can be important in solid simulations.23-25 In particular, for aromatic systems such as RNA/DNA bases, the dispersion energy may play a major role in the stabilization due to the interaction between the surface with the π system.26-28 For that purpose, we included the simple Grimme’s correction29 (∆ED), as implemented in the Moldraw package.16 ∆ED has been added to the final energy of the optimized systems, once corrected for lateral interactions; that is, the final total energy is computed as ∆Etotal ) ∆EDFT ∆EL + ∆ED. This correction for dispersion is based on pairwise interatomic potentials of the form C6R-6, where the C6 values are derived from the ionization potentials and the static polarizabilities of the considered neutral atoms. In our system,

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Figure 3. Nucleobases’ atom numbering.

Figure 2. Map of the electrostatic potential (ESP). Code: negative ESP regions are assigned according to the scale -4.12 to 0 eV with the following color spectrum: red < orange < yellow < green < light blue; and positive ESP regions (ESP g 0) are in dark blue. Atoms’ color code: H, yellow; O, red; Na, magenta; Mg, blue; Al, light blue; Si, green.

sodium is in its cationic form, i.e. the ionization potential is much larger and the polarizability much smaller for Na+ than for Na. Therefore, in order to give a reasonable estimation of the dispersion interaction between the base and the clay surface, the contribution of the Na+ cation was omitted. Electronic Properties of Na+-Montmorillonite. Since we are interested in the adsorption of DNA bases on the surface of Na+-montmorillonite, we performed an analysis of the electrostatic potential (ESP), which has already been successfully used to describe the basicity of oxygen atoms in previous cluster calculations.30-32 For this purpose, a high precision single point calculation on the optimized Na+-montmorillonite cell was carried out, with the energy cut off being increased to 500 eV and the energy convergence threshold set to 10-6 eV. Figure 2 shows the electrostatic potential mapped on a slab defined in the ac plane (perpendicular to the b lattice vector) and passing through the Na+ cation. The electrostatic potential map shows a dipolar nature of the montmorillonitic slab in which negative values are close to the oxygen atoms of the siloxane bridges, whereas a prominent positive region is seen on top of the Na+ ion, as expected. Thus, the map indicates that the nucleobases and montmorillonite may interact via hydrogen bonding near the regions containing negative ESP values or through cation-π, cation-heteroatom interactions near the regions containing positive ESP values. Results and Discussion For each nucleobase, adsorption on model external surfaces of both sides of the Na+-montmorillonite layer were considered.

Results are organized accordingly. That is, we first present the adsorption of nucleobases (orthogonal and face-to-face) on the surface side free from Na+. Second, the results corresponding to the direct interaction of nucleobases with the balancing Na+ cation, either through the nucleobase heteroatoms (see Figure 3 for atoms’ numbering) or through the π system, are discussed. Table 1 reports the adsorption energies for all systems and orientations. We will mainly consider the corrected DFT and the total adsorption energies. ∆EDFT -L ) ∆EDFT - ∆EL values include the correction for lateral interactions between bases of adjacent cells and, thus, reflect only the (electrostatic) base-surface interactions. ∆Etotal ) ∆EDFT - ∆EL + ∆ED values include the Grimme’s correction for dispersion. Interaction with the Montmorillonite Surface. Orthogonal Orientation. Figure 4 displays the most stable adsorbed complexes for each base along with the dipole moment of the isolated bases superimposed onto the complex. It can be observed that in all cases the orientation of the base favors a stabilizing electrostatic interaction between the dipole moments of the base and the surface. Other less stable orientations were computed for adenine and guanine interacting with the montmorillonite surface oxygen atoms by H-bonds via N6H and C2H for adenine and N2H and N1H for guanine (data not shown). In these orientations, the dipole moment of the bases points toward the surface, leading to unfavorable dipole-surface interactions, and as a consequence, the adsorbed complexes were found to be less stable by about 4 kcal mol-1, as compared to the orientations shown in Figure 4. Thus, the interaction between the molecular dipole and the surface appears to be an important factor for the stabilization of these orthogonal configurations, although other factors related to the number and strength of hydrogen bonds may also play a role. The sequence of the computed DFT adsorption energies (∆EDFT-L), which is A ∼ U ∼ T < C < G, parallels reasonably well the sequence of the dipole moment of the bases, which at the B3LYP/6-31G* level is A (2.37 D) < T (4.20 D) < U (4.26 D) < C (6.38 D) < G (6.83 D). That is, guanine with the largest dipole moment and stronger hydrogen bonds exhibits the largest corrected adsorption energy (-3.4 kcal mol-1). Moreover, guanine is adsorbed above the 6-membered ring of montmorillonite, reducing the repulsion between the N3 atom and surface oxygen atoms. Cytosine, with a slightly smaller dipole moment and weaker hydrogen bonds with the surface, presents a smaller adsorption energy (-0.2 kcal mol-1). Finally, thymine, uracil, and adenine display lower

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TABLE 1: Distance between the Central OH Oxygen of Montmorillonite and Na+ (Å), and Adsorption Energy Contributions of Nucleobases on Na+-montmorillonite (in kcal mol-1) dNa+-OH

∆EDFT

∆ELa

∆EDFT-L

∆EDb

∆Etotala

Adenine orthogonal face-to-face cation-π cation-heteroatom

orthogonal face-to-face cation-π cation-heteroatom

orthogonal face-to-face cation-π cation-heteroatom

orthogonal face-to-face cation-π cation-heteroatom

(5) mb. ring (6) mb. ring displaced (N1) N7 N1 N3

2.99 2.90 3.12 3.12 3.33 3.09 3.26 2.93

0.5 0.4 -3.4 -5.7 -10.4 -12.9 -15.8 -16.2

0.0 -0.1 0.4 -0.4 0.1 0.5 -0.1 -0.3

0.5 0.5 -3.8 -5.3 -10.5 -13.4 -15.7 -15.9

-4.2 -11.3 -6.0 -6.3 -6.5 -4.1 -3.2 -4.3

-3.7 -10.8 -9.8 -11.6 -17.0 -17.5 -18.9 -20.2

(6) mb. ring displaced (N3O2) O2 O 2N 3

2.93 2.92 2.95 3.41 3.18 3.35

Cytosine 1.1 -2.0 -4.0 -20.4 -21.3 -23.0

1.3 -0.9 -0.9 -1.2 1.0 0.0

-0.2 -1.1 -3.1 -19.2 -22.3 -23.0

-6.4 -8.0 -7.1 -7.4 -1.7 -4.0

-6.6 -9.1 -10.2 -26.6 -24.0 -27.0

(5) mb. ring (6) mb. Ring displaced (N7O6) N3 O6a O6b N7 O 6N 7

2.90 2.91 3.12 3.05 3.40 2.95 3.24 3.18 3.22 3.35

Guanine -1.4 -3.7 -11.0 -4.9 -18.9 -11.7 -19.5 -20.6 -21.6 -21.8

2.0 -3.3 -5.4 -0.6 -1.0 1.3 0.8 -1.0 0.1 1.8

-3.4 -0.4 -5.6 -4.3 -17.9 -13.0 -20.3 -19.6 -21.7 -23.6

-7.9 -10.5 -7.5 -7.6 -8.2 -6.5 -1.9 -5.4 -3.4 -4.0

-11.3 -10.9 -13.1 -11.9 -26.1 -19.5 -22.2 -25.0 -25.1 -27.6

(6) mb. ring displaced (O4) O2 O4

2.94 2.89 2.91 3.38 2.86 3.04

Thymine 1.4 -3.1 -2.1 -14.6 -15.5 -16.1

0.8 -1.6 -1.5 -0.4 -0.1 -0.4

0.6 -1.5 -0.6 -14.2 -15.4 -15.7

-7.9 -9.2 -7.0 -7.5 -1.9 -3.4

-7.3 -10.7 -7.6 -21.7 -17.3 -19.1

(6) mb. ring displaced (O4) O2 O4

2.97 2.91 2.91 3.37 2.95 3.04

1.3 -1.5 -1.5 -0.3 -0.5 -0.1

0.5 -0.2 0.4 -14.5 -14.2 -16.7

-6.2 -8.3 -6.1 -6.7 -2.0 -2.1

-5.7 -8.5 -5.7 -21.2 -16.2 -18.8

Uracil orthogonal face-to-face cation-π cation-heteroatom a

1.8 -1.6 -1.1 -14.8 -14.7 -16.8

Lateral interactions (∆EL) between bases of adjacent cells are computed as explained in the Computational Details section. Grimme’s correction for dispersion, and ∆Etotal ) ∆EDFT - ∆EL + ∆ED.

adsorption energies due to their smaller dipole moments. In these cases, the role of hydrogen bonds and dipole moments may be balanced. In addition, one can notice in Table 1 that, in all cases, the Grimme’s correction for dispersion (∆ED ) -4.2 kcal mol-1 to -7.9 kcal mol-1) is actually the dominant contribution to the adsorption energy, thus indicating that the major part of the complex stabilization arises from dispersive forces. Taking all corrections (lateral interactions and dispersion forces) into account results in ∆Etotal values that range from -3.7 to -11.3 kcal mol-1, with adenine being the nucleobase with a smaller adsorption energy, mainly because of the smaller dispersion contribution. Face-to-Face Orientation. Minimum energy structures of the adsorbed complexes are shown in Figure 5 along with the distance R between the base and the montmorillonite surface. This R value corresponds to the distance between the centroid of the nucleobase (defined by all heavy atoms) and the average plane defined by the 12 oxygens of the surface. As can be observed, the base is almost coplanar to the montmorillonite surface and the distance between the base and the surface

b

∆ED is the

corresponds to that found between stacked bases in DNA, around 3.2-3.3 Å.27 Stable structures are found for all cases, although ∆EDFT-L is positive for adenine. The ∆EDFT-L values are very small with lateral interactions between bases of adjacent cells of the same order of magnitude as the adsorption energy. On the other hand, similarly to the orthogonal orientation, data in Table 1 show that the dispersion interaction (∆ED) constitutes the main and almost the only contribution to the total adsorption energy. As expected, the larger dispersion energy contributions are obtained for adenine and guanine, which have a larger aromatic system. Overall, ∆Etotal values for purines (-10.9 and -10.8 kcal mol-1, for guanine and adenine, respectively) are somewhat larger than those of cytosine and uracil pyrimidines (-9.1 and -8.5 kcal mol-1, respectively). ∆Etotal value for thymine (-10.7 kcal mol-1), however, is as large as that of purines due to the extradispersion contribution arising from the methyl group. Comparison between the orthogonal and face-to-face orientations indicates that, in all cases except for guanine, the faceto-face interaction appears to be the preferred mode of adsorp-

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Figure 4. Geometries of the adsorbed nucleobases in the orthogonal configuration. Distances are given in angstroms. The arrow indicates only the orientation of the dipole moment vector computed for the isolated bases and superimposed on the adsorbed bases. The magnitude of the dipole moment of the nucleobases is as follows: A (2.37), G (6.83), C (6.38), T (4.20), U (4.26) in Debye. Atoms’ color code: H, gray; C, brown; N, blue; O, red; Na, green; Mg, cyan; Al, magenta; Si, yellow.

tion of nucleobases on the montmorillonite surface side that does not contain the Na+ cation. For guanine, because of the largest dipole moment and strongest H-bonds occurring in the orthogonal orientation, both adsorption modes are competitive. Interaction with the Na+ Cation. Cation-π Interaction. Several π-like approaches of the nucleobases to the Na+montmorillonite surface have been considered. First, nucleobases were approached to Na+ along the axes perpendicular to the different aromatic rings and passing through their respective centers. For purines, this implies that the cation lies below the center of the five- or the six-membered ring. These configurations will be referred to hereafter as Baseπ(5) or Baseπ(6) to indicate whether the interaction occurs with the five- or the sixmembered ring, respectively, of the bicyclic purines. However, the presence of cyclic and exocyclic heteroatoms tends to diminish the cation-π interaction at the center of the ring. Indeed, a previous study on cation-π interactions between DNA bases and Na+ shows that the interaction energy may be larger out of the ring, with the cation located in the same parallel plane but displaced toward the exocyclic heteroatoms.33 Therefore, these configurations were also explored and hereafter will be referred to as Baseπ(xy), where x and y indicate the heteroatoms interacting with the metal cation. Cation-π/Ring Interaction. Let us first consider the π interaction between Na+ and the five- or six-membered rings of the nucleobases. In these configurations, the nucleobases lay almost parallel to the surface (Figure 6) and the interaction with the cation is mainly electrostatic and described by ∆EDFT-L. It

Figure 5. Geometries of the adsorbed nucleobases in the face-to-face configuration. Distances are given in angstroms. The distance between the nucleobase and the surface is defined as the distance between the centroid of the molecule and the average plane determined by the 12 surface oxygen atoms.

should be noted that for Gπ(5) the computed ∆EL value is quite large and negative due to attractive lateral interactions between bases of adjacent cells, in particular between one hydrogen of the amino group and the N7 and O6 atoms. Overall, the ∆EDFT-L values are negative in all cases, except uracil, and follow the sequence, Gπ(5) ≈ Aπ(6) > Gπ(6) ≈ Aπ(5) ≈ C π(6) > T π(6) ≈ U π(6). This trend is in reasonable agreement with that resulting from the interaction between the nucleobase and Na+ computed in the gas phase at the MP2 level:33 Aπ(6) (-17.1) ≈ Gπ(5) (-16.8) > G π(6) (-13.4) ≈ C π(6) (-13.3) ≈ Aπ(5) (-12.7) > T π(6) (-5.4). As expected, interaction energies are larger in the gas phase than in Na+-montmorillonite due to screening and charge transfer effects from the surface to the Na+ ion. It is worth noting that the distance between Na+ and the central OH group of montmorillonite, which measures the Na+ displacement from the surface, is correlated with ∆EDFT-L (see Table 1). In free Na+-montmorillonite, this distance is computed to be 2.86 Å, whereas for the adsorbed complexes this value can increase up to 3.12 Å. Indeed, the larger the Na+ displacement, the lower the charge transfer to the surface oxygen atoms and the larger the base-cation electrostatic interaction.

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Figure 6. Geometries of the adsorbed nucleobases in the cation-π/ring configuration. Distances are given in angstroms. The distance between the nucleobase and Na+ is defined as the distance between the average plane made of the five or six atoms of the considered ring of the molecule and the cation.

The base-surface interaction is mainly driven by dispersion and constitutes the main part of the complex stabilization, with the total adsorption energies ranging now from -5.7 kcal mol-1 for Uπ(6) to -13.1 kcal mol-1 for Gπ(5). The magnitude of the dispersion energy is related to the size of the nucleobase π system and to the distance R (as defined above; see Face-toFace paragraph) between the base and the surface, which is (in Å) 3.80 (Aπ(5)), 3.88 (Aπ(6)), 3.39 (Cπ(6)), 3.59 (Gπ(5)), 3.61 (Gπ(6)), 3.60 (Tπ(6)), and 3.48 (U π(6)). That is, the small value of the dispersion interaction computed for adenine can be explained by the large distance to the surface and vice versa for cytosine. As a result, the sequence of total adsorption energies of different nucleobases, Gπ(5) > Gπ(6) > Aπ(6) > C π(6) > Aπ(5) > T π(6) > U π(6), is now somewhat different from that determined without including base-surface dispersion interactions. Cation-π/Displaced Interaction. The configurations arising from a π interaction between the metal cation and π orbitals of exocyclic heteroatoms were set up according to a previous study33 on cation-π interactions between DNA bases and Na+. In this study, the largest π-interaction with guanine was determined to occur when the base was placed with the Na+ cation below the O6 and N7 atoms. For cytosine the maximum stabilization was found when Na+ was below the O2 and N3 atoms, and for adenine and thymine/uracil it was found when Na+ was close to N1 and O4, respectively. Optimized geometries are given in Figure 7. It can be observed in Table 1 that ∆EDFT-L values are significantly more negative than those obtained for the com-

plexes derived from cation-π interactions with the five- or sixmember rings of the base, with the corrected DFT energies ranging from -10.5 for adenine to -19.2 kcal mol-1 for cytosine. On the other hand, the distance between Na+ and the central OH group of montmorillonite (Table 1) is larger than that for all other configurations, probably due to the rather large Na+-base interaction. These data show that the base-cation-π interaction is quite strong, despite the fact that the cation is not interacting with the heteroatoms in the plane of the base, as for gas-phase systems.34-37 Furthermore, in these configurations, the aromatic ring stays almost coplanar to the surface with a distance ranging from 3.36 to 3.73 Å. As a result, the dispersion interaction is also large and comparable to that obtained for the cation-π configurations. Overall, due to the favorable electrostatic and dispersive interactions, the total adsorption energies become rather large (from -17.0 for adenine to -26.6 kcal mol-1 for cytosine). Cation-Heteroatom Interaction. The orientations of the bases as well as the optimized main geometrical parameters for adsorbed purines and pyrimidines are shown in Figures 8 and 9, respectively. As expected, due to the stabilizing electrostatic interaction, the ∆EDFT-L values are all negative and quite large. Similarly to the cation-π/displaced orientation, the main contribution to the adsorption energy comes from the electrostatic interaction between the base and the cation (Table 1), whereas the dispersion contribution to the energy is significantly smaller, between -1.7 and -6.5 kcal mol-1.

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Figure 7. Geometries of the adsorbed nucleobases in the cation-π/ displaced configuration. Distances are given in angstroms. The distance between the nucleobase and the surface is defined as the distance between the centroid of the molecule and the average plane made of the 12 surface oxygen atoms.

For adenine, the interaction of Na+ with the N3, N1, and N7 heteroatoms was considered. Figure 7 shows that, in addition to the cation-base interaction, adsorbed complexes exhibit H-bond interactions between the base and the siloxane oxygens of the surface. These H-bonds, however, appear to be relatively weak, according to the rather large distance (2.90-3.45 Å) between the surface oxygen atoms and the hydrogen atoms of the base, and, thus, are not expected to significantly contribute to the adsorption energies. Indeed, the sequence in ∆EDFT-L adsorption energies, N3 > N1 > N7, is in nice agreement with that obtained for the proton affinity of the considered nitrogen atoms in the gas phase computed at the MP2 level.37 For guanine, we considered the monodentate coordination through N7, O6, and N3 as well as the bidentate coordination via N7 and O6 (see Figure 8). The total adsorption energies of guanine on Na+-montmorillonite follow the sequence O6N7 > N7 > O6b > O6a > N3, with the interaction with both N7 and O6 leading, as expected, to the largest adsorption energy. Quite noticeably, the adsorption energies follow again the sequence observed for gas phase proton affinities (N7 > O6 > N3).37 The interaction via N3 shows a small ∆EDFT-L adsorption energy

Figure 8. Geometries of the adsorbed purines in the cation-heteroatom configuration. Distances are given in angstroms.

which is partially compensated by a rather large dispersion contribution, due to the proximity of the amino group to the surface. For cytosine, coordination through N3, O2, or both (N3 and O2) heteroatoms was considered (see Figure 9). The interaction with both N3 and O2 leads to the highest stabilization energies, with the O2 coordination being less stable by about 1 kcal mol-1 (corrected DFT energy). It should be mentioned that a minimum corresponding to the interaction between the base and the cation via only N3 could not be obtained. All attempts to obtain such a structure, starting from a guess geometry with the metal cation coordinating via N3, collapsed to the bidentate N3O2 structure. Since the stabilization due to dispersion interactions is larger for the N3O2 adduct, because of the proximity of the amino group to the surface, the N3O2 orientation leads to a total adsorption energy that is larger than that of the O2 adduct by about 4 kcal mol-1. Uracil and thymine show the same trends, with the adsorption energy with Na+ being larger for O4 than for O2. This is in agreement with the proton affinities computed

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Mignon et al. those obtained in the present work. An important difference observed is that for adenine and cytosine the coordination to the alkali metal in the gas phase involves the rotation of the amino group, which rehybridizes from sp2 to sp3 to coordinate to the metal cation. This leads to a bidentate interaction between Na+ and N7 and N6 for adenine, and N3 and N4 for cytosine. This sp3 rehybridization, however, is not observed in solution40 nor in the present study. Indeed, the interaction of Na+ with water or with the surface reduces the electrostatic interaction with the nucleobase, and thus, it does not compensate for the cost of amino group rotation.41 For adenine, the sp3 amino group rehybridization and bidentate interaction via N7 and N6 lead to the most stable structure in the gas phase,34,36,39 in contrast to what is observed for the adsorption of adenine on Na+-montmorillonite, for which the interaction via N3 leads to the most stable complex. For the other nucleobases, the most favorable coordinations in the gas phase correspond to the adsorption orientations which exhibit the largest adsorption energies found in the present study. Nevertheless, the gas phase interaction energies, computed at the B3LYP/ 6-311+G(2df,2p) level36 (-50.1 kcal mol-1 for cytosine, -54.4 kcal mol-1 for guanine, and -34.2 and -34.1 kcal mol-1 for the O4 coordination to thymine and uracil, respectively) are much larger (around twice) than those computed for the adsorption energies of the nucleobase on Na+-montmorillonite. Moreover, the distances between Na+ and the bases are larger in the present study as compared to the ones found from gas phase calculations.39 Although the method we used, PBE plane waves periodic calculations, is different from the hybrid approach adopted for gas-phase calculations, this clearly shows a weaker interaction between the base and Na+ adsorbed on montmorillonite due to the screening of the Na+ charge by the surface. Conclusions

Figure9. Geometriesoftheadsorbedpyrimidinesinthecation-heteroatom configuration. Distances are given in angstroms.

in the gas phase, which show the following order: O4 > O2.37 In addition, the proton affinity is larger for thymine than for uracil, as found in our computed DFT corrected energies. This order, however, is changed upon inclusion of the dispersion energy. The total adsorption energies for the five nucleobases interacting with Na+-montmorillonite in this cation heteroatom configuration follow the following order: GN7O6 (-27.6) ∼ CN3O2 (-27.0) > AN3 (-20.2) ∼ TO4 (-19.1) ∼ UO4 (-18.8). Therefore, the major differences appear between bidentate (G and C) and monodentate complexes (A, T, and U), with the former ones presenting significantly larger adsorption energies. As a consequence of this efficient bidentate electrostatic interaction, this is the preferred mode of adsorption for guanine and cytosine on a Na+-montmorillonite surface. Notwithstanding this, the displaced cation-π orientations in which the cation interacts with the same heteroatoms can be competitive due to stabilizing base/surface dispersion interaction (see Table 1). Comparison with Gas Phase Calculations. Numerous works have investigated the alkali metal cation-nucleobase interactions in the gas phase,34-39 and it is interesting to compare them with

This paper addresses the adsorption of DNA/RNA nucleobases on Na+-montmorillonite external surfaces by means of periodic DFT plane wave calculations based on the PBE functional. Because of the well-known flaws of DFT methods in dealing with dispersive interactions, this contribution has been simply computed by means of the empirical correction proposed by Grimme29,42 at the optimized geometry and added to the DFT energy. Adsorption on both sides (with and without Na+ cation) of the layer has been considered, as well as different orientations (parallel and orthogonal). Adsorption energies onto the surface free from the Na+ cation range from -4 to -11 kcal mol-1. Both in the face-to-face and orthogonal orientations the dispersion correction constitutes almost the total contribution to the energy and, as expected, is larger in the former than in the latter orientation. Overall, and after correcting for lateral interactions and dispersion forces, all bases except guanine show a clear preference for the faceto-face configuration due to the larger dispersive contribution. For guanine, however, the orthogonal orientation appears to be slightly more favorable by 0.4 kcal mol-1 due to its largest dipole moment and the presence of weak hydrogen bonds with the surface. Adsorption of nucleobases onto the Na+ containing surface can be 3-fold, i.e. as cation-π, cation-π/displaced, and cation/ heteroatom configurations. For the classical cation-π interaction, the electrostatic contribution is far smaller than the pure dispersive one. This view changes dramatically for the cation-π/ displaced orientation, where the electrostatic contribution increases significantly, becoming almost twice as large as the

Adsorption of RNA/DNA Bases on Na+-Montmorillonite dispersive one. The cation/heteroatom orientation, however, renders these cases less effective in exploiting dispersion interactions, which are indeed the smallest for all considered orientations. As a result, the relative energy between cation-π/ displaced and cation/heteroatom configurations is less than 3 kcal mol-1, with the preference for one adsorption mode or another depending on the nucleobase considered. For guanine and cytosine, with a bidendate coordination, the cation/heteroatom is the preferred mode of adsorption due to the efficient electrostatic interaction. Consequently, these two bases exhibit the largest adsorption energies: -27.6 kcal mol-1 for GO6N7 and -27.0 kcal mol-1 for CO2N3. The remaining three bases present smaller adsorption energies (-21.7 for Tπ(O4), -21.2 for Uπ(O4) and -20.2 kcal mol-1 for AN3), with thymine and uracil displaying a preference for the cation-π/displaced configuration. Overall, the present work shows that dispersive forces between the nucleobases and the surface are essential to stabilize the adsorbed complexes in the face-to-face and cation/πdisplaced configurations, which, as suggested by Ferris et al., might explain the more favorable binding of inosine to montmorillonite as compared to cytosine.14 Nevertheless, we can only highlight that the face-to-face adsorption mode, as proposed by Ferris, is highly plausible. Other adsorption modes appear to also be possible, but their relative stability may differ in the presence of water due to the solvation of the metal cation. This should be the subject of forthcoming studies on the effect of water on the binding of DNA bases on Na+-montmorillonite. Acknowledgment. Financial support from MCYT and DURSI, through the CTQ2008-06381/BQU and SGR2005-00244 projects, and the use of the Catalonia Supercomputer Centre (CESCA) are gratefully acknowledged. M.S. and P.U. kindly acknowledge BSC-MN for generous allowance of computing time (project QCM-2008-2-0022: montmorillonite clay catalyzed synthesis of RNA oligomers). P.M. thanks M.E.C. for a Juan de la Cierva research associate contract. References and Notes (1) Patwardhan, S. V.; Patwardhan, G.; Perry, C. C. J. Mater. Chem. 2007, 17, 2875. (2) Davis, S. A.; Dujardin, E.; Mann, S. Curr. Opin. Solid State Mater. Sci. 2003, 7, 273. (3) Donhauser, Z. J.; Mantooth, B. A.; Kelly, K. F.; Bumm, L. A.; Monnell, J. D.; Stapleton, J. J.; Price, D. W.; Rawlett, A. M.; Allara, D. L.; Tour, J. M.; Weiss, P. S. Science 2001, 292, 2303. (4) Bain, C. D.; Evans, S. D. Chem. Br. 1995, 31, 46. (5) Fields, G. B. Methods Enzymol. Solid-Phase Peptide Synth. 1997, xxxi+780p.

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