Specific Solvation Effects on Structures and Properties of Isocytosine

Inclusion of six instead of four water molecules has crucial effects both on the .... Nurbosyn U. Zhanpeisov, Woodrow Wilson Cox, Jr, and Jerzy Leszcz...
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J. Phys. Chem. B 1998, 102, 9109-9118

9109

Specific Solvation Effects on Structures and Properties of Isocytosine-Cytosine Complexes: A Theoretical ab Initio Study Nurbosyn U. Zhanpeisov†,‡ and Jerzy Leszczynski*,† Department of Chemistry, Jackson State UniVersity, Jackson, Mississippi 39217, and BoreskoV Institute of Catalysis, NoVosibirsk 630090, Russia ReceiVed: April 3, 1998; In Final Form: August 26, 1998

Ab initio quantum chemical studies at the Hartree-Fock (HF) level with the 6-31G* basis set were performed for four different hydrogen-bonded isocytosine-cytosine (iCC) complexes in the gas phase and in a water solution. Full geometry optimizations without any constraints on the planarity of these complexes were carried out. The water solution was modeled by explicit inclusion of different numbers of water molecules, up to six, which creates the first coordination sphere around the iCC base pair. Single point calculations were also performed at the correlated MP2/6-31G*//HF/6-31G* level. The interaction and solvation energies were corrected for the basis set superposition error by using the full Boys-Bernardi counterpoise correction scheme. It was shown that the base pair corresponding to the standard Watson-Crick pair (denoted as iCC1) is the global minimum on the potential energy surface both in the gas phase and in a water solution. Inclusion of six instead of four water molecules has crucial effects both on the geometries and relative stabilities of iCC complexes. Complexes involving six water molecules become strongly nonplanar, whereas in the case of four or fewer water molecules, only a slight deviation from planarity is observed. Moreover, the relative stability order changes when one considers six water molecules, and the zwitterionic form (denoted as iCC4) becomes the second most stable species after the Watson-Crick iCC1 base pair. Since the structure of isocytosine mimics the six-membered parts of guanine, the results of this study could provide important insights into the structures and properties of analogous guanine-cytosine complexes in a water solution.

Introduction Nucleic acid base associations stabilized via hydrogen (H) bonding and base stacking have been well studied, and various cross-linking methods have been utilized to examine the structural interactions between bases or strands of bases.1-14 Such studies are of fundamental importance both in physical chemistry and in molecular biology. It is well known that the possibility of the existence of one or more DNA bases in a rare tautomeric form can increase the probability of mispairings and lead to point mutation.15 Since the energy scale of biomolecular processes is very tiny and the mutationally significant concentrations of rare tautomeric base pairs in DNA fall below the detection limits of the available experimental techniques, highly accurate ab initio calculations could shed light on such phenomena. Several papers have discussed the tautomerism of nucleic acid bases, including the cytosine molecule in the gas phase and in a polar solution from both experimental and theoretical points of view. Florian et al. studied the relative stabilities of tautomers of protonated cytosine in the gas phase and in a polar solvent at the ab initio Hartree-Fock (HF), second-order MøllerPlesset (MP2), and polarizable continuum approximations.16 In addition the infrared (IR) and Raman spectra frequencies and intensities for the cytosine molecule and its two protonated forms were calculated on the basis of the double harmonic approximation and scaled quantum mechanical force fields methodology.16 Previously, such vibrational spectra of neutral cytosine have * Corresponding author. † Jackson State University. ‡ Boreskov Institute.

been studied using empirical and ab initio force fields.17-20 The tautomeric properties of isocytosine were reported recently by Kwiatkowski et al.19b Sˇ poner et al. have performed ab initio studies of stacked and H-bonded neutral and protonated cytosine dimers and the reverse Watson-Crick (RWC) isocytosinecytosine (iCC) base pair at the HF and MP2 level of theory using a medium-size basis set.2,21 The RWC iCC base pair contains one H-bond surrounded by mutual carbonyl group and amino group contacts.21b,c As is expected, H-bonded and stacked protonated base pairs are more stable than the neutral base pairs because of ion-dipole and induction interactions.21a The amino-group hydrogens in the RWC iCC base pair adopt a highly nonplanar geometry due to the mutual interaction between the amino-group hydrogens and the negatively charged lone electron pair of nitrogen of the opposite base.21b,c However, the existence of such RWC iCC base pair stabilized via mutual carbonyl group and amino group contacts is indeed very doubtful. In a series of papers Maes, Adamowicz, and collaborators have reported the matrix isolation Fourier transform (FT) IR studies and ab initio calculations on H-bonded complexes of molecules modeling cytosine and isocytosine tautomers.22 They found that the amino-oxo form of the cytosine-water complex is stable in regard to the proton-transfer reaction, which leads to the imino-oxo tautomeric form both at the ground and excited states. Young et al. have applied the self-consistent reaction field method to estimate the effect of solvation on the interaction energy of the guanine-cytosine (GC) base pair in chloroform modeled by a dielectric constant of 4.81.23 They concluded that the electrostatic term is dominant in the solvation energy

10.1021/jp9817271 CCC: $15.00 © 1998 American Chemical Society Published on Web 10/14/1998

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of both GC and the adenine-thymine base pairs. However, the model that was applied allows only for polarization of the solute molecules, but it does not include geometry optimization of the solute in the reaction field and does not account for specfic H-bond interactions. Recently, Colominas et al. have studied the tautomerism and protonation of guanine and cytosine in the gas phase and in an aqueous solution with the use of high-level ab initio calculations and the SCRF model.24 In our recent work we performed an ab initio electroncorrelated study on the proton-transfer reactions for the GC base pairs in the gas phase.15 We have shown that the tautomeric transition between the canonical (denoted as GC1) and rare (denoted as GC2) base pairs is likely to occur in 1 in 106-109 GC base pairs. This frequency is significant from the point of view of fidelity of DNA replication. Previously, the structure and energetics of the base pairing and proton transfer in GC in the gas phase and polar solvents were studied at the HF level with the small MINI-1 basis set.25 The polar environment approximated by the continuum model stabilizes the canonical GC1 structure compared with the rare tautomers. The present study concentrates on the interactions of the isocytosine molecule with cytosine in the gas phase and in a water solution. The latter was modeled by explicit inclusion of water molecules creating the first coordination sphere around the iCC base pair. Such methodology is well-known as the “supermolecular approach.” Although simulations involving explicit interactions with water, which require full geometry optimization, are very expensive computationally, these specific solvation effects cannot be described within other computational techniques as a Monte Carlo or molecular dynamics simulations and by modern implementations of continuum models.26-31 However, this very interesting subject is beyond the scope of this study, and the reader can refer to several reviews in ref 32 and the original papers. Even though we believe that the applied “supermolecular approach” is currently the most accurate approximation for a study of the interactions of relatively large systems such as base pairs with water, it has certain limitations. By virtue of its approach, it does not reveal any information about the dynamical aspects of interactions, and it does neglect the bulk solvent influence. However, the latter effect has a very limited influence on the structures and energetics of the DNA base pairs15 and the proton-transfer phenomenon.33 Although isocytosine itself has not been detected in nucleic acids, molecules containing an isocytosine residue have been found in biological materials (see references in ref 19). The structure of isocytosine mimics that of the six-membered parts of guanine, and because it is significantly smaller than guanine, the first solvation shell of eight water molecules for GC is reduced to six waters for iCC pairs; the replacement of the GC by the iCC pairs allowed us to complete this project using the available computer resources. We believe that the present results on iCC complexes in a water environment will also provide important insights into the structures and properties of analogous GC complexes in water. Method The ab initio molecular orbital calculations were performed using Gaussian92 and Gaussian94 program packages.34 Full geometry optimizations of the four different H-bonded iCC complexes in the gas phase and in a water solution were carried out at the HF level of the theory using the standard split-valence 6-31G* basis set. The water environment that creates the first coordination sphere around the iCC base pair was modeled by explicit inclusion of four and six water molecules attached to

Figure 1. A sketch of some iCC complexes in the gas phase: (a) iCC1, (b) iCC2, (c) iCC3, (d) iCC4, and (e) iCC5 structures. Numbered atoms correspond to distinct atomic sites. H-bond distances are in angstroms.

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Figure 2. The considered iCC complexes with four water molecules in structure I: (a) iCC1‚4H2O, (b) iCC2‚4H2O, (c) iCC3‚4H2O, and (d) iCC4‚4H2O. Numbered atoms correspond to distinct atomic sites. H-bond distances are in angstroms.

the polar exocyclic groups of the iCC complex. The interaction energies for the different iCC complexes were corrected for the basis set superposition error (BSSE) by using the full BoysBernardi counterpoise correction scheme.35 The effects of electron correlation were accounted for by using the secondorder Møller-Plesset perturbation theory with the frozen-core approximation and performing single-point calculations. Results and Discussion 1. Geometries and Relative Energies. Several possible complexes of iCC have been considered in this study. These structures are shown in Figures 1-4, where the numbering of the atoms is also defined. The first complex denoted as iCC1 corresponds to the canonical Watson-Crick GC base pair. The isocytosine molecule acts there as a double proton donor to and a single proton acceptor from the cytosine molecule (Figure 1a). Because there are three parallel H bonds, there are two ways in which protons can be rearranged by a double proton transfer while keeping each monomer in its neutral form. By

analogy with the GC base pair,15 the minor tautomers of the base pairs formed in this way are denoted as iCC2 and iCC3 (Figure 1b and 1c, respectively). The other complexes studied correspond to a single proton transfer from isocytosine to cytosine via forming zwitterionic tautomers denoted as iCC4 and iCC5 (Figure 1d and 1e, respectively). However, our attempts to localize the iCC5 structure on the potential energy surface (PES) were unsuccessful: the full optimization of the gas-phase geometry of the iCC5 complex, which corresponds to the single proton transfer from the amino group of isocytosine to cytosine, led to the formation of a more stable iCC1 complex. The analogous result was obtained by us before15 during the study of the corresponding complex of GC, and it was ascribed to the repulsive dipole-dipole interactions between the monomers forming the GC5 base pair. Consequently, the interactions with a water environment were studied only for iCC1, iCC2, iCC3, and iCC4 base pair complexes (Figures 2-4). The optimized bond distances, bond angles, and the major dihedral angles of the studied complexes are collected in Tables

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Figure 3. The considered iCC complexes with four water molecules in structure II: (a) iCC1‚4H2O, (b) iCC2‚4H2O, (c) iCC3‚4H2O, and (d) iCC4‚4H2O. Numbered atoms correspond to distinct atomic sites. H-bond distances are in angstroms.

1-3. Tables 4 and 5 show the energetic characteristics of these complexes obtained at the HF/6-31G*//HF/6-31G* and MP2/ 6-31G*//HF/6-31G* levels of the theory. At both applied levels, the iCC1 canonical Watson-Crick base pair is the global minimum for PES of the isolated and interacting with water pairs. This complex is stabilized via formation of three relatively parallel H bonds. For the isolated complex the N4-O6 bond distance is the shortest one, indicating a relatively strong proton acceptor ability for the O6 site of the isocytosine molecule compared with the O2 site of the cytosine molecule (Figure 1a). This finding remains unchanged when one considers the interaction of the iCC1 complex with four water molecules. In this case there are two different possibilities of attaching waters directly to the exocyclic atoms involved in H bonds (Figures 2a and 3a, structures Ia and IIa, respectively). Complex Ia is stabilized via formation of two eight-membered cyclic structures both on the minor and major grooves of the iCC1 base pair (Figure 2a). In complex IIa, two water molecules form an eightmembered cyclic structure on the major groove while the other two water molecules form separately two six-membered ringlike structures on the minor groove of the iCC1 base pair (Figure 3a). Note that structure Ia (Figure 2a) lies ca. 3.1 kcal/mol higher at the PES compared with complex IIa (Figure 3a) at the HF level, and this difference in energy further increases at the correlated MP2 level (ca. 5.3 kcal/mol). The most important

change in geometry is an increase by ca. 0.05 Å in all of these H-bond distances in complex Ia, whereas the N4-O6 and N2O2 distances are very similar in complex IIa because of the changes of their values in the opposite directions (ca. 0.05 Å) compared with the isolated iCC1 base pair and their slight deviation from linearity (see Tables 1 and 2). The geometry dramatically changes when the water environment is represented by six water molecules. Two additional water molecules are attached to the N3 site of isocytosine and the N1-H group of cytosine (see Figure 4a and Table 1). In this case the O2-N2 bond distance becomes the shortest one because of a more preferable orientation of these water molecules around the iCC1 complex (Table 3). Consequently, the whole iCC1 complex is strongly nonplanar and adopts a buckling structure. The buckle angle calculated as an angle at the crossing point of two normals from the isocytosine and cytosine planes is 31.2°. Note that this angle amounts only to 3.6°, 6.1°, and 3.2°, respectively, for the isolated iCC1 base pair and its iCC1‚4H2O complexes (structures Ia and IIa). At the HF/6-31G* level, the isolated iCC1 base pair is perfectly planar, including the amino groups of the isocytosine and cytosine fragments (dihedral H-N4C4-Ha and H-N2-C2-Hc angles, see Table 1). However, the solvation of this complex with four water molecules leads to significant pyramidalization of these amino groups (Table 2), and this effect is even more pronounced if one considers

Solvation Effects on Isocytosine-Cytosine Complexes

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Figure 4. The considered iCC complexes with six water molecules: (a) iCC1‚6H2O, (b) iCC2‚6H2O, (c) iCC3‚6H2O, and (d) iCC4‚6H2O. Numbered atoms correspond to distinct atomic sites. H-bond distances are in angstroms.

six water molecules (Table 1). These findings show that the water molecules in the first coordination sphere play an important role in determining the base-pairs structure and, consequently, represents an inherent part of them because of a very tight binding to the base pairs. Let us now discuss the complexes iCC2 and iCC3, which are stabilized via forming three H bonds through a double proton transfer and keeping the isocytosine and cytosine monomers in their neutral forms. In the former case, iCC2 corresponds to the amino group proton transfer of cytosine to the O6 site of isocytosine and the N1-H group proton of isocytosine to the N3 site of cytosine molecules (Figure 1b), whereas in the case of the iCC3 complex, such a double proton transfer involves both amino-group protons and the O6, O2 sites of the isocytosine and cytosine molecules (Figure 1c). The iCC2 complex is ca. 30 and 25 kcal/mol more stable than the iCC3 form both in the gas phase and in a water solution at the HF/6-31G*//HF/6-31G* and MP2/6-31G*//HF/6-31G* levels of theory, respectively (Tables 4 and 5), although the canonical Watson-Crick iCC1 structure gains further stability by interactions with waters compared with the iCC2 and iCC3 complexes (see relative

energies, Tables 4 and 5). This is in line with the conclusions of the previous study, although the stabilization accounted for in the GC1 complex in a polar environment amounts only to 1.3 kcal/mol compared with the rare GC base pair.25 Such conclusions were due to the use of a small MINI-1 basis set and unreliable self-consistent reaction field techniques in which a polar environment only represents a continuous dielectric medium of uniform dielectric constant r ) 40 and fixed cavity radii and does not take into account the specific solvation effects. The N4-O6 bond distance is still the shortest one in the iCC2 structure as in the iCC1 base pair for the gas phase, indicating a strong proton acceptor ability for the N4 site on the precursor amino group of the cytosine molecule compared with the O2 site of the cytosine and N1 site of isocytosine molecules (Figure 1b). Moreover, this H bond becomes shorter and stronger in the iCC2 structure compared with that of the isolated iCC1 base pair, and the relative order of these H-bond distances remains unchanged when one considers the water environment (Tables 1 and 2, Figures 2b, 3b, and 4b). The interactions with four instead of six water molecules lead to further significant pyramidalization of the amino group of the isocytosine fragment

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TABLE 1: Geometry (Bond Length, A-B, Å; Bond Angle, A-B-C, and Dihedral Angle, A-B-C-D, deg) of the Isolated Isocytosine-Cytosine Base Pairs (iCC1, iCC2, iCC3, iCC4) and Their Complexes with Six Water Moleculesa

b

bond/angleb

iCC1

iCC2

iCC3

iCC4

N4-O6 N4-Ha O6-Ha N4-Ha-O6 C4-N4-Ha C6-O6-Ha N3-N1 N3-Hb N1-Hb N3-Hb-N1 O2-N2 O2-Hc N2-Hc O2-Hc-N2 C2-O2-Hc C2-N2-Hc H-N4-C4-Ha H-N2-C2-Hc C4-N1-N3 C6-N3-N1 C4-N1-C6 C6-N3-C4

2.935; 3.066 1.009; 1.002 1.927; 2.082 177.1; 166.7 120.4; 118.7 127.8; 124.9 3.019; 3.048 2.012; 2.062 1.009; 1.010 176.4; 164.6 3.039; 2.923 2.038; 1.951 1.002; 1.002 176.4; 162.7 121.7; 120.7 123.0; 120.7 -180.0; 166.6 -179.9; 164.4 179.0; 164.6 177.4; 164.2 179.8; 157.2 177.9; 157.1

2.889; 2.815 1.930; 1.863 0.966; 0.975 171.9; 164.7 125.5; 125.0 113.1; 112.8 3.040; 3.039 1.011; 1.007 2.031; 2.063 176.1; 162.6 3.145; 3.080 2.148; 2.138 0.997; 0.996 177.6; 156.9 118.6; 118.6 121.9; 119.5 -177.9; 163.2 -167.1; 161.0 177.0; 161.0 177.4; 162.3 177.7; 153.0 178.2; 153.7

2.847; 2.670 1.871; 1.666 0.977; 1.009 177.3; 172.9 126.3; 126.9 115.0; 115.2 2.858; 2.830 1.850; 1.827 1.011; 1.015 173.8; 169.2 2.694; 2.754 1.007; 0.988 1.688; 1.770 177.7; 173.4 112.5; 111.7 130.6; 129.3 180.0; 169.7 180.0; 167.3 172.2; 168.1 177.3; 165.4 173.5; 162.5 178.9; 161.1

2.546; 2.717 1.084; 1.028 1.463; 1.701 176.5; 168.6 122.6; 120.9 122.7; 121.2 2.815; 2.897 1.049; 1.032 1.769; 1.887 174.9; 165.4 3.201; 3.077 2.220; 2.106 0.996; 0.995 167.9; 165.0 118.4; 120.5 118.1; 118.5 -175.5; -169.6 -142.3; -149.6 176.2; 157.3 175.3; 162.5 176.2; 148.9 175.5; 151.6

a Two numbers in each column correspond to the gas phase and a water solution modeled by explicit inclusion of six water molecules, respectively. For the atom numbering, see Figures 1 and 4.

TABLE 2: Geometry (Bond Length, A-B, Å; Bond Angle, A-B-C, and Dihedral Angle, A-B-C-D, deg) of the Isocytosine-Cytosine Base Pairs (iCC1, iCC2, iCC3, iCC4) and Their Complexes with Four Water Moleculesa bond/angle

iCC1

iCC2

iCC3

iCC4

N4-O6 N4-Ha O6-Ha N4-Ha-O6 C4-N4-Ha C6-O6-Ha N3-N1 N3-Hb N1-Hb N3-Hb-N1 O2-N2 O2-Hc N2-Hc O2-Hc-N2 C2-O2-Hc C2-N2-Hc H-N4-C4-Ha H-N2-C2-Hc C4-N1-N3 C6-N3-N1 C4-N1-C6 C6-N3-C4

2.972; 2.998 1.005; 1.003 1.968; 1.996 176.3; 177.4 119.4; 119.1 125.3; 125.6 3.067; 3.029 2.058; 2.017 1.009; 1.012 177.9; 178.7 3.086; 2.995 2.087; 1.992 1.000; 1.004 175.9; 179.0 118.0; 121.0 121.5; 122.2 -176.8; -176.9 -170.4; -174.7 178.2; 179.5 175.7; 177.3 176.3; 178.3 174.9; 177.1

2.786; 2.770 1.823; 1.802 0.975; 0.979 169.1; 169.3 127.3; 126.6 112.7; 113.3 3.087; 3.052 1.009; 1.008 2.084; 2.048 172.4; 173.3 3.295; 3.227 2.346; 2.230 0.996; 0.997 158.8; 178.2 115.1; 117.8 118.0; 121.0 -177.9; -176.8 -147.4; -170.3 177.9; 177.9 174.3; 175.3 178.9; 177.5 175.2; 175.5

2.715; 2.704 1.722; 1.708 0.996; 0.999 174.4; 174.7 126.8; 126.8 115.1; 115.2 2.841; 2.831 1.830; 1.819 1.013; 1.014 174.8; 175.6 2.771; 2.743 0.992; 0.998 1.779; 1.746 177.8; 177.3 111.8; 112.0 129.2; 129.3 -176.6; -177.7 -169.0; -177.7 172.5; 173.4 175.4; 175.8 173.8; 175.2 176.4; 178.1

2.644; 2.672 1.041; 1.034 1.606; 1.640 174.6; 174.7 121.7; 121.1 121.7; 122.4 2.915; 2.895 1.036; 1.037 1.882; 1.860 174.3; 175.7 3.216; 3.193 2.353; 2.206 0.997; 0.995 144.3; 171.2 118.0; 119.6 115.2; 118.4 -178.0; -174.7 -133.9; -149.1 174.1; 177.4 176.1; 177.0 172.5; 177.1 173.6; 176.8

a Two numbers in each column correspond to the different orientation of four water molecules, structures I and II, respectively. For the atom numbering, see Figures 2 and 3.

in complex Ib (ca. 20°, cf. dihedral H-N2-C2-Hc angles for the iCC2 structure, Tables 1 and 2, Figure 2b). In addition, the iCC2 complex with six water molecules strongly deviates from planarity and also becomes a buckling structure (Figure 4b, Table 1). The iCC3 complex is the least favorable among these complexes, both in the gas phase and in a water environment. In the former case, the N2-O2 bond distance is the shortest one, whereas, in a water environment, the N4-O6 bond becomes again the shortest and strongest one among the considered H bonds of the iCC3 complex. We note that the N2 atom of the precursor amino group of the isocytosine fragment prefers to form bifurcated H bonds with the Ow2containing water (the subscript w stands for a water molecule) in the case of four water molecules in complex Ic (Figure 3c),

although we started the calculations with the use of a trial geometry in which Ow1- and Ow2-containing water molecules were initially attached to the O2 site of cytosine and the N2-H group of the isocytosine fragments, respectively (Table 3). However, the full geometry optimization of this iCC3 complex results in a bifurcated H-bonded structure in which the initial Ow1- and Ow2-containing water molecules become as the Ow2and Ow6-containing ones, respectively (Figure 3c). This arrangement is not observed when one includes six water molecules (Figure 4c). Finally, we considered the zwitterionic iCC4 complex, which also has three H bonds and corresponds to the single proton transfer from isocytosine to cytosine (Figure 1d). It is only 23.8 and 17.6 kcal/mol higher in energy than the canonical iCC1 base pair in the gas phase at the HF/6-31G*//HF/6-31G* and

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TABLE 3: The First Coordination Sphere Geometry (Bond Length, A-B, Å; Bond Angle, A-B-C, deg) of the Isocytosine-Cytosine Base Pairs (iCC1, iCC2, iCC3, iCC4) in a Water Solutiona bond/angle

iCC1

iCC2

iCC3b

iCC4c

O2-Ow1 O2-H-Ow1 N2-Ow2 N2-H-Ow2 N4-Ow3 N4-H-Ow3 O6-Ow4 O6-H-Ow4 Ow1-Ow2 Ow1-H-Ow2 Ow3-Ow4 Ow3-H-Ow4 N1-Ow5 N1-H-Ow5 N3-Ow6 N3-H-Ow6 Ow1-Ow5 Ow1-H-Ow5 Ow2-Ow6 Ow2-H-Ow6

2.871; 2.861; 2.815 161.3; 145.7; 169.5 2.974; 3.040; 2.975 144.8; 147.4; 152.6 2.931; 2.942; 2.947 151.6; 150.1; 151.5 2.836; 2.853; 2.845 163.9; 163.7; 163.9 2.898; -; 3.232 164.6; -; 154.8 2.857; 2.868; 2.862 169.8; 170.4; 170.3 -; -; 2.955 -; -; 166.2 -; -; 3.023 -; -; 171.7 -; -; 2.939 -; -; 160.7 -; -; 2.895 -; -; 150.8

2.972; 2.896; 2.844 153.4; 141.5; 164.5 3.050; 3.083; 3.035 140.5; 147.4; 151.2 3.068; 3.086; 3.098 156.4; 155.6; 155.3 2.974; 2.984; 2.981 159.8; 160.3; 160.2 2.898; -; 3.288 158.5; -; 153.9 2.903; 2.909; 2.906 171.6; 172.1; 172.6 -; -; 2.943 -; -; 162.8 -; -; 3.015 -; -; 172.5 -; -; 2.954 -; -; 162.3 -; -; 2.894 -; -; 152.4

-; 2.988; 3.529 -; 127.5; 34.3 3.161; 3.358; 3.653 154.9; 149.3; 123.5 3.103; 3.127; 3.159 155.4; 154.3; 154.7 3.028; 3.013; 2.999 157.0; 157.6; 158.2 -; -; 2.885 -; -; 156.2 2.920; 2.923; 2.924 172.2; 172.9; 172.8 -; -; 2.872 -; -; 165.2 3.117; -; 2.949 147.7; -; 164.7 -; -; 2.856 -; -; 174.9 3.026; -; 2.923 151.3; -; 168.2

3.125; 2.935; 2.952 142.8; 132.1; 153.1 3.180; 3.147; 3.458 133.2; 146.2; 138.5 2.862; 2.867; 2.867 156.2; 154.3; 156.5 2.754; 2.757; 2.774 162.1; 162.4; 165.1 2.926; -; 2.929 159.1; -; 157.4 2.812; 2.819; 2.814 166.6; 167.4; 166.4 -; -; 2.846 -; -; 1640 -; -; 2.913 -; -; 165.0 -; -; 2.788 -; -; 157.3 -; -; 2.848 -; -; 168.6

a Three numbers in each column correspond to a water solution modeled by explicit inclusion of four (structure I), four (structure II), and six water molecules, respectively. For the atom numbering, see Figures 2-4. b In the case of structure I, Ow1 and Ow2 centers become as Ow2 and Ow6, respectively. c In the case of structure I the N2 atom of the isocytosine fragment prefers to have an additional H-bond with the Ow1-containing water molecule. Its respective characteristics are: N2-Ow1, 3.009 Å; N2-H-Ow1, 141.4°.

TABLE 4: Total (Et, a.u.), Relative (Erel, kcal/mol), Interaction (Eint, kcal/mol), and Solvation (Esolv, kcal/mol) Energies Calculated at the HF/6-31G*//HF/6-31G* and MP2/6-31G*//HF/6-31G* Levels of Theory for the Studied Forms of the Isocytosine-Cytosine Base Pairs (iCC1, iCC2, iCC3, iCC4) in the Gas Phase and in A Water Solution Modeled by Explicit Inclusion of Six Water Moleculesa property

phase state

Et

gas

Erelb Eint Et

with six waters

Erelc -Eint -Esolv

iCC1

iCC2

iCC3

iCC4

-785.27311 (-787.57268) 0 (0) 24.9 (26.2) -1241.43467 (-1244.87724) 0 (0) 24.7 (25.9) 38.8 (43.1)

-785.25916 (-787.56068) 8.8 (7.5) 15.2 (18.2) -1241.40893 (-1244.85317) 16.2 (15.1) 13.5 (16.8) 31.6 (36.4)

-785.21086 (-787.52017) 39.1(33.0) 43.5(45.9) -1241.35952 (-1244.80995) 47.2 (42.2) 42.3 (45.1) 26.6 (31.3)

-785.23527 (-787.54464) 23.8 (17.6) 122.3 (126.7) -1241.41467 (-1244.86499) 12.6 (7.7) 113.5 (117.6) 48.4 (53.2)

a The MP2/6-31G*//HF/6-31G* data are given in parentheses. b Total energy of the isolated iCC1 base pair is taken as an internal reference. The relative energies for the isolated guanine-cytosine GC1, GC2, GC3, and GC4 base pairs equal to 0, 9.6, 41.2, and 23.6 kcal/mol, respectively, at the same HF/6-31G*//HF/6-31G* level of theory.15 c Total energy of the iCC1‚6H2O complex is taken as an internal reference.

TABLE 5: Total (Et, a.u.), Relative (Erel, kcal/mol), Interaction (Eint, kcal/mol), and Solvation (Esolv, kcal/mol) Energies Calculated at the HF/6-31G*//HF/6-31G* and MP2/6-31G*//HF/6-31G* Levels of Theory for Two Different Structures of the Isocytosine-Cytosine Base Pair (iCC1, iCC2, iCC3, iCC4) Complexes with Four Water Moleculesa property Et

structure

iCC1

iCC2

iCC3

iCC4

I

-1089.37695 (-1092.43489) 0 (0) 25.9 (27.1) 24.5 (26.6) -1089.38202 (-1092.44338) 0 (0) 26.0 (27.1) 30.8 (34.1)

-1089.35236 (-1092.41318) 15.4 (13.6) 13.7 (16.8) 17.7 (20.6) -1089.35820 (-1092.42130) 14.9 (13.9) 14.9 (18.1) 24.9 (28.6)

-1089.29947 (-1092.36913) 48.6 (41.3) 42.4 (45.1) 14.5 (17.7) -1089.30377 (-1092.37421) 49.1 (43.4) 42.5 (45.3) 21.7 (25.8)

-1089.34510 (-1092.41325) 20.0 (13.6) 116.5 (120.2) 28.8 (31.8) -1089.35589 (-1092.42473) 16.4 (11.7) 117.2 (121.0) 39.3 (42.8)

Erelb

-Eint -Esolv Et

Erelc -Eint -Esolv

II

a The MP2/6-31G*//HF/6-31G* data are given in parentheses. b Total energy of the iCC1‚4H O complex (structure I) is taken as an internal 2 reference. cTotal energy of the iCC1‚4H2O complex (structure II) is taken as an internal reference.

MP2/6-31G*//HF/6-31G* levels of theory, respectively (Table 4). However, as can be expected,36-38 a zwitterionic structure due to ion-dipole interactions is much more stabilized in a water environment than the neutral base pairs. Consequently, the iCC4 complex has relatively the same order of stability as the neutral iCC2 form when one considers the water environment modeled by four water molecules, but it is even more stabilized if six

water molecules are taken into account (Tables 4 and 5, Figures 2d, 3d, and 4d). In the latter case of six waters, the iCC4 zwitterionic structure lies closer to the canonical iCC1 WatsonCrick base pair (ca. 12.6 and 7.7 kcal/mol higher in energy than the complex iCC1 at the HF and MP2 levels of theory, respectively). Such relative stability of the zwitterionic base pair combined with experimental evidence of the existence of

9116 J. Phys. Chem. B, Vol. 102, No. 45, 1998

Zhanpeisov and Leszczynski

TABLE 6: Net Atomic Mulliken Charges (Q, e-) and Dipole Moments (D, Debye) Calculated at the HF/6-31G*//HF/6-31G* Level of Theory for the Isolated Forms of the Isocytosine-Cytosine Base Pair (iCC1, iCC2, iCC3, iCC4) and Their Complexes with Six Water Moleculesa QN4 QHa QO6 QN3 QHb QN1 QO2 QHc QN2 D

iCC1

iCC2

iCC3

iCC4

-0.963; -0.991 0.508; 0.466 -0.705; -0.733 -0.828; -0.825 0.517; 0.510 -0.960; -0.950 -0.674; -0.747 0.486; 0.480 -0.989; -1.017 8.01; 3.99

-0.828; -0.888 0.552; 0.560 -0.778; -0.823 -0.972; -0.951 0.524; 0.507 -0.797; -0.788 -0.639; -0.707 0.456; 0.444 -0.967; -0.988 7.53; 3.75

-0.857; -0.959 0.564; 0.582 -0.777; -0.828 -0.814; -0.830 0.544; 0.549 -0.952; -0.947 -0.769; -0.766 0.587; 0.578 -0.951; -0.927 7.20; 2.01

-0.956; -0.999 0.584; 0.533 -0.836; -0.831 -0.988; -0.976 0.565; 0.545 -0.886; -0.856 -0.596; -0.645 0.417; 0.435 -0.938; -0.959 13.61; 7.30

a Two numbers in each column correspond to the gas phase and a water solution modeled by explicit inclusion of six water molecules, respectively. For the atom numbering, see Figures 1 and 4.

TABLE 7: Net Atomic Mulliken Charges (Q, e-) and Dipole Moments (D, Debye) Calculated at the HF/6-31G*//HF/6-31G* Level of Theory for Two Different Structures of the Isocytosine-Cytosine Base Pair (iCC1, iCC2, iCC3, iCC4) Complexes with Four Water Moleculesa QN4 QHa QO6 QN3 QHb QN1 QO2 QHc QN2 D a

iCC1

iCC2

iCC3

iCC4

-1.003; -1.005 0.486; 0.478 -0.752; -0.736 -0.830; -0.840 0.515; 0.525 -0.957; -0.962 -0.724; -0.735 0.465; 0.492 -1.014; -1.017 6.31; 3.76

-0.891; -0.905 0.567; 0.570 -0.831; -0.828 -0.969; -0.971 0.515; 0.518 -0.783; -0.793 -0.767; -0.691 0.416; 0.450 -0.979; -0.994 5.61; 3.66

-0.933; -0.942 0.580; 0.581 -0.826; -0.829 -0.823; -0.828 0.552; 0.553 -0.953; -0.958 -0.768; -0.800 0.577; 0.583 -0.983; -0.949 7.81; 4.59

-0.998; -1.000 0.552; 0.545 -0.857; -0.848 -0.988; -0.988 0.554; 0.557 -0.853; -0.869 -0.618; -0.642 0.396; 0.423 -0.971; -0.979 11.93; 10.80

Two numbers in each column correspond to the structure I and II, respectively (see Figures 2 and 3).

a large number of ion-pair structures that have been found in the crystal structures of the amino acids and the amines cocrystallized with the carboxylic acids36,39 indicates the possible importance of the zwitterionic structure in biological systems. It is also of importance in many fundamental biological processes, including protein folding and conformation, enzymesubstrate binding, and acid-base chemistry.40 As for geometric parameters of this iCC4 complex, the N4-O6 bond is the shortest one, and the configuration of the amino group of the isocytosine fragment is significantly more pyramidal compared with cytosine both in the gas phase and in a water environment (Tables 1 and 2). Inclusion of six instead of four water molecules leads to a stronger buckling structure. We also note that the N2 atom of the cytosine amino group tends to be involved in three H bonds with Ow1- and Ow2-containing water molecules and the O2 site of the cytosine fragment (Table 2), although the initial trial geometry differs considerably from the fully optimized one. One can also observe that geometries of the isolated iCC base pairs listed in Table 1 are very close in values to those of the isolated GC base pairs (see Table 2 in ref 15). The average differences in bond distances, bond angles, and the relative energies for the isolated iCC1, iCC2, iCC3, iCC4 and the isolated GC1, GC2, GC3, GC4 base-pair complexes are within ca. 0.01-0.02 Å, 1-2°, and 1-2 kcal/mol, respectively. Such relatively small differences cannot cause large variations in the geometry and properties of the respective iCC and GC base pairs. Indeed, the relative stability order of the isolated iCC and GC base pairs coincides with each other (see Table 4). This further supports our suggestion that the iCC complexes in a water environment could also provide some important insights into the analogous GC complexes in water. There is some analogy between the shape of the iCC complexes in water considered in this study and the small

clusters of the water molecules.41,42 According to high-level ab initio and density functional theory calculations, the cyclic structures correspond to the lowest energy minima for small clusters, at least up to five molecules.41,42 For the water tetramer, the energy minimum corresponds to a flat, ringlike structure with the H bonds being shorter than in the trimer case, whereas for the water hexamer a hexagonal chairlike geometry, with free OH bonds pointing alternatively in opposite directions, is optimal after taking the zero-point energy corrections into account. Four O atoms lie on a plane, whereas the remaining two are out of the plane by ca. 16.1° and lead to a nonplanar, highly symmetric structure.42 2. Interaction and Solvation Energies. The HF/6-31G*// HF/6-31G* and the single-point MP2/6-31G*//HF/6-31G* calculations show that the BSSEs corrected interaction energies calculated as the energy difference between the complex and the sum of isolated monomers for the zwitterionic iCC4 and rare iCC3 forms are the relatively highest among the considered structures both in the gas phase and in a water environment (Tables 4 and 5). Note that we use the standard Boys-Bernardi counterpoise correction scheme,34 whereas additional corrections for BSSE take into account also the geometry reorganization when going from the isolated subsystems to the complex, as is discussed in the references.35,43 The interaction energies for all complexes in water are determined from the difference between the energy of the complex and the energy of the isolated monomers, so such interaction energies for the complexes in water do reflect the influence of the structural changes induced from the water molecules. The highest interaction energy value for the iCC4 complex is not surprising because it corresponds mainly to ion-ion electrostatic interactions. Because molecular recognition processes are driven by energy changes and not by the interaction energy,8 the comparison is made between the interaction energies for the canonical Watson-Crick iCC1 base

Solvation Effects on Isocytosine-Cytosine Complexes pair and the zwitterionic iCC4 structure. Interaction energy for the iCC1 base pair calculated for the gas phase is 24.9 kcal/ mol at the HF/6-31G*//HF/6-31G* level of theory and differs only slightly from the analogous one of the GC1 Watson-Crick base pair (25.0 kcal/mol).8 The water environment has relatively small effects on its interaction energy both at the HF and MP2 levels of theory, although their changes slightly depend on the number of water molecules in the first coordination sphere (Tables 4 and 5). As usual, these values increase by ca. 1-2 kcal/mol at the correlated MP2 level compared with the HF level of theory. In contrast to this case, the interaction energy decreases for the zwitterionic iCC4 structure in a water environment compared with that of the gas phase. Such a decrease is a function of the number of water molecules involved in the first coordination sphere. Probably this is due to the delocalization of the net atomic Mulliken charges on the atoms and the decreasing dipole moments of the complexes in a water environment compared with the gas phase (Tables 6 and 7); the latter decreases approximately two times for all the iCCl‚ 6H2O complexes studied. The BSSE-corrected solvation energies are also calculated as the energy differences between the complex with the water molecules and the sum of the isolated complex and water molecules in the same way as the interaction energies described above. The zwitterionic iCC4 and canonical iCC1 base pairs have the relatively highest solvation energies among the considered structures both at the Hartree-Fock and correlated levels of theory (Tables 4 and 5). This is in line with the fact25,37,38 that a polar environment further stabilizes the standard canonical Watson-Crick base pair25 and the rare zwitterionic structures.25,37,38 Conclusions Ab initio quantum chemical studies at the HF/6-31G*//HF/ 6-31G* and MP2/6-31G*//HF/6-31G* levels of theory have been performed for four different H-bonded iCC complexes in the gas phase and in a water solution. The water solution was modeled by explicit inclusion of water molecules, up to six, that create the first coordination sphere around the iCC base pair. It was shown that the standard Watson-Crick iCC1 base pair is the global minimum on PES both in the gas phase and in a water solution. Inclusion of six instead of four water molecules has crucial effects both on the geometries and relative stabilities of the iCC complexes. The relative stability of the iCC complexes are changed when one considers six water molecules, and the zwitterionic form iCC4‚6H2O becomes the second most stable species after the Watson-Crick iCC1‚6H2O complex. Although simulations involving explicit water are very expensive computationally, our study shows that it is necessary to perform such investigations because the specific solvation effects are vital in the DNA base-pair interactions. The water molecules in the first coordination sphere represent an inherent part of the DNA structure. The DNA fragments are flexible and easily could change their planar structures depending on the number of water molecules in the first hydration shell: the solvation of all exocyclic groups of DNA base pairs strongly enhances the nonplanar, buckling structures. Acknowledgment. The authors thank the Mississippi Center for Supercomputing Research for the computational facilities. This work was facilitated by NSF grant OSR-9452857 and by Office of Naval Research Grant no. N00014-98-7-0592 and by a contract (DAAL 03-89-0038) between the Army Research

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