π Interactions in DNA and Proteins. A Theoretical Study - The

Jul 11, 2007 - A systematic study of the CH/π interactions of methane with the purine and pyrimidine bases of nucleic acids and with the lateral chai...
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J. Phys. Chem. B 2007, 111, 9372-9379

CH/π Interactions in DNA and Proteins. A Theoretical Study Adria` Gil, Vicenc¸ Branchadell, Joan Bertran,* and Antoni Oliva Departament de Quı´mica, UniVersitat Auto` noma de Barcelona, 08193 Bellaterra, Spain ReceiVed: March 5, 2007; In Final Form: June 6, 2007

A systematic study of the CH/π interactions of methane with the purine and pyrimidine bases of nucleic acids and with the lateral chains of the four natural aromatic amino acids has been carried out for the first time. The MPWB1K/6-31+G(d,p) method has shown to be adequate for the study of these weak interactions in which dispersion forces play a main role. It has been shown that two different kinds of clusters exist, depending on whether one or two CH bonds point to the aromatic system. The latter one, which we have called bifurcated, is usually more stable. With regard to aromatic amino acids, our calculations agree with experimental data in the fact that tryptophan leads to the strongest interaction, while hystidine leads to the weakest one. In the case of nucleic acid bases, the differences in binding energies are not large. This is specially true for thymine and uracil, showing that these two bases have a similar acceptor character in CH/π interactions.

Introduction The CH/π interaction1 is the weakest extreme of hydrogen bonds2 that takes place between a soft acid (CH) and a soft base (π-system).3 Other hydrogen bonds are the conventional ones (between hard acids and hard bases), the XH/π interactions (between a hard acid and a soft base), and the CH/n interactions (between a soft acid and a hard base). In the latter case, n stands for a lone pair of an electronegative atom (O, N, etc.) The hydrogen bond character of CH/π interactions has been demonstrated through different experiments on the electronic effect of a substituent on stereoselectivity,4 conformational equilibrium,5 crystal packing,6 and enantioselectivity.7 Theoretical calculations8-10 have confirmed the hydrogen-bonded nature of CH/π interactions and its borderline character with van der Waals complexes. In particular, several theoretical studies11-22 have shown that the stabilization of the CH/π bond comes, essentially, from the dispersion energy. Energetic contribution from the electrostatic energy is usually not important except for species involving strong CH donors such as chloroform or acetylenic CH. In spite of their weakness, experimental and theoretical studies have shown that CH/π interactions play an important role in many fields such as in crystals,23 organic reactions,24-26 conformational analysis,27-28 and molecular recognition.29-32 They are of special interest in the stability of biological structures since these soft-acid soft-base hydrogen bonds are dominated by dispersion and polarization energy, and thus, they are persistent in both highly polar and apolar environments such as those found in the interior of proteins.33 Weiss and coworkers, for instance, showed that three-quarters of the Trprings, half of all Phe- and Tyr-rings, and a quarter of all Hisrings are involved as acceptors in CH/π interactions.34 Other authors have invoked the role of these interactions in the stability of proteins,35-37 the binding of carbohydrates to proteins,38-39 and the packing of the adenine ring40 or guanine nucleotide41 in protein structures. Finally, CH/π contacts of the methyl group of thymine or the backbone sugars with DNA or proteins have been described.42-44

The object of this work has been the study of the CH/π interactions between an aliphatic CH bond and aromatic rings of nucleic acids (adenine, guanine, cytosine, thymine, and uracil) and of protein amino acids containing an aromatic ring (phenylalanine, tyrosine, histidine, and tryptophan). We have used methane as the simplest model of an aliphatic compound, we have modeled the 4 above-mentioned amino acids by toluene, p-cresol, 5-methylimidazole, and 3-methylindole, respectively, and we have not considered the backbone chain in the nucleic acids. Computational Method The standard method for introducing dispersion energy in theoretical studies is to combine MP2 theory in the complete basis set (CBS) limit with a ∆CCSD(T) correction computed in a smaller basis to estimate the CBS CCSD(T) results.12,13,16-18,20-22 However this approach is not feasible for large systems of biological interest. A possible alternative would be the use of methods based on density functional theory (DFT), but classical functionals have been shown to not be appropriate in treating systems in which dispersion forces are crucial.45-46 One simple but somewhat effective solution47-51 is to add damped pairwise interatomic potentials of the form -C6/r6, with C6 dispersion coefficients dependent on the atoms involved, but this empirical correction has been the object of some criticism.46,52 Recently Becke53 has proposed to generate C6 coefficients from a model based on the exchange-hole dipole moment. A different approach has been the building up of new functionals such as those proposed by Truhlar and coworkers.54-59 Both the non-empirical and empirical DFT methods can be assigned to various rungs of “Jacob’s ladder”, according to the number and kind of the ingredients in the functional.56 The lowest rung is the local spin density approximation (LSDA). The second rung is the generalized gradient approximation (GGA). The third rung is meta-GGA, in which the density functional also depends on kinetic energy density. The fourth rung is hyper-GGA which employs some percentage of HF exchange. In particular, the MPWB1K54

10.1021/jp0717847 CCC: $37.00 © 2007 American Chemical Society Published on Web 07/11/2007

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J. Phys. Chem. B, Vol. 111, No. 31, 2007 9373 TABLE 2: Binding Energiesa for Complexes of Methane with Benzene, Phenol, and Indole benzene phenol indole (r6)d indole (r5)d indole (bif)d

MP2/DZb

CCSD(T)/DZb

MPWB1K/6-31+G(d,p)c

1.52 1.58 1.87 1.75 2.38

1.21 1.20 1.47 1.41 1.85

0.80 0.96 0.96 0.70 1.12

a Energy in kcal mol-1. b Results taken from ref 32. c This work. Geometries taken from ref 32. d r6, r5, and bif indicate whether methane interacts with the six-membered ring, the five-membered ring, or with both rings of indole, respectively.

Figure 1. Minimum energy structure for the methane/benzene system.

TABLE 1: Binding Energy and Distance, R, from the Carbon Atom of Methane to the Aromatic Ring for the Benzene-Methane Cluster method B3LYP/6-31G(d,p)c MPWB1K/6-31+G(d,p)c MPWB1K/6-311++G(3df,2pd)c MP2 (limit)d CCSD(T) (limit)d a

binding energya

Rb

0.032 1.034 1.182 1.803 1.428

5.60 3.87 3.88 3.6 3.8

Energy in kcal mol-1. b Distance in Å. c This work. d Reference 20.

functional is a hyper-GGA method, and it has been shown to be the most adequate for the study of four types of nonbonded interactions: hydrogen binding, charge transfer, dipole interactions, and weak interactions.55 It also has good behavior in thermochemistry and thermochemical kinetics.56-57 Furthermore, Truhlar et al. have found that this functional describes well the staking interactions in biological systems58 and also the hydrogen bonds to π-acceptors.59 Nevertheless only OH, NH, and ClH have been used as donors. So, the use of this functional for the study of CH/π interactions requires an initial test to see if these interactions are well represented. This test has been carried out by us using the benzenemethane model system, since the CH/π interaction energy has been accurately determined, both theoretically and experimentally. The experimentally determined binding energy (D0) is 1.03-1.13 kcal mol-1.20 Table 1 presents the results obtained in this work at different levels of calculation along with the values calculated in ref 20. The optimization of the benzenemethane system with the 6-31+G(d,p) basis set60 has led to a minimum energy C3V structure in which a CH bond of methane points to the center of the benzene ring, the distance of the C atom to the ring being 3.87 Å (see Figure 1). The corresponding binding energy is 1.034 kcal mol-1. The good agreement between this value and the experimental result is only apparent since basis set superposition error and zero-point corrections are not included. In the benchmark calculations of Tsuzuki et al.,20 the binding energy at the MP2 limit is 1.803 kcal mol-1 (for a carbon atom distance to the ring of 3.6 Å), while the ∆CCSD(T) correction amounts to 0.375 kcal mol-1, thus leading to a binding energy of 1.428 kcal mol-1 which approaches the experimental value when the zero-point correction (about 0.296 kcal mol-1) is taken into account. It can be concluded that our calculations underestimate the binding energy by 0.394 kcal mol-1, while the CBS MP2 method overestimates it by 0.375 kcal mol-1. We have calculated the binding energy using the same functional with the larger 6-311++G(3df,2pd) basis set, and the result obtained is 1.182 kcal mol-1. The increase of the binding energy is coherent with the importance of the dispersion term which, as it is well-known, is very sensitive to the basis

set size. Nevertheless, the big size of our systems and the flatness of the potential energy surface (due to the weak CH/π interactions) justify the use of the 6-31+G(d,p) basis set throughout the optimizations. In order to verify if the chosen density functional correctly describes the relative energetics of different complexes, we have computed the binding energies of the systems studied by Sherrill et al.32 through single-point calculations using the MPWB1K/ 6-31+G(d,p) method, and the results obtained are shown in Table 2. The relative ordering obtained with the MPWB1K functional between benzene and phenol on one hand and between the three indole complexes on the other hand is the same as the one corresponding to MP2. However, we observe that the MPWB1K functional seems to underestimate the binding energies of indole with respect to benzenic systems. As we have already observed for the methane-benzene complex (Table 1), the CCSD(T) binding energies are between the MP2 and MPWB1K values. As a result of this comparison, we can conclude that the relative binding energies for very different π systems obtained with the MPWB1K functional should be treated with some caution. All calculations have been performed with the Gaussian 03 package.61 All minimum energy structures have been characterized through the calculation of the harmonic vibrational frequencies to verify that all frequencies are real. Results and Discussion The results corresponding to the CH/π interactions between methane and the model aromatic amino acids will be presented first. Afterward, the interactions corresponding to the bases of nucleic acids will be treated. In each case the minimum energy structures of the clusters have been obtained at the MPWB1K/ 6-31+G(d,p) level of calculation. Amino Acids. As mentioned in the Introduction, phenylalanine, tyrosine, histidine, and tryptophan have been modeled by toluene, p-cresol, 5-methylimidazole, and 3-methylindole, respectively, by eliminating the main chain and replacing the CR atom by a hydrogen atom. For the search of energy minima in monocyclic amino acids we have started by placing methane with one of its CH bonds pointing to the center of the ring. The optimization procedure generally leads to stationary points with a variable number of negative eigenvalues of the force constants matrix. The structures shown in Figure 2, which are real energy minima, have been obtained after eliminating all the negative eigenvalues. For 3-methylindole, we have calculated the potential energy surface corresponding to its interaction with a methane molecule placed with one of its CH bonds pointing to the plane of the molecule and with the hydrogen atom at 2.8 Å above the plane. The results obtained are shown in Figure 3. The geometries of methane and 3-methylindole have been kept frozen, and the x and y

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Figure 2. Minimum energy structures for the clusters between methane and the modeled aromatic amino acids computed at the MPWB1K/631+G(d,p) level of calculation. For bifurcated structures, numbers 1 and 2 indicate the two H atoms that are closer to the plane of the aromatic system.

Figure 3. Potential energy surface for the interaction of a methane molecule with 3-methylindole. One of the CH bonds of methane is perpendicular to the aromatic plane, and the hydrogen atom is 2.8 Å above the plane. Interaction energies are in kcal mol-1.

coordinates represent the displacement of the methane molecule over 3-methylindole. In Figure 3, we can observe the presence of two relative minima centered in each ring. The minimum over the sixmembered ring is slightly more favorable (interaction energy around -1.0 kcal mol-1) than that over the five-membered ring (interaction energy around -0.9 kcal mol-1). For this reason, we have taken three different starting points for the geometry optimization, placing the methane molecule over each one of the two rings and a bifurcated structure. Table 3 presents the binding energy and some geometry parameters corresponding to the six structures which have been found as energy minima for the cluster between methane and the aromatic amino acid models: one for each monocyclic

amino acid and three for Trp. As in Table 1, R stands for the distance of the carbon atom of methane to the plane of the aromatic ring (as the CH/π interaction is very weak, the aromatic ring remains quite close to planarity). R1 and R2 stand for the distances to the plane of the aromatic ring of the hydrogen atoms of methane which are closer to that ring than the C atom.62 In Figure 2, the six obtained minimum energy structures are depicted by the projection of methane on the plane of the aromatic system. The interaction clusters can be classified into two different groups according to the number of hydrogen atoms of methane which are closer to the aromatic ring than the carbon atom. It can be observed that in three cases, only one distance appears in Table 1, thus indicating that in these clusters methane is placed with one CH bond pointing to the ring. In the other

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TABLE 3: Binding Energy and Geometry Parameters for Minimum Energy Structures of the Clusters between Methane and the Modeled Aromatic Amino Acids amino acid

binding energya

Rb

R1b

R2b

Phe Tyr His Trp1 Trp2 Trp3

1.072 (2.188) 0.983 (2.349) 0.848 (2.102) 1.291 (3.484) 0.948 (2.875) 0.900 (2.468)

3.88 3.87 3.57 3.42 3.67 3.87

2.81 2.79 2.92 2.77 2.82 2.78

2.96 2.80 3.33 -

Energy in kcal mol-1. In parentheses are values computed at the MP2/6-31+G(d,p)//MPWB1K/6-31+G(d,p) level. b Distance in Å. a

three cases, which could be called bifurcated structures, methane adopts a different orientation, in such a way that two of its CH bonds, labeled 1 and 2 in Figure 2, point to the aromatic system. The orientation of methane and of the toluene methyl group in the methane/toluene cluster agree quite well with those indicated by Tsuzuki et al.22 The increase of binding energy when going from benzene to toluene was also found by these authors with MP2 calculations. This had to be expected given that the increase of polarization produced by the methyl group enhances the stabilization of the system through the dispersion energy term. To our knowledge no calculations have been done for the other clusters. However, Sherrill32 showed that the binding energy for the methane/phenol system is quite similar to that of the methane/benzene system, a result that agrees quite well with the binding energies obtained for toluene and p-cresol, which only differ by less than 0.1 kcal mol-1 (see Table 2). In the case of 5-methylimidazole, the results obtained in this work can be analyzed through the comparison with the study of the interaction between methane and pyridine.29 In this study, different representative positions of methane with respect to the pyridine ring were investigated without geometry optimization, finding that a bifurcated structure with one H atom of methane placed over the N atom of pyridine and another H atom pointing to the aromatic ring is the most favorable one. Figure 2 shows that the methane/5-methylimidazole cluster has a very similar structure, where the H2 atom is over the pyridinic N atom of 5-methylimidazole and the H1 atom is over the five-member ring. This orientation of methane can be understood through the electrostatic interaction of the H atom with the electronic density of the pyridinic N atom. It has been shown12,16 that although electrostatic interactions are considerably weaker than dispersion ones, the former are highly orientation dependent,12,16 and thus they are important to determine the orientation of the methane molecule. As it has been mentioned, three minimum energy structures have been obtained for 3-methylindole (the model system used for tryptophan). Figure 2 and Table 3 show that the two most stable structures have a bifurcated nature while in the less stable one only one hydrogen atom points to the center of the sixmember ring of the aromatic system. In both bifurcated structures, one CH bond of methane points to the five-member ring of 3-methylindole. In the most stable one, the second CH bond points to the six-member ring while in the other bifurcated structure, the second CH bond points to the exterior of the aromatic system. In the above-mentioned work, Sherrill and coworkers32 have studied different positions of methane over indole, but complete geometry optimization has not been done in any case. Their results predict the existence of three structures: one which is bifurcated and the two others in which one CH points to the center of each ring. As in our results, the

bifurcated structure is clearly the most stable one. The other bifurcated structure was not investigated by Sherrill, the cluster with methane pointing to the center of the six- and five-member rings being the other two structures considered in his work. In our case, complete geometry optimization of the cluster where methane is centered over the five-member ring leads to the bifurcated structure named Trp2 in Figure 2, which is slightly more stable than Trp3. Table 3 also presents the values of binding energies computed at the MP2 level of calculation for the geometries optimized at the MPWB1K level. It is to be noted that the relative ordering of the three Trp structures is the same as for the MPWB1K functional, in contrast with the partially optimized structures of Sherril et al.32 (see Table 2). The His cluster has the lowest binding energy. On the other hand, the binding energies of Phe and Tyr clusters are very similar, but their relative ordering changes with respect to MPWB1K. As we have already mentioned, the difference between Trp and the other amino acids is amplified at the MP2 level. Finally, it has to be emphasized that the binding energies presented in Table 3 show that the most stable cluster is the one formed by 3-methylindole, that 5-methylimidazole leads to the less stable cluster, and that the binding energy corresponding to the other two modeled aromatic amino acids are intermediate and quite similar. Our results are in qualitative agreement with the experimental analysis done by Weiss and co-workers34 from a systematic study of a non-redundant set of 1154 protein structures from the Protein Data Bank. They found that about three-quarters of the Trp-rings, half of all Phe- and Tyr-rings, and a quarter of all His-rings are involved as acceptors in CH/π interactions. This agreement confirms that MPWB1K/ 6-31+G(d,p) calculations are adequate for the study of CH/π interactions in molecular systems of biological interest. Nucleic Acid Bases. As mentioned in the Introduction, the backbone chain in the nucleic acids has not been considered in such a way that the C1′ atom of the sugar has been replaced by a hydrogen atom. So, we have studied the interactions of methane with adenine, guanine, thymine, uracil, and cytosine. To the best of our knowledge there are no previous theoretical studies on this kind of systems. On the contrary, experimental studies with adenine and guanine have shown that CH/π interactions are important to explain the binding between DNA and proteins.40-41 The strategy for the search of energy minima has been similar to that used for amino acids. For monocyclic systems methane was placed with one of its CH bonds pointing to the center of the ring. This procedure led to the structures shown in Figure 4 for thymine and cytosine, whereas for uracil the structure named U2 was obtained. Due to the large difference between this structure and the one corresponding to thymine, another starting point was considered for uracil, leading to structure U1, which is much more stable than U2. For adenine, many starting points were considered by placing methane over each one of the rings and over all heavy atoms. We found that only the two structures shown in Figure 4 are energy minima. Finally, for guanine we have calculated the potential energy surface for its interaction with methane using a procedure similar to that for 3-methylindole, and the results are shown in Figure 5. We can observe the presence of two relative minima centered in each ring. In contrast to the results obtained for 3-methylindole (Figure 3), the minimum on the five-membered ring is more favorable (interaction energy around -0.9 kcal mol-1) than the one over the six-membered ring (interaction energy around -0.7

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Figure 4. Minimum energy structures for the clusters between methane and the nucleic acid bases computed at the MPWB1K/6-31+G(d,p) level of calculation. For bifurcated structures, numbers 1 and 2 indicate the two H atoms that are closer to the plane of the aromatic system.

kcal mol-1). In this case, only the structure presented in Figure 4 has been obtained as an energy minimum. Table 4 presents the binding energy and some geometry parameters corresponding to the seven structures which have been found. In Figure 4, the seven minimum energy structures are depicted by the projection of methane on the plane of the aromatic system. It can be observed that all the methane/base clusters, except one of the two minima corresponding to uracil (U2), have a bifurcated nature. Let us first consider the clusters for purine bases which can be compared with the 3-methylindole clusters (Trp). In the case of adenine, only two of the three minima obtained for 3-methylindole (two bifurcated structures) have been located. However, the most stable structure is now the one in which one CH bond points to the center of the five-membered ring and the other CH bond to the exterior of the aromatic system. For guanine, only this latter bifurcated structure appears. These results are coherent with the experimental studies on DNA in which the methyl group of thymine in the A-T step is found to be placed over the five-membered ring of the purine.42-43 Given that hydrogen atoms are not detected in X-ray diffraction analysis, these experimental studies do not permit the discussion of where the CH bonds are pointing to.

It is interesting to compare the electrostatic potentials63 computed at a distance of 2.8 Å above the molecular planes of guanine and 3-methylindole (see Supporting Information). While for 3-methylindole the potential over the two rings is favorable for interaction with a positively charged hydrogen atom, in the case of guanine the electrostatic potential is repulsive over the two rings and attractive in regions out of the rings. So, the electrostatic term of the interaction favors the structures obtained for the 3-methylindole (Trp1) and guanine clusters (see Figures 2 and 4). Let us now present the results obtained for the pyrimidine bases. Apart from the U2 methane/uracil cluster, which is the less stable structure we have found, all the remaining minimum energy structures have a bifurcated character, with one CH bond pointing to the center of the ring and another one to the middle of the C-O bond. As in previous cases, the orientation of methane can be explained through the electrostatic interaction of the H atom with the electronic density of the O atom, those interactions having been shown to play an important role in the orientation of the methane molecule.12,16 We have computed the electrostatic potential at a distance of 2.8 Å above the molecular plane of cytosine and uracil (see Supporting Informa-

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Figure 5. Potential energy surface for the interaction of a methane molecule with guanine. One of the CH bonds of methane is perpendicular to the aromatic plane, and the hydrogen atom is 2.8 Å above the plane. Interaction energies are in kcal mol-1.

TABLE 4: Binding Energy and Geometry Parameters for Minimum Energy Structures of the Clusters between Methane and the Bases of Nucleic Acids base

binding energya

Rb

R1b

R2b

A1 A2 G T U1 U2 C

0.843 (2.623) 0.802 (2.966) 1.098 (2.927) 1.039 (2.345) 1.094 (2.231) 0.542 (1.771) 1.062 (2.509)

3.62 3.38 3.48 3.58 3.51 3.79 3.43

2.77 2.72 2.83 2.98 2.97 2.71 2.81

3.29 2.79 2.90 3.06 3.02 2.87

a Energy in kcal mol-1. In parentheses are values computed at the MP2/6-31+G(d,p)//MPWB1K/6-31+G(d,p) level. b Distances in Å.

tion). In both cases the potential inside the ring is repulsive, while it is attractive in the regions above oxygen atoms. Regarding the binding energies, Table 4 shows that, except in the case of U2, they are quite similar to those obtained for the methane/benzene system. It is smaller in the case of adenine and slightly larger for thymine, cytosine, uracil, and guanine. These binding energies are coherent with the experimental fact that, in DNA, the H2′ atom of the sugar interacts with all the bases, the CH of methylthymine interacts with adenine, and methylcythosine of modified DNA interacts with guanine.42,43 Regarding the comparison between MPWB1K and MP2 binding energies, we can observe that the relative ordering between both adenine clusters changes. Moreover, the binding energies of adenine and guanine clusters become very similar. These results indicate that probably the MPWB1K functional overestimates the stability of bifurcated structures such as the one of A1 and that of the guanine cluster. Of special interest is the comparison between thymine and uracil since, as it is well-known, thymine forms part of DNA, while uracil is one of the bases of RNA. Our results indicate that the difference in binding energies corresponding to the clusters between these two bases and methane is only of about

Figure 6. Minimum energy structures for the clusters between methane and thymine and uracil obtained at the MP2/6-31+G(d,p) level of calculation. The distances of hydrogen atoms 1, 2, and 3 to the plane of the aromatic system are, respectively, 2.61, 3.03, and 3.14 Å for thymine and 2.64, 3.02, and 3.21 Å for uracil. The distances of the methane carbon atom to the plane are 3.27 Å for thymine and 3.30 Å for uracil.

0.05 kcal mol-1. So the different behavior of these two pyrimidines cannot be attributed to their role as acceptor in weak hydrogen bonds, but instead to the donor capacity of thymine due to the presence of the methyl group. To gain insight into the differences between thymine and uracil, we have optimized the geometries of their methane clusters at the MP2/6-31+G(d,p) level of calculation, and the corresponding structures are shown in Figure 6. For uracil only the U1 structure has been obtained as an energy minimum. If we compare these structures with the ones obtained at the MPWB1K level (see Figure 4), we can observe in both cases a slight displacement of the methane molecule over the ring. Moreover, both structures become trifurcated. The MPWB1K structures were bifurcated, but the distance to the plane of the third hydrogen atom was only slightly larger than that of the carbon atom. The MP2 binding energies are 2.775 and 2.555 kcal mol-1 for tymine and uracil, respectively. These values are, as expected, larger than the ones computed at the MPWB1K

9378 J. Phys. Chem. B, Vol. 111, No. 31, 2007 level. However, they are similar for both bases, and the conclusion obtained in the precedent paragraph is still valid. Conclusions In this work, a systematic study of the CH/π interactions of methane with the purine and pyrimidine bases of nucleic acids and with the lateral chains of the four natural aromatic amino acids has been carried out for the first time. We have shown that the MPWB1K/6-31+G(d,p) method is adequate to study these weak interactions in which dispersion forces play a main role. Given the flatness of the potential energy surfaces, it has been hard to detect the real minimum energy structures, since many stationary points with negative eigenvalues of the force constant matrix are also present. All the structures of this work have no negative eigenvalues, but we cannot exclude the possible existence of some other minima. It has been shown that two different kinds of clusters exist, depending on whether one or two CH bonds point to the aromatic system. The latter ones, which we have called bifurcated, are usually the most stable ones. With regard to aromatic amino acids, our calculations agree with experimental data in the fact that tryptophan leads to the strongest interaction, while histidine leads to the weakest one. In the case of the nucleic acid bases, the differences in binding energies are not large. This is especially true for thymine and uracil, showing that these two bases have a similar acceptor character in CH/π interactions. Given that these two pyrimidines differ in the methyl group of thymine, it can be inferred that the interactions of this group with aromatic systems would be crucial in understanding the different behavior of DNA and RNA. As has been emphasized by Umezawa and Nishio,42 “It is fascinating to speculate that for this reason nature chose thymine but not uracil as the partner of adenine in the duplex DNA”. Supporting Information Available: Total energies of model amino acids, DNA bases and their methane clusters, Cartesian coordinates and harmonic vibrational frequencies of methane clusters, and electrostatic potential maps for guanine, tryptophan, cytosine, and uracil. This information is available free or charge via the Internet at http://pubs.acs.org. References and Notes (1) Nishio, M.; Hirota, M.; Umezawa, Y. The CH/π Interaction. EVidence, Nature and Consequences; Wiley-VCH: New York, 1998. (2) Steiner, T. Angew. Chem., Int. Ed. 2002, 48-76 (3) Nishio, M.; Hirota, M. Tetrahedron 1989, 45, 7201-7245. (4) Nakamura, M.; Okawa, H.; Kida, S. Bull. Chem. Soc. Jpn. 1985, 58, 3377-3378. (5) Suezawa, H.; Hashimoto, T.; Tsuchinaga, K.; Yoshida, T.; Yuzuri, T.; Sakakibara, K.; Hirota, M.; Nishio, M. J. Chem. Soc., Perkin Trans. 2000, 2, 1243-1249. (6) Kinbara, K.; Harada, Y.; Saigo, K. J. Chem. Soc., Perkin Trans. 2000, 2, 1339-1348. (7) Yamakawa, M.; Yamada, I.; Noyori, R. Angew. Chem., Int. Ed. 2001, 113, 2818-2821. (8) Novoa, J. J.; Mota, F. Chem. Phys. Lett. 2000, 318, 345-354. (9) Takahashi, O.; Kohno, Y.; Saito, K. Chem. Phys. Lett. 2003, 378, 509-515. (10) Ran, J.; Wong, M. W. J. Phys. Chem. A 2006, 110, 9702-9709. (11) Tsuzuki, S.; Honda, K.; Uchimaru, T.; Mikami, M.; Tanabe, K. J. Phys. Chem. A 1999, 103, 8265-8271. (12) Tsuzuki, S.; Honda, K.; Uchimaru, T.; Mikami, M.; Tanabe, K. J. Am. Chem. Soc. 2000, 122, 3746-3753. (13) Tsuzuki, S.; Honda, K.; Uchimaru, T.; Mikami, M.; Tanabe, K. J. Am. Chem. Soc. 2000, 122, 11450-11458. (14) Tarakeshwar, P.; Choi, H. S.; Kim, K. S. J. Am. Chem. Soc. 2001, 123, 3323-3331. (15) Ugozzoli, F.; Arduini, A.; Massera, C.; Pocchini, A.; Secchi, A. New J. Chem. 2002, 26, 1718-1723.

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J. Phys. Chem. B, Vol. 111, No. 31, 2007 9379 T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; and Pople, J. A. Gaussian, Inc.: Wallingford, CT, 2004. (62) The cartesian coordinates of all structures can be found as Supporting Information, with the aromatic system being placed in the xy plane and the z coordinate being the distance to that plane. (63) (a) Molden, version 4.4; http://www.cmbi.ru.nl/molden/molden.html. (b) Schaftenaar, G.; Noordik, J. H.; J. Comput.-Aided Mol. Des. 2000, 14, 123-134.