Reactivity and Aromaticity of Nucleobases are Sensitive Toward

Article pubs.acs.org/JPCB

Reactivity and Aromaticity of Nucleobases are Sensitive Toward External Electric Field Biswa Jyoti Dutta and Pradip Kr. Bhattacharyya* Department of Chemistry, Arya Vidyapeeth College, Guwahati, Assam 781016, India S Supporting Information *

ABSTRACT: Reactivity and aromaticity of DNA and RNA bases toward an external electric field are analyzed using density functional theory (DFT) and density functional reactivity theory (DFRT). Reactivity of the nucleobases is measured in terms of the DFT-based reactivity descriptor, such as energy of the HOMO, global hardness, electrophilicity, etc. and is observed to be sensitive toward the strength as well as direction of the applied external electric field. In addition, the reactivity pattern follows the maximum hardness and minimum electrophilicity principles. Further, aromaticity of the species is observed to be effected by the presence of an external electric field.

1. INTRODUCTION The sequence of nucleobases in double-helical DNA forms the genetic code that serves as the blueprint for all cellular operations.1 Transcription of cellular DNA requires accurate readout of these codes. During cell division, a trusty replication of DNA is of utmost importance to yield daughter cells that contain exact copies of the genetic code.2 Any chemical modification of cellular DNA may have profound biological consequences, including induction of DNA repair proteins, inhibition of cell growth, or cell death.3,4 Moreover, among different biomolecules, DNA/RNA bases happen to be the most preferred site for different chemical reactions.5 DNA alkylation is one of such major reaction with therapaeutic relevance. DNA alkylation is one of the major reactions.6,7 Cytotoxicity of different anticancer drugs such as nitrogen mustard, cis-platin, etc. arises because of DNA alkylation.8 For example, nitrogen mustards, mitomycin C and cis-platin preferentially alkylate guanine N7,9,10 psoralens alkylate thymine,11 and CENU’s alkylate guanine N1 and O6.12,13 Alkylation at a particular site in the DNA/RNA bases depends on the reactivity of the concerned site.14−16 Thus, reactivity of the site of attack (in nucleobases) bears importance, and a number of experimental studies have been devoted to the understanding of reactions in DNA.17 Reaction of an isolated DNA and that in intact cells is different and this confers the influence of the cellular environment on DNA reactions. Reactivity at a particular site in the nucleobases is affected by a number of factors such as polarity of solvent, surrounding ions, their conformations, adjacent base pairs, etc. The ions present in the cellular environment as well as the polar sugar−phosphate backbone and charged histones impart a strong local electric field which might affect the reactivity of the DNA/ RNA bases.18 Recently, we observed a significant variation in the reactivity of the aziridinium ion intermediate on application of the external electric field.19 Effect of the external electric field on the stability of drug-guanine adducts is also documented.20 Cellular environments are much more complicated to model theoretically. © 2014 American Chemical Society

Solvation models are often used for this purpose; however, the role of the ions present in the cellular environment is not incorporated. In a cellular environment, the biomolecules may experience the electric field and their reactivity pattern may be altered. Moreover, when tissues are exposed to the external electric field, it gets damaged.21 In recent years density functional theory (DFT) has proved its applicability to interpret chemical reactivity in complex phenomenon.22−28 Density functional reactivity theory (DFRT) can be used to estimate reactivity parameters. These parameters, called reactivity descriptors, defined within the framework of density functional theory and are global hardness (also called chemical hardness), electrophilicity, chemical potential, local softness, Fukui functions, etc.29 These descriptors have been tested and studied by several research groups and are found to be very useful in rationalizing the reactivity patterns in the molecular systems.30−34 Geerlings et al. and Chattaraj et al. have reviewed the theoretical basis for these descriptors and their applicability.35,36 Some of the recent developments and applications of these descriptors are highly appreciable.37−41 The effect of the external electric field on chemical reactions is common.42−45 The effect of the electric field on the chemical reactivity has been carried out in several earlier studies.46−59 The chemical reactivity as a function of orientation in the electric field has been investigated in depth.46,47 The influence of an external electric field on the s and p states of atoms and their compounds can affect their chemical properties, spectral, optical, and magnetic resonance parameters.48,49 Pal and co-workers have studied the behavior of these descriptors in the presence of the external electric field as well as solvent media.50−53 Earlier, Received: May 14, 2014 Revised: July 23, 2014 Published: July 23, 2014 9573

dx.doi.org/10.1021/jp5047535 | J. Phys. Chem. B 2014, 118, 9573−9582

The Journal of Physical Chemistry B

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in the case of the electric field induced crystallization of ionic crystals and in some biological systems, weak external electric fields have been applied (100−1000 V m−1).54,55 Recent work shows that biological systems can experience a strong field of magnitude ranging from ∼108 to ∼1010 V m−1.18,56 Hirao et al. observed the effect of the external electric field on the C−H bond activation reactivity of nonheme iron-oxo reagents using density functional theory.57 Structural characterization of a water− micelle system in the presence of an external electric field has been extensively investigated by the use of MD simulations.58 Chattaraj and his co-workers have observed the effect of the electric field on the global and local reactivity indices and confirmed that the electric field considerably affects all the local reactivity indices, and thus one might expect that the site of attack and selectivity be affected by the external electric field.59 Morphology of solid surfaces is also affected by the application of an external electric field.60 The effect of the external electric field on hydrogen adsorption over activated carbon separated by dielectric materials was studied by Zhang.61 Accordingly, introduction of the electric field influences both physical and chemical properties of various molecular systems. Recently, a number of works has been devoted to the study of application of the external electric field on biological molecules.62−65 As consideration of the complete cellular environment is not possible, herein, we have considered DNA/RNA nucleobases and their corresponding nucleosides and attempted to exploit the DFT-based reactivity descriptors to study the variation of their reactivity in the presence of such external electric fields (Figure 1).

2. THEORETICAL DETAILS OF THE REACTIVITY DESCRIPTORS AND COMPUTATIONAL DETAILS In DFT, chemical potential (μ) and global hardness (η) are defined as the first and second derivative of energy with respect to the number of electrons, respectively.66,67 Use of finite difference approximation and Koopmans’ theorem68 leads to the working formulas for μ and η as ε − εHOMO η = LUMO (1) 2 and ε + εHOMO μ = LUMO (2) 2 Parr and co-workers proposed electrophilicity (ω) as a measure of electrophilic power of a ligand and its propensity to soak up electrons.69 ω=

μ2 2η

Figure 1. Optimized structures of the nucleobases and nucleosides (subscript n refer to the nucleosides).

The geometrical minima of the species are obtained using the 6-31+G(d,p) basis set with Becke three parameter exchange and the Lee, Yang, and Parr correlation functional (B3LYP)72,73 and is confirmed by frequency calculations. After locating the minima, single point energy calculations are carried out at different external electric field values along six directions (along positive and negative directions of x, y, and z axes, + means that the field is applied along the + direction of the axis and − means that the field is applied along the − direction of the axis). Earlier it was shown that the biological systems such as DNA base pairs can experience intense local electric fields of order of ∼1010 V m−1.56 Accordingly, the range of strength of the external field is chosen from 0.00 to 0.01 au [1 au = 51.4 V/Å = 51.4 × 1010 V m−1]. The global reactivity descriptors (chemical potential, global hardness, and electrophilicity) are calculated using eqs 1−3. Fukui functions (f −x ) are calculated using eq 5. To quantify the effect of the size of considered moiety, we consider nucleobases, their corresponding nucleosides, and GC base pair and calculated the reactivity parameters at the same level of theory. Effect of the external electric fields on the aromaticity of the six-membered rings in the nucleobases is

(3)

The Fukui function (FF) is the most important reactivity index to observe reactivity at a particular site, defined as70 ⎛ ∂μ ⎞ ⎛ ∂ρ(r ) ⎞ f (r ) = ⎜ ⎟ ⎟ =⎜ ⎝ ∂ν(r ) ⎠ N ⎝ ∂N ⎠ν( r )⃗

(4)

The Fukui function [f(r)] can be obtained by using finite difference approximation; for electrophilic attack, the Fukui function ( f −x ) can be expressed as71 f x− = [ρx (N0) − ρx (N0 − 1)]

(5)

where, ρx(N0) and ρx(N0 − 1) are electronic population on atom x of the molecule with N0 and N0 − 1 electrons, respectively. 9574



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Figure 2. (a−e) Variation of εHOMO of bases and (f−j) nucleosides at the B3LYP/6-31+G(d,p) level of theory. (■ along the x axis, ● along the y axis, and ▲ along the z axis). (k) Variation of εHOMO along the x axis at different functional and basis sets. (l) Variation of εHOMO of the GC base pair.

assessed by the nucleus-independent chemical shift (NICS) calculations. The density functional study on the aromaticity becomes quite fruitful, and a number of such studies have been made in recent years.74−76 NICS index is defined as the negative value of the absolute shielding computed at a ring center or at some other point of interest in the system, usually above the ring center. Rings with large negative NICS values are considered

aromatic. The more negative the NICS values, the more aromatic the rings are. Nonaromatic species have NICS values close to zero and positive NICS values are indicative of antiaromaticity. NICS is usually computed at ring centers [NICS(0)] determined by the nonweighted mean of the heavy atoms coordinates.77 But it can also be calculated at a certain distance above or below the center of the ring. In fact, the NICS obtained at 1 Å above the 9575



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Figure 3. Variation of global hardness (η, represented by □) and electrophilicity (ω, represented by ●) of the nucleobases along the x and y axes (denoted by subscript) at the B3LYP/6-31+G(d,p) level of theory. Figure 3(p) represents the variation of global hardness at a different level of theory along the x axis of adenine, and Figure 3(q) is for electrophilicity of adenine.

molecular plane [NICS(1)] is considered to better reflect the p-electron effects than NICS(0).78 NICS(0) and NICS(1) values are calculated79−82 using the gauge-including atomic orbital method (GIAO)83,84 implemented in Gaussian09. Further, to observe the effect of functional on the reactivity pattern, we repeated the calculations with the CAM-B3LYP functional. This functional was tested and confirmed to provide results to acceptable accuracy.85 Moreover, to test the effect of

the basis set, we repeated the calculations with the 6-311+ +G(d,p) basis set. All the calculations are carried out using Gaussian09.86

3. RESULTS AND DISCUSSION 3.1. Effect of the Electric Field on Energy of HOMO of the Nucleobases and Nucleosides. The hetero atoms in the nucleobases are prone to electrophilic attack, and hence, energy 9576



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Figure 4. Variation of f −x at a different site of the adenine figure (a) represents the variation along the x axis and (b and c) along the y and z axes, respectively. (■ N9, ● N7, ▲ 6-amino N, ▼ N1, and ⧫ N3; labels are in accordance with IUPAC).

Application of the electric field along the y and z axes impart almost no effect on εHOMO (Figure 2, panels f−j). The extent of lowering the εHOMO is observed to be Adn (20.04 kcal/mol) > Gun (17.22 kcal/mol) > Cyn (11.45 kcal/mol) > Thn (10.01 kcal/mol) > Urn (4.92 kcal/mol). Thus, the effect of external electric fields in nucleosides is much more significant as compared to the isolated nucleobases. A comparatively larger lowering of εHOMO of the nucleosides confirmed that upon application of an external electric field, nucleosides are more stable toward the reaction that involves electron donation as compared to nucleobases. Figure 2k represented the variation of εHOMO of adenine along the x axis with two different functional and basis sets. It is worth noting that the values at the B3LYP/ 6-31+G(d,p) and B3LYP/6-311++G(d,p) levels of theory are very close; however, as we use the CAM-B3LYP functional, significant drop in εHOMO is observed. At field = 0.01 au, εHOMO is dropped by 0.0416 au (26.13 kcal/mol). To observe the size sensitivity of εHOMO trends, we further consider the GC base pair; variations of εHOMO along the three axes are shown in Figure 2l. Importantly, the pattern is different from that of individual bases and their corresponding nucleosides. Interestingly, variation of εHOMO with the CAM-B3LYP/6-31+G(d,p) level of theory are similar to that of results obtained at the B3LYP/6-31+G(d,p) and B3LYP/6-311++G(d,p) levels of theory (Figures S1−S2 of the Supporting Information). Thus, results of the foregoing analysis confirm the sensitivity of the effect of an external electric field toward the size of the DNA fragment consideration. 3.2. Variation of the Reactivity Parameters. Our earlier works confirmed that an external electric field influences the reactivity of the aziridinium ion intermediate as well as the drug− DNA adduct.18,19 Here we analyzed the effect of such an external electric field on the local as well as global reactivity descriptors of the nucleobases and their corresponding nucleosides. Figure 3 summarizes the effect of the application of an external electric field on global hardness (η) and electrophilicity (ω) of the nucleobases in the B3LYP/6-31+G(d,p) level of theory. It is important to note that the global reactivity of the nucleobases is influenced to a large extent by the presence of an external electric field. Application of the field along the +x direction stabilizes cytosine, thymine, and uracil (hardness increases, according to the maximum hardness principle, MHP, maximum hardness leads to maximum stability) and the reverse is observed in the cases of adenine and guanine (Figure 3, panels a−e). However, except guanine and thymine, application of the field along the −y direction stabilizes the molecules (Figure 3, panels f−j).

Table 1. NICS Values of the Nucleobases and Nucleosides at the B3LYP/6-31+G(d,p) Level of Theory nucleobases benzene adenine cytosine guanine thymine uracil

nucleosides

NICS(0)

NICS(1)

NICS(0)

NICS(1)

−8.2 −6.8 −0.8 −3.1 −1.4 −1.0

−10.2 −8.4 −2.7 −3.5 −1.9 −1.6

−6.7 −1.3 −3.1 −1.5 −1.5

−8.3 −3.3 −3.7 −2.2 −2.2

of the HOMO (εHOMO) of the nucleobases plays an important role. In order to examine the effect of the external electric field on the εHOMO of the nucleobases (Figure 1, panels a−e), nucleosides (Figure 1, panels f−j), and GC base pair, we varied the electric field along the three axes, and the observations at the B3LYP/ 6-31+G(d,p) level of theory are summarized in Figure 2. In the case of the nucleobases, it is interesting to see that the application of the field along the x and y axes (which are in the plan of the molecule) leads to a sharp variation in εHOMO. In contrast, the field applied to the direction perpendicular to the plane of the molecules (along the z axis) hardly exerts any effect on εHOMO. In the case of adenine, a sharp drop in εHOMO is observed when the field is applied along the x and −y directions [e.g., upon applying a field of strength 0.010 au along the x direction drops εHOMO by 0.00276 au (1.73 kcal/mol) and application of the same field strength along the −y direction results in a drop of εHOMO by 0.00325 au (2.04 kcal/mol)] (Figure 2a). In the case of cytosine, the effect of the field is different from that in the case of adenine; application of field along the x direction stabilizes εHOMO by 0.0042 au (2.6 kcal/mol) (Figure 2b). Field applied along the y axis results in a slight change in εHOMO. In the case of guanine, the field applied along the x direction leads to a maximum lowering of εHOMO (0.0024 au, 1.51 kcal/mol, with field strength 0.01 au) (Figure 2c) and εHOMO of thymine is observed to be lowered by 0.0059 au (3.71 kcal/mol) with a field (strength 0.01 au) applied along the −y direction; variation in εHOMO along the x axis is not so prominent (Figure 2d). Pattern of variation of εHOMOin the case of uracil is similar to that of thymine; lowest εHOMO is observed with an applied field (of strength 0.01 au) along the +y direction (Figure 2e). In contrast to the nucleobases, variations of εHOMO in case of their corresponding nucleosides are different. εHOMO is observed to be effected to a large extent by the field along the x axis only. 9577



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Figure 5. Variation of NICS(0) (presented by □) and NICS(1) (presented by ●) of the nucleobases and corresponding nucleosides along the z axis at the B3LYP/6-31G(d,p) level of theory.

decreases), and in the case of guanine, application of the field along the −z direction stabilizes the molecule (Figure 3, panels k−o). Variation of electrophilicity occurs in a reverse manner to that of global hardness, and interestingly, in all the cases, thee variations obey the maximum hardness principle (MHP) and minimum electrophilicity principle (MEP).87 Variation of these

On the other hand, variation of global hardness and electrophilicity upon application of the field along the z axis (perpendicular to the molecular plane) is somewhat different from that along the x and y axes (Figure 3, panels k−o). In the case of adenine, cytosine, and uracil, application of the field along the +z or −z direction destabilizes the molecule (hardness 9578



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strength along the x axis, the nucleophilic nature of the nitrogen centers is affected significantly; however, application of the same field along the y axis does not exert such a prominent effect except on N7. It is conclusive to comment that direction as well as field strength matters whenever one looks into the reactivity of a particular site. Similar observations are made in the cases of other nucleobases too (Figure S9 of the Supporting Information). 3.3. Effect of the Field on the Aromaticity of the Nucleobases. The aromaticity of the nucleobases had previously been studied by several researchers by calculating NICS values.88−92 Since we were interested in estimating the effect on aromaticity of the six-membered rings of the nucleobases upon application of the external electric field, we calculated the NICS of all the nucleobases and nucleosides in the absence and presence of the field at the B3LYP/6-31+G(d,p) level of theory and the results are summarized in Table 1. The observed result (in absence of electric field) is in agreement with previous literature data.93 Values indicated that adenine is the only nucleobase that shows NICS values (of the six-membered ring) closer to those of benzene [the NICS(0) and NICS(1) values of benzene are computed to be −8.2 and −10.2 ppm at the same level of theory]. In all the nucleobases, NICS values are lower than that of benzene, indicating less aromatic character as compared to benzene (Table 1). Variation of the NICS values of the nucleobases and the nucleosides at the B3LYP/6-31+G(d,p) level of theory along the z axis are shown in Figure 5, and Figure S10 of the Supporting Information summarized the variations along the x and y axes. A hefty impact of the external electric field on the aromatic character is reflected in Figure 5. In the case of most of the nucleobases, NICS(0) values decrease on application of the electric field on either side of the z axis; a parabolic pattern is observed. However, variation of the NICS(1) values are observed to be different from that of the NICS(0) values. In the case of adenine, thymine, and uracil, NICS(1) values decrease on application of the field along the +z direction, while the reverse is observed on the application of the same along the −z direction; variation are nearly linear. In contrast, cytosine and guanine exhibit a parabolic variation in NICS(1) values. Variation of the NICS(0) and NICS(1) values of the nucleobases along the x and y axes at the B3LYP/6-31+G(d,p) level of theory are observed to be linear (Figure S10 of the Supporting Information). Further, B3LYP/6-311++G(d,p) and CAM-B3LYP/6-31+G(d,p) levels of theory also advocate the same trend (Figures S11−S14 of the Supporting Information). To get a more accurate view of the effect of the external electric field on the aromaticity of the nucleobases, we obtained the 3D NICS on the 0.001 au electron density isosurface spatial representation of adenine (as a representative case) and it is shown in Figure 6. Comparison of the isosurfaces of adenine at different field values shows similar features to that in the zero field value. However, we observed an increase in the negative charges along the direction of the applied field (Figure 6) (shown by the orange color). 3.4. Effect of the Field on the Structures of the Nucleobases, Nucleosides, and Base Pair. In the preceding sections, variations of the HOMO, reactivity descriptors, and aromaticity are observed by using single-point calculations. However, it is important to mention that the structures might undergo some changes on allowing the fragments to optimize under the applied field. Therefore, we have obtained the optimized structures of adenine, adenosine, and the GC base pair at two different field strengths (0.002 au and 0.01 au applied

Figure 6. 3D representation of the electron density isosurfaces of adenine.

parameters in the case of corresponding nucleosides also advocates the significant influence of field on their reactivity (Figure S3 of the Supporting Information). These variations clearly indicate a strong interaction of the molecule with the applied field. It is thus inferred that any environment producing an electric field impart a large impact on the reactivity of the nucleobases and in turn is expected to influence the rate of biological reactions of DNA/RNA bases. The effect of variation of functional and basis sets on the reactivity pattern of adenine (along x axis) as a representative case is summarized in Figure 3, panels p and q and the rest are shown in Figures S4−S7 of the Supporting Information. It is important to note that the variation of the functional as well as the basis sets are observed to impart no significant changes on the reactivity pattern (variation of global hardness and electrophilicity) of the nucleobases and nucleosides. To examine the effect of the external electric field on the local reactivity of the species, we considered f −x . As a representative case, variation of f −x at different sites in adenine along the three axes are presented in Figure 4 and variations for other nucleobases are shown in Figure S8 of the Supporting Information. It is evident that the nucleophilic nature of the sites (in absence of any external electric field) is on the order: N (6-amino) > N3 > N9 ≈ N7 ≈ N1 (Figure 4). Interestingly, on application of the electric field along the molecular plane (x and y axes) results in a larger effect compared to the field applied along the z axis, which is perpendicular to the molecular plane. On varying the field 9579



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computational model of the biochemical reaction must include the effect of the ions present in the environment and not simply be replaced by the aqueous phase. It is also interesting to see that the aromaticity of the nucleobases is affected by the presence of an external electric field, which might in turn affect the reactivity of the species. Thus, one can manipulate the reactivity of nucleobases by varying the strength of the applied external electric field.

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ASSOCIATED CONTENT

S Supporting Information *

Variations of HOMO energies of the nucleobases and nucleosides (Figures S1 and S2). Variations of reactivity parameters of nucleobases and nucleosides at different functional and basis sets (Figures S3−S7). Variations of Fukui functions (Figures S8 and S9). Figures S10−S14 contain NICS values and Figure S15 contains structural parameters of optimized structures of adenosine and GC base pair. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

Figure 7. Optimized structures of adenine obtained at B3LYP/631+G(d,p) level of theory with field values (a) 0.000 au, (b) 0.002 au, and (c) 0.01 au applied along the +x direction (directions of the axes are shown in Figure 1).

Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS Authors thank UGC, New Delhi for financial support (F. 41201/2012(SR)).

along the positive direction of the x axis). Optimized structures of adenine as a representative case is shown in Figure 7, and adenosine and the GC base pair are presented in Figure S15 of the Supporting Information. We do not observe any substantial change on the structural parameters (bond length and bond angles) upon application of the electric field. When field strength of 0.002 au is applied, we observed a negligible change on the bond angles (by ∼1°), whereas no significant changes are observed on the bond lengths. On application of a field of strength of 0.01 au, few bond angles are observed to change by ∼2° and no significant change on the bond lengths are observed (few bond lengths are changed by 0.02 Å) (Figure 7). No prominent change on the structural parameters of adenosine is observed upon optimization (Figure 15 of the Supporting Information). However, one of the hydrogen bonds in the GC base pair is affected to some extent (bond length is elongated by 0.20 Å). It is thus commendable that performing single-point calculations is an appreciable approximation when the effect of the electric field is taken into account.

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REFERENCES

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4. CONCLUSIONS The present work involves insight into the effect of the external electric field on the DNA/RNA nucleobases and their corresponding nucleosides. Our results suggest that global as well as local reactivity of the DNA/RNA nucleobases are affected by the application of the external electric field. Variation of the reactivity pattern of the nucleobases and their corresponding nucleosides indicates that their reactivity may be modified in the presence of the external electric field and thus their rate of reactions toward electrophiles might be altered in such an environment. The ions present in the cytoplasm thus might affect the reactivity of the species by exerting an electric field on the species. Variation in global as well local reactivity of the nucleobases with the variation of field strength suggest that the 9580



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Reactivity and Aromaticity of Nucleobases are Sensitive Toward

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