Theoretical Investigation of the Binding of Nucleobases to

Subscriber access provided by HACETTEPE UNIVERSITESI KUTUPHANESI

Article

Theoretical Investigation of the Binding of Nucleobases to Cucurbiturils by Dispersion Corrected DFT Approaches Natarajan Sathiyamoorthy Venkataramanan, and Ambigapathy Suvitha J. Phys. Chem. B, Just Accepted Manuscript • Publication Date (Web): 21 Apr 2017 Downloaded from http://pubs.acs.org on April 21, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

The Journal of Physical Chemistry B is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 15

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

Theoretical Investigation of the Binding of Nucleobases to Cucurbiturils by Dispersion Corrected DFT Approaches Natarajan Sathiyamoorthy Venkataramanan.a,b* Ambigapathy Suvithab a

Centre for Computational Chemistry and Materials Science, SASTRA University, Thanjavur-614 001, India

b

Department of Chemistry, School of Chemical and Biotechnology (SCBT), SASTRA University, Thanjavur-614 001, India.

ABSTRACT: The encapsulation of nucleobases, inside CB7 has gained prominence due to its use as anticancer and antiviral drugs. With this respect, the nonconvalent interactions exists in the nucleobases encapsulated inside the CB7 cavity have been analyzed employing the dispersion corrected density functional theory. The CBn cavity has the ability to encapsulate two guest nucleobases molecules, when they are aligned in parallel configuration. The computed association energy using the two and three body correction method computed at B3LYP-D3 level is close to the experimental estimate. The use of dispersion corrected DF’s are essential to identify the correct binding energies. The solvation energy plays a vital role in the estimation of association energy. QTAIM analysis shows that the Laplacian of the charge density (∇2ρ), are negative and the presence of covalent interaction between the guest and host molecule. The NCI-RDG isosurface shows the presence of noncovalent intermolecular interactions such as van der Waals and hydrogen bonding. The existence of “splattering” of charges in guanine@CB7 molecule is responsible for its higher stability. From the AIM, NCI-RDG and EDA results, we conclude that noncovalent and electrostatic interaction with partial covalent character exists in the intermolecular bonding between the host and the guest nucleobases. The ramification of such intermolecular bonds reflects in the 1H NMR and 13NMR spectra.

Nucelobase are biomolecules that are rich in nitrogen. They are categorized as heterocycles and are found to be the building blocks of nucleic acids.1,2 The nucleobases are listed as purines (adenine(A) and guanine (G)) and pyrmidines (cytosine (C), thymine (T) and uracil), and constitutes the entire genetic diversity exhibited by the DNA and RNA.3 The presence of array of noncovalent interactions which include the electrostatic, hydrogen bonding and hydrophobic interactions made the nucleobases, responsible for the storage, expression and transmission of genetic information.4 The presence of such interaction between the nucleobases lead to the development of functionalized nanomaterial’s with potential application in molecular therapeutics, biomimetics, as 3D coordination polymers and in electronics.5,6 Nucleobases are widely used as biochemical catalysts in several metabolic pathways, in agricultural and chemical industries. Among the five canonical members of nucleobases, uracil has gained prominence due to its efficiency

as anticancer and antiviral drugs.7,8 Though there exist diverse applications for nucleobases, their poor solubility in water makes them less likely to exploit its full potential. For example, adenine was found to have 0.1 wt% solubility, and cytosine has 0.7 wt% solubility. The pharmaceutically important uracil has a solubility of 0.3 wt% in water.9,10 To understand the solubility of nucleobases, Zielenkiewicz et al. carried out a series of studies and found that polar interactions made by nucleobases are key to their solubility.11 On the contrary, nucleobase show only slight improvements in their solubility in water containing polar additives, like organic and inorganic salts. Cucurbituril (CBn with n=5-8, 10) are class of structurally simple rigid macrocyles with barrel shape. They are water-soluble macrocyclic molecules and have received renewed interest due to their ability to act as artificial receptors and are used as efficient vehicle for targeted intracellular delivery of hydrophobic drugs.12 Among the available CBs, CB7 has high solubility (2 x 10-2 mol/L),

ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

which is close to that of β-cyclodextrin solubility.13 The binding affinity of CBn molecules are almost equivalent to that of biological biotin-avidin pair which is considered to be one of the tightest binding biomolecular system. 14,15 In biotin-avidin pair, such a high affinity was possible due to the multiple noncovalent interactions and the cooperativity of H-bonds that prevails in those systems.16 To understand the mechanism of molecular recognition between the host CBn and guest molecules several theoretical studies were carried out. It was suggested that the presence of hydrophobic inner cavity and two identical carbonyl-fringed portals play a major role in increasing the binding affinity of the host molecules.17 There exist interesting studies concerning molecular recognition of nucleobases by different macrocyclic receptor.18-20 Out of the existing macromolecules, studies on CBs gain importance due to their potential use as drug delivery system, because of its enzyme mimic activity.21 The binding of amino acids to CBn receptors was studied in the past using isothermal titration calorimetry. Buschmann and coworkers found that Glycine, Alanine, Valine and Phenyl alanine forms exclusion complex with CB6 due to the week interactions between them.22 The interaction between CB7 and adenine have been studied in detailed by various spectroscopy techniques.23 Adenine has the highest formation constant compared to its derivatives. Furthermore, adenine and its derivatives interact with CB7 more efficiently in the pH range 2-4. Very recently Mutihac et al. have studied the interactions of CB7 and β-cyclodextrin with guanine and cytosine using UV spectroscopy and fluorescence spectroscopy.24 From the Job’s plot the stoichiometric for the formation of CB7cytosine was found to be 1:1, while β-CD forms a 1:1 complex with guanine. In this work, we aim to analyze the nucleobases-CBn complexes formed, with the objective of understanding the driving force for large binding constant for the nucleobases. We have benchmarked some of the popularly used DFs for the binding of nucleobases with CB7 host molecules. In addition, we would like answer some of the questions (i) which nucleobases can bind to CB7 more firmly (ii) what are the forces responsible for the binding of nucleobases inside the cavity (iii) How well the modern DFT methods are able to reproduce the experimental observed association energies (iv) which are the noncovalent interaction’s that prevail in these systems (v) how well they are able to apprehended by AIM, EDA and NCI-RDG analysis and (vi) whether, these forces are reflected in NMR spectra. We believe that our work should be useful for the understanding, at molecular level, the relevant structural and thermodynamic properties responsible for the stabilization of nucleobases, which could in turn help to understand the interactions of drug carriers such as CB7 with DNA.

Computational Methods We used the dispersion corrected (D2 correction) BP86 functional25,26 along with valence triple-zeta basis set with

Page 2 of 15

polarization (TZVP basis set) functions on all atoms for geometrical optimization. To speed up the calculation we used the density fitting procedure. Compared to the existing popular funcationals, BP86-D2 predicts binding affinity of alkenes on CB6 with the least MAE value and could reproduced the geometrical parameters of CB6 molecule more closely and is reported to be suitable in representing Noncovalent interactions.27 The interaction energies are calculated as the difference in total energies of the supramolecular-water complex and the individual units namely, the CB7 and the nucleobases. The energies are evaluated using def2-TZVP basis set and are basis set superposition error (BSSE) corrected. The use of higher basis set has not improved the binding free energies. The solution phase association energies are calculated using the sum of the three contributions as shown in equation (1) = ∆ + ∆

+ ∆ (1)

where Egas, GRRHO and ∆G0solv are the gas-phase electronic energy including the BSSE correction, the rigid-rotor harmonic oscillator contribution, and the solvation free energy respectively.28-31 Solvation energies were computed on the gas phase optimized geometry with the use of SMD model using the Klamt radii optimized for the COSOM-RS method.32 The rigid-rotor harmonic oscillator contribution to the energy term is obtained from the frequencies computed at the BP86-D2/TZVP level of theory. The association energies are computed using the following density functional: BP86, BLYP,33 B2LYP, B3LYP, the dispersion corrected functional B3LYP-D2, B3LYP-D3, BP86-D3, and B3LYP-D3(BJ) (B3LYP-D3 functional with Becke-Jonshon damping). All the density functional theory calculations were carried out using the GAUSSIAN 09 suite of programs.34 The effect of waster as solvent, was implemented using the CPCM method, with sphere radii optimized for COSMO-RS proposed by Klamt.35 NMR chemical shifts (δ) were computed in water using BP86D2/TZVP//B3LYP-D3/TZVP level of theory. The reported 1 H and 13C chemical shifts were obtained by subtracting the nuclear magnetic shielding tensors of proton in CB7 and nucleobase molecule from those in the tetramethylsilane (as reference) using the gauge-independent atomic orbital (GIAO) method.36 The energy decomposition analysis (EDA) is carried out at the B3LYP-D3/TZP level of theory using ADF(2016) program package.37 Topological parameters were derived with the QTIAM approach using the AIM2000 or AIMALL program.38 Noncovalent interaction (NCI) reduced density gradient (RDG) method has further been used to visualize the nature of interactions between the guest and host molecules. 39 The NCI-RDG analysis were carried out using the Multiwfn program.40 Blue, green, and red color codes are used to represent stabilizing H-bonding, Weak van der Waals, and destabilizing steric interactions, respectively, in the NCI isosurfaces. The visualization of the gradient isosurfaces in real-space was made using Chemcraft program.


Page 3 of 15

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 1. Calculated gas phase stabilization energy, sum of two and three-body dispersion contribution, gasphase RRHO free enthalpy contributions, free energy of solvation in water and the association free energy for the encapsulated molecules computed at BP86-D2/TZVP//B3LYP-D3/def2-TZVP functional. o

a

∆Egas

∆Edis,3body

∆GRRHO

∆Gsolv

G

Adenine

-30.26

7.31

26.10

-7.54

-4.39

-

Cytosine

-29.79

3.09

25.10

-7.94

-9.54

-4.95

Guanine

-37.08

8.13

26.96

-11.74

-13.73

-

Thiamine

-28.52

5.22

22.21

-11.55

-12.65

-

Uracil

-26.12

1.28

21.98

-9.66

-12.52

-

a

From Mutihac et.al.

sol

G

o

Guest

sol, Expt

24

Figure 1. Perspective view of optimized structures of encapsulated nucleobases in their parallel and perpendicular orientation

Results and Discussion 3.1. Equilibrium geometry and Interaction energy Based on our previous experience with inclusion complexes, we have considered various modes of interaction of nucleobases with CB7 which includes the perpendicular, parallel, on top and side wise.41,42 The minimum energy geometry and next low lying isomer for all the nucleobases studied are shown in Figure 1, while the other lower energy geometries are shown in Supporting Information Figure S1. We note that irrespective of nucleobases studied, the guest molecules prefer to accommodate deep inside the cavity and are in perpendicular orientation; however, they occupy different locations within CB7. Interestingly, the cavity size plays a major role in the encapsulation process of the nucleobases. The fully optimized structures, were found to have enlargement in one direction, while the opposite side undergoes a contraction in the cavity size. The diameter distances measured from the oxygen atom of the carbonyl fringe to the methylene hydrogen are shown in supporting information Table S1. Upon encapsulation, the cage undergoes a distortion, with shrinkage in one direction and enlargement in opposite direction. It is found that the distortion is significant for the guanine nucleobase and was least for the adenine base. The distortion in the geometry of the host and guest are reflected in the computed deformation energy ∆EDef, which is provided in the supporting information Table S1. ∆EDef is the energy need to deform the host or guest during the encapsulation process and is computed as the energy difference between the free molecules and the molecules with the constrained geometry in the encapsulated supramolecule.432,44 The ∆EDef values for the host and guest molecules are larger in the case of guanine@CB7 which is due to the larger deformation of CB7 host and the guanine nucleobase. The least deformation is observed for the adenine@CB7 system which has the least structural changes on the CB7 and adenine nucleobase. The BSSE corrected stabilization energy values (Estabiliz) for the encapsulation process are provided in Table S1. Estabiliz values reflects the stability of the encapsulated systems and are obtained as the total energy difference between the complex and the individual host and guest molecules.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 15

Table 2. Calculated free energy of solvation for inclusion complexes with various functional using def2-TZVP basis set on the BP86-D2/TZVP optimized geometry. Guest

BP86

BP86-D2

BP86-D3

BP86-D3BJ

BLYP

B3LYP

B3LYP-D2

B3LYP-D3

B3LYP-D3BJ

Adenine

25.54

-15.63

-20.44

-18.12

59.89

21.33

-19.88

-4.39

-15.80

Cytosine

15.89

-16.18

-22.63

-21.23

50.14

12.66

-19.41

-9.55

-18.65

Guanine

19.18

-21.85

-27.32

-25.90

54.39

13.75

-27.28

-13.73

-24.32

Thiamine

15.55

-20.38

-25.98

-23.09

45.54

12.26

-23.67

-12.65

-21.02

Uracil

15.68

-18.56

-25.00

-22.97

45.66

12.73

-21.51

-12.52

-20.43

Estabiliz is highest for the guanine base (-36.92 kcal/mol), while the small guest molecule uracil has least stabilization energy (-26.48 kcal/mol). It is interesting to observe that cytosine and thymine which are congeners, with similar geometrical features with a five-membered ring have different, stabilizing energy. Similarly, adenine and guanine have similar structure with five membered ring fused to the six-membered ring, and were found to have different stabilization energy. The inclusion complexes are found to have H-bonds between the guest and host molecule. The larger electronegativity of carbonyl O atom in guanine facilitate the formation of stronger H-bonds in guanine@CB7 than that in adenine@CB7 making the former more stable.45 Comparison between thymine and uracil, the former has an electron releasing methyl grouping it, making the thymine@CB7 complex to be more stable. On the contrary, comparison between thymine and cytosine, thymine shows higher stability owing to the number of carbonyl oxygen atom. Thus, in general the guest with high surface contact area and more carbonyl O atom which creates acidic hydrogen are found to make stable hydrogen bond with the carbonyl fringe portal of CB7 making the encapsulated molecules more stable. We now turn our attention to the formation thermodynamics of inclusion complex in aqueous media. Most often, association thermodynamics in solution is discussed in terms of association Gibbs energies, which is directly related to the association equilibrium constants obtained experimentally. Very recently Mutihac et al. have studied the interactions of CB7 and cytosine using UV-Vis spectroscopy.24 From the Job’s plot, the stoichiometric for the formation of CB7-cytosine was found to be 1:1, with the association energy of 3008±1002 M-1. The observed association energy is extraordinarily high for such small systems; however, there exists several reports with high association energy for CB7 as host molecule.46-48 The theoretical estimation of Gibbs energies has been done widely using the equation one; however, the terms used in the calculations faces problems as reported recently by Jensen.49 However, such a procedure has been successfully applied to do a blind prediction of association energy of various complex.50-52 In Table 1 we report the contributions to association Gibbs energy, the gas-phase electronic energy ∆E, the sum of two-body and three body dispersion energy, the thermal correction from energy to free energy and the solvation free energy for all the encapsulated complexes. Though the sum of two and three-

body interactions have low contribution to the energy, but was found to be essential in small to medium size systems. For all the systems, the two and three body dispersion contribution was found to be destabilizing in nature. As a consequence of near similarity in the geometry of adenine and guanine the two and three-body dispersion terms are near isoenergetic in nature. Furthermore, the other destabilizing term the ∆GRRHO, for the systems are nearly the same for the systems which have similar geometry. It is evident from the Table 1, the computed association energy computed at B3LYP-D3 level is for the cytosine@CB7 is -9.54 kcal mol-1, close to the experimental estimate. Among the host studied the association energy, for the guanine with CB7 was found to be largest. While the adenine, which has similar geometry that of guanine was found to have the least association energy. Furthermore, the computed association energy for the smallest host uracil was -12.52 kcal mol-1, while the larger host cytosine has less association energy. This discrepancy has arisen mainly from the solvation factor and the stabilization energy in gas phase, as the other factors namely the

∆Edis,3body and ∆GRRHO are not affected by the functionals largely used in the calculation for similar endohedral larger systems such as cyclo crysenylene and fullerenopyrrolidine complex.49 To understand the quality of the chosen theoretical methods in the estimations of association free energies of inclusion complexes, we have computed the solvation energy and stabilization energy for the inclusion complex using various DF’s (BP86, BP86-D2, BP86-D3, BP86-D3BJ, BLYP, B3LYP, B3LYP-D3, B3LYP-D3 and B3LYP-D3BJ) and are listed in Table S2. The gas phase stabilization energy was found to be unfavorable when computed with the pure functionals BP86 and BLYP. The use of the popular hybrid B3LYP show that guest such as cytosine, guanine and thymine are stabilized inside the cavity. The use of dispersion corrected DF’s show that guest molecules bind more strongly to the host. Comparison between different dispersion functionals show that D2 correction provides higher stabilization energy than D3 functionals. Furthermore, the use of Becke-John damping has reduced the stabilization energy in most cases and the pure functional with D2 dispersion correction BP86-D2 was found to have stabilization energy closer to the B3LYP-D3 functional. The computed solvation energy with pure functionals (BP86 and BLYP) and the popular hybrid B3LYP functional are provided in supporting information Table S2, which


Page 5 of 15

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


were found to be largely unfavorable. The use of D2 dispersion increases the solvation energy, while the use of D3 dispersion with Becke-John damping decreases the solvation energy. A comparison between the pure and hybrid functional with D3 dispersion correction, shows that hybrid has the lowest solvation energy. In the association energy calculation, ∆Edis,3body and ∆GRRHO are kept constant as these destabilizing factors are not affected by the DF’s.49 The computed association energy using various DF’s for all the systems are provided in Table 2. It is evident for the Table 2, the functionals without dispersion correction shows unfavorable binding for the nucleobases. The other functionals with dispersion factors show a larger deviation from the experimentally estimated association energy for cytosine@CB7 complex, however, shows a favorable association energy for all the nucleobases. Among the nucleobases studied, guanine was found to have higher association energy consistently in all the calculations with dispersion correction and the B3LYP-D3 function predicts the association energy reasonably. Thus, extreme care should be taken in to account in choosing the functionals in computing the association energies of inclusion complexes.

3.2. Number of Encapsulated Guest Molecules. To identify the number of nucleobases that can be encapsulated within the CB7 cavitand, we introduced the se-

cond nucleobases inside the cavitand in the possible two different orientations (nucleobases in parallel and antiparallel orientation). The full optimized geometries are shown in Figure S2. The guest molecules were found to be inside the cavity, expect the anti-parallel configuration of guanine, in which part of a guanine molecule projects out of the CB7 cavity. It is observed that in guanine and thymine, the guest molecules undergone dimerization inside the CB7 molecule while inserted in the parallel configuration. In all the systems, the anti-parallel was found to stabilize more inside the cavity than the parallel configuration. The dimerization of substituted trans-1,2bis(n-pyridyl) ethylene di-hydrochloride and trans-nstilbazole hydrochlorides has earlier been observed within the CB[8] cavity experimentally by Ramamurthy et. al. and yielded a syn dimer.53,54 Theoretically Gejji et. al. studied the dimerization within the cavitand and noticed the anti-head-to-head conformer is more stabilized inside the cavity.55 Furthermore, the interaction energy between the CB7 and nucleobases is much higher than the reported nucleobase dimer formation energies.56-61 From the above results and the present work, it is clear that the CBn cavity has the ability to include two guest molecules of appropriate size however, when guest molecules are aligned in parallel configuration can yield a syn head-head dimer.

Figure 2. Electrostatic potential maps of nucleobases and their CB7 complexes, superimposed on the isodensity surface of the structures (isovalue 0.002), computed at B3PLY-D3BJ/Def2-TZVP level.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

3.3. Nature of Interaction 3.3.1. Molecular electrostatic potential (MESP) Molecular electrostatic attraction between host and guest molecules is considered to be one of the important driving force for the formation of inclusion complexes when CB is used a guest molecule.42,62,63 To investigate the above hypothesis, DFT calculations of the electrostatic potential for the host and guest molecules were performed. The results are visualized in Figure 2. as electrostatic potential mapped onto isoelectronic surface. In the guest molecules, the positive electrostatic potentials are localized around the hydrogen atoms of amino and the imido groups and the negative potentials are localized on carbonyl oxygen and on the nitrogen atoms. In the CB molecule, the positive potential is localized on the glycouril part and the methylene moiety connecting the two glycouril units. The negative potentials are localized on the carbonyl oxygen portals present at the top and bottom on the CB molecule. In the complexes, it is interesting to observe that the positive potentials of imido or amino hydrogen of guest nucleobases matches the negative potentials on the carbonyl oxygen portals of CB molecule, and the negative potential of nucleobases matches with the positive potentials observed in the cavity of CB molecule. Thus, it seems very likely that the charge distribution in host and guest nucleobases could be a major driving force for the formation inclusion complexes. This interpretation is corroborated by the quantitative molecular electrostatic potential values obtained on the free nucleobases and on the inclusion complexes at the 0.002 electrons/Bohr3 isodensity surface. The quantitative molecular electrostatic potential (MESP) values for all free nucleobases and their inclusion complexes are provided in supporting information Table S4 – S14. In the host CB7, positive and negative potentials are designated as Vs,max and Vs,min, respectively. The bare host molecules has Vs,max values of 30.52, and 34.69 kcal/mol near the ethylene bridge and at the middle of the eight membered ring that exists between two glycouril units. The Vs,min values of -57.53 and -17.04 kcal/mol were found on top of the carbonyl portal and nitrogen atom in the glycouril unit respectively. On the guest molecule in general the Vs,max were found on the hydrogen atom of amino group or on top of the hydrogen atom on cyclic amine group, while the Vs,min were localized on the top of the nitrogen atoms. In thymine and uracil, the Vs,min values are found on top and bottom of the cyclic ring. The highest Vs,max and Vs,min were observed for the guanine molecule. The most electropositive regions of the potential surface are located in between the amine and NH group of guanine molecule with a value of -61.47 kcal/mol. It should be pointed out here that the carbonyl portal which has Vs,min values of -57.53 kcal/mol in host molecule, upon encapsulation of guanine decrease the potential at the surface to -43.88 kcal/mol. During the encapsulation process, the carbonyl portal away from the amino group of guest gains charge and has a value of 70.82 kcal/mol. Similarly, there has been a considerable

Page 6 of 15

decrease in the Vs,min values of the CB7 closer to the amino group of the guest molecule upon encapsulation. These results suggest that N-H···O=C hydrogen bonding between the guest and the carbonylated rims of CB7 exists in these systems along with a charge distribution in the host and guest molecules.

3.3.2. Energy gap and electron density analysis Theoretical studies suggest that the HOMO-LUMO energy separation is an indicator of the kinetic stability of a system.40,42 A large HOMO-LUMO energy gas of a system implies its reluctance toward the acceptance of electron in the LUMO and the removal of the electron from the HOMO with provides electronic stability to the system. The HOMO–LUMO gaps (∆Egap) computed for the inclusion complexes are provided in supporting information Table S15. The host molecule CB7 has a ∆Egap of 6.50 eV, while the inclusion complexes have lower values. The ∆Egap for the guest molecules where in the range of 2.47 – 5.30 eV, which indicates that the guest molecules are all chemically more reactive compared to the host molecule. The lower ∆Egap for the inclusion complex shows that complex formation can be a reversible process and are kinetically controllable. The frontier orbital for all complexes at the B3LYPD3 level are provided in supporting information Figure S3. From the Figure S3, it is evident that the HOMO and LUMO orbitals are located mainly on the guest molecules except the uracil, which indicates that inclusion complexes do not alter the electronic structure of the CB7 and the encapsulation occurs by a physical adsorption process. The quantum theory of atoms in molecules (QTAIM) has been extensively applied to analyze the nature of interactions in various molecular systems and to classify bonding interactions in terms of a quantum mechanical parameter as electron density.64,65 The quantity of electron density at the BCP provides the information about the nature and strength of bonding between the two monomers in any inclusion complex.66 The sign of Laplacian is determined by energy that dominates in the bonding zone. A positive ∇2ρ indicates that kinetic electron energy density G(r) is greater than the potential electron energy density V(r). Such an interaction is observed in closed shell systems or a noncovalent interaction, where the depletion of electronic charge along the bond path is observed.67 A negative value of ∇2ρ at BCP indicates a covalent bond. The positive value of H(cp), also indicate the existence of noncovalent interaction at the BCP. Besides the above terms, if the ratio of –G(cp)/V(cp) > 1, then the interaction can also be classified as noncovalent.68 The calculated change density (ρ), Laplacian of the charge density (∇2ρ), local potential energy density (VCP), local gradient kinetic energy density (GCP) and total energy density (HCP) for the intermolecular bonding between the guest CB and the host nucleobases are provided in Tables S16 – S20. The summation of the above terms that exists in the intermolecular interactions are provided in Table 3.


Page 7 of 15

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 3. QTAIM Parameters Corresponding to Intermolecular Bonding between the Nucleobases and CB7 host molecule in the host-guest complexes. 2

Nucleobases

Σ ρ (r)

Σ ∇ ρ (r)

Σ λ1

Σ λ2

Σ λ3

Σ Η (r)

- Σ G(r)/ Σ V(r)

Adenine

0.1322

-0.4986

0.1101

0.0783

-0.6870

0.0234

1.4043

Cytosine

0.0787

-0.3032

0.0587

0.0404

-0.4024

0.0150

1.6237

Guanine

0.1185

-0.4639

0.1056

0.0887

-0.6583

0.0224

1.4835

Thymine

0.1203

-0.4756

0.1101

0.0785

-0.6642

-0.4756

1.5462

Uracil

0.1159

-0.4372

0.1057

0.0767

-0.6196

0.0181

1.5798

complexes, adenine@CB7 has the highest number of BCP’s and the lowest was observed for the thymine@CB7. Among the nucleobases, guanine, adenine, and cytosine bases have amino groups, which can form hydrogen bonding while the uracil and thymine bases possess only carbonyl oxygen atoms, whose lone-pair can form bonding’s with the substrate. In adenine, cytosine and guanine we observe the amine hydrogen to form an N-H…O=C intermolecular interactions. The local electron density ρ parameters were all positive and fall in the range 0.000 a.u. to 0.029 a.u.. This value falls in the range of hydrogen bonding, predicted in previous studies.69 In all the inclusion complexes, the N-H…O=C or the NH…O=C type, are found to have the highest ρ indicting their strength of interaction. In the adenine@CB7 complex, 16 BCPs were observed, which can be categorized as bifurcated 9NH…O=C type, bifurcated 2C-H…O=C type, bifurcated 3N…N type, 5C…N type, 1N…O=C type, 3N…C type and amino N…O=C type interaction. In cytosine@CB7 there were 11 number of BCP’s which can be classified into interactions such as, carbonyl oxygen on the 2C atom with the carbonyl carbon, and nitrogen of the guest molecule. In guanine, the main interactions between the guest and host are the 9NH…O=C, amine N…O=C, 8C…O=C, 9N…C, 1NH…O=C and 3N…C. In the thymine and uracil, we observed the existence of 1NH…O=C interaction. The heteroatom interactions in these systems were in the range of 0.000 to 0.002 a.u, which are well within those observed for the weak noncovalent interactions.

Figure 3. Molecular topography analysis for CB[7] and the inclusion complexes with nucleobases. The molecular topological graphs of various systems are shown in Figure 3. A close analysis of the results presented in Figure 3, shows that the, bond paths are not

straight lines but are slightly curved toward the CB7 guest. The presence of cage critical points (CCP) in the inclusion complex (which does not exist in CB7) clearly indicates the existence of interaction between the nucleobases and CB7. In addition, the number of intermolecular BCP’s, RCP’s and CCP’s exists in the inclusion complexes differs by the guest molecule. Among the inclusion

The Laplacian of electron density at all the BCPs are negative, indicating the presence of covalent interaction between the guest and host molecule. However, the H(cp) obtained in the intermolecular interactions are positive for the inclusion complexes formed with the guest’s adenine, cytosine, guanine and uracil, indicating the existence of noncovalent interaction. Therefore, the intermolecular bonds in these systems can be classified under a category with partially covalent and with a partial electrostatic in character. Further, the ratio of the ratio of – G(cp)/V(cp) is > 1 ranging from 1.404 to 1.623, suggesting that these interactions could be of dispersive in nature. Earlier reports on hydrogen bonds have suggested to be composed of components representing covalent as well as electrostatic and van der Waals interactions to a varying degree.70,71



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

3.3.3. Non-covalent interactions The elegance of NCI-RDG analysis lines in its ability to provide the interaction in real-space, thereby enabling a graphical visualization of the regions where noncovalent interactions occur, which facilitates to understand the nature of interaction in different types of systems.72,73 The nature of bonding could be best described by the phenomenon of charge accumulation or depletion in a plane perpendicular to that of the interaction. The second eigenvalue (λ2) contains interesting information. For the bonding interaction, such as H-bond, λ2

Theoretical Investigation of the Binding of Nucleobases to

Recommend Documents