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β-cyclodextrin supramolecular structure: AIM, NBO analysis
Accepted Manuscript A hybrid MP2/DFT scheme for N-Nitroso-N-(2-chloroethyl)-N’-sulfamoylprolinate/β-Cyclodextrin supramolecular structure: AIM, NBO analysis Amel. Bouzitouna, Djameleddine. Khatmi, Ouassila. Attoui-Yahia PII: DOI: Reference:
S2210-271X(16)30490-X http://dx.doi.org/10.1016/j.comptc.2016.12.004 COMPTC 2321
To appear in:
Computational & Theoretical Chemistry
Received Date: Revised Date: Accepted Date:
11 June 2016 20 September 2016 2 December 2016
Please cite this article as: Amel. Bouzitouna, Djameleddine. Khatmi, Ouassila. Attoui-Yahia, A hybrid MP2/DFT scheme for N-Nitroso-N-(2-chloroethyl)-N’-sulfamoylprolinate/β-Cyclodextrin supramolecular structure: AIM, NBO analysis, Computational & Theoretical Chemistry (2016), doi: http://dx.doi.org/10.1016/j.comptc. 2016.12.004
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A hybrid MP2/DFT scheme for N-Nitroso-N-(2-chloroethyl)-N’sulfamoylprolinate/β-Cyclodextrin supramolecular structure: AIM, NBO analysis Amel. BOUZITOUNAa, Djameleddine. KHATMIb , Ouassila. ATTOUI-YAHIAc, a. Department of chemistry, Badji-Mokhtar University, Annaba, Algeria b. Laboratory of computational chemistry and nanostructures BP: 401, University of Guelma, Algeria c. Applied Organic Chemistry Laboratory, Department of Chemistry, Faculty of Science, BadjiMokhtar University, BP 12 Annaba, Algeria
[email protected]
graphical abstract
Abstract: N-Nitroso-N-(2-chloroethyl)-N’-sulfamoylprolinate (CENS-proline) is a poorly water soluble antineoplastic drug, and to improve its solubility and bioavailability it was experimentally complexed with β -cyclodextrin. To predict the 3-dimensional arrangement of host-guest systems, a complete conformational analysis has been done using PM7 and ONIOM2 hybrid calculations. Both PM7 and ONIOM2 result have revealed that CENS-prolinate drug is totally encapsulated inside the β -cyclodextrin cavity, in consistency with experimental observation. Our calculations reasonably illustrated that using (MP2/6-31G*: B3LYP /3-21G*) combination describe considerably better the geometry of the system than other DFT methods. To highlight the nature of supramolecular interactions and their impacts to the encapsulation process phenomena, the NBO analysis demonstrates that the hydrogen bonds interactions are of type N=O···H and S=O···H with stabilization energies greater than 9 and 5 kcal mol-1 respectively. Based on our AIM results, the acceptable ρ, λ1, λ2, λ3 and positive ∇2ρ values confirmed efficient and non-covalent interaction between CENS-prolinate and β-CD.
Key words: 'β-Cyclodextrin', 'HOMO-LUMO Analysis', 'ONIOM', 'PM7', MP2', 'AIM'.
1. Introduction The frontiers of modern medicinal chemistry largely involved macromolecular host–guest systems in the molecular drugs design of novel effective therapeutics [1]. The vital role of CDs in many key chemical and biological processes, and the complexity of their structural and physical phenomena lead to increasing interest on CDs supramolecular ensembles, stimulating more and more research efforts [1]. Cyclodextrins (CDs) are biodegradable cyclic oligosaccharides classified by the number of D-(+) - glucopyranose subunits which typically numbers six (α–cyclodextrin), seven (β– cyclodextrin) and eight (γ–cyclodextrin) arranged in a truncated cone shape structure, shown in (Fig. 1a).
Fig. 1. Optimized geometrical structures of (a) β -CD and (b) CENS-prolinate calculated at B3LYP/6-31G* level of theory.
Many hydroxyl groups delineate the outside part of the ring, which make the cyclodextrin both hydrophilic and soluble in water [2]. In terms of lipophilic micro-environment cavity, cyclodextrin can host a large variety of organic and inorganic compounds of suitable size [3] with biological activity might be embedded. The specific structure of the cyclodextrine present remarkable properties in improving aqueous solubility, chemical stability, and bioavailability of drugs, nevertheless, the inclusion complexes can exhibit considerable thermodynamic stability [4]. The binding forces between host and guest molecule belong to weak interactions such as van der Waals and hydrophobic interactions and non-covalent hydrogen bonding interactions [5]. 2-Chloroethylnitrosoureas (CENU) are recognized as bifunctional alkylation agents, which have important clinical applications for the treatment variety of hematological and solid tumors. However, their clinical usefulness has been limited by toxic and carcinogenic side effect [6]. N-nitroso-N-(2-chloroethyl)-N’-sulfamoylprolinate (CENS-prolinate) is a new component presented very promising anticancer properties against a variety of tumors, which was synthesized
from
the
2-Chloroethylnitrosoureas
(CENU)
structure,
without
any
carbamoylating activity. See (Fig. 1b) [7]. Most of the chemotherapeutic agents discarded due to their poor aqueous solubility, these molecules are associated with poor physicochemical and biopharmaceutical properties that hinder the effectiveness of chemotherapy. An important approach in this regard is the use of combination of β-cyclodextrin and nanotechnology in delivery system. A systematic experimental study carried out by M. Kadri et al. [8] investigated the physicochemical property of the host/guest complex and evaluated the complexation ability of β-cyclodextrin with CENS-prolinate drug using UV–visible spectroscopy and 1H, 13C and
15N NMR techniques; they reported that CENS-prolinate molecule has some instability and poor water solubility. These properties clearly improved by the formation of inclusion complexe with β-CD [9].The 1HNMR spectra Analysis confirmed the formation of a 1:1 [host:guest] stoichiometric complex. In general, the experimental approaches provide indirect information on the complex geometries and their encapsulation process; it is often difficult to obtain detailed host–guest interaction mechanisms [10]. To overcome these drawbacks, we suggest in the current paper a systematic computational methodology to describe complexation energy of the CENS-prolinate /β-CD system with the aim to have some structural information about the geometry, electronic properties and the driving forces governing the formation of the inclusion complex. The present work is organized as follows.
First, to examine in detail the insertion
pathways we have investigated the docking processes of CENS-prolinate with the β-CD molecule using the parameterized model seven PM7 quantum semiempirical method [11, 12]. In the second part of work, we extend our investigation with an ONIOM (Our Own Nlayer Integrated molecular Orbital and molecular Mechanics Mechanics) [13, 14] hybrid calculation. More specifically, we have used (DFT/DFT) and (MP2/DFT) combinations. Finally, for more information about the nature of the nonbonding interactions occuring between host and guest molecules, the study was completed using natural bond orbital (NBO) [15] and topology analysis technique proposed by Bader for analyzing electron charge density in "atoms in molecules" (AIM) theory [16, 17]. 2. Structure entry and computational methods
The quantum chemical investigation of host–guest inclusion complex were performed with MOPAC 2012 (Molecular Orbital Package, version12.301W) [18] and GAUSSIAN 09 [19] software package, The input files for both programs were prepared and visualized by GaussView 5.0 [20] and Gabidit (version 2.4.5) [21] programs respectively. The individual CENS-prolinate structure sketched using Chem3D Ultra Cambridge soft (version 10.0), and the β-CD crystallographic structure was taken from its Cambridge Structural Database (CSD). Starting host and guest geometries were fully optimized using the density functional theory (DFT) method with B3LYP hybrid exchange-correlation functional using standard split valence 6-31G* basis set. See (Fig. 2).
Fig. 2. Schematic illustration of the CENS-prolinate binding mode inside β-CD cavity forming both orientations.
The Different conformers of CENS-prolinate/β-CD complex constructed following the procedure described in reference [22]. Shown in (Fig. 2) .Briefly; the β-CD center defined as the origin of the coordinate system, then their glycosidic oxygen atoms positioned onto the plane, afterwards the -
and -
groups were pro ected into
space.
he
N
guest bond initially placed along the Z-axis and the guest position determined by the Zcoordinate of the sulfur atom. Two possible orientations of the guest molecule in the complex: Orientation 1: the alkyl group point toward the secondary hydroxyl of β–CD. Orientation 2: the proline cycle points toward the secondary hydroxyl of β–CD. he docking was started by keeping β-CD molecule at a fixed position (center) and moving the guest molecule along the Z-axis from +6 to –6, at 1Å intervals by steps. To attain optimized structure, the conformational searches evaluated in two steps. at the first step, the guest molecule was rotated around the
N bond by 30° from 0° to
360°.The resulting geometries were converted into a MOPAC input file. In order to maximize the electrostatic and hydrophobic interaction between the host and the guest molecules, a second step is then achieved along the Z-axis from +1 to –2 with a stepwise of 1 A°. The CENS-prolinate molecule rotated around the Z-axis from 0° to 360° at 10° interval. It is worth mentioning that the initial structures studied at the second step are the most stables complexes obtained in the first step. The resulting geometry at both steps completely optimized using the semi-empirical quantum mechanics PM7method implemented in the MOPAC 2012 software package. The complexation and deformation energy was calculated for the minimum energy structures by the following equation Eq. (1) and Eq. (2): Ecomplexation=Ecomplex
(Eguest+Ehost)
DEF[component]= E[component]spopt
(1) E[component]opt
(2)
Where Ecomplex, Eguest and Ehost represent respectively the relative energies of complex, free CENS-proline and free β-CD molecules. Besides The deformation energy for each component, the guest or the host molecule, throughout the formation of the complex, was defined as the difference in the energy of the total optimized component compared to its energy in the complex. In order to understand the nature of electronic transitions within CENS-prolinate /β-CD complex, Using the molecular properties such as the orbital energies, HOMO the ionization potential (I) can be expressed as: I = -EHOMO and LUMO electron affinity (A) can be expressed as: A = -ELUMO, we can calculate the molecular properties such as Eq. (3) [23]: χ= (I+A)/2
(3)
μ = -χ
(4)
η = (I-A)/2
(5)
ω = μ2 / η
(6)
he electronic potential (μ) which is Eq. (4):
he hardness (η) Eq. (5):
And global electrophilicity index (ω) Eq. (6):
To improve the precision of the conformational analysis results, both CENS-prolinate /β-CD complexes were also completely optimized using the two-layered ONIOM-2 method. The full system called ‘‘real’’ is treated with an inexpensive model chemistry (low level of theory) and is divided into two layers is termed “models”:
Outer layer (β-CD) can be modeled with low level of theory using DFT/B3LYP calculation.
Inner layer (CENS-prolinate) is treated at the high level of theory with four DFT functional (B3LYP, M05-
, ωB97 -D and B3PW91) and the second order Møller-
Plesset method (MP2). Herein, the medium 6-31G(d) basis set was applied to CENS-prolinate model , the most important part, and the small 3-21G(d) basis set to cyclodextrin molecule which is considered as environment. The total ONIOM energy EONIOM is given by Eq. (7): EONIOM = E (high; model) + E (low; real) E (low; model)
(7)
Where E (high, model) is the energy of the guest, E (low, real) is the energy of the complex, and E (low, model) is the energy of the host. In order to understand the structure-property relationship, The second-order Fock matrix was used to evaluate the donor–acceptor interactions at the B3LYP/6-311G(d,p) level employing the NBO 3.1 program [24] implemented in the Gaussian 09 package. Finally, The wave function generated from the previously single point calculation (B3LYP/611G(d,p)), was used for calculated the topological properties such as electron density ρ, Laplacian of electron density ∇2ρ and eigenvalues (λ) of the
essian matrix at the bond
critical points BCPs, employing the Bader’s theory of ‘Atoms in Molecules’ implemented in AIM 2000 software [25, 26] . 3. Results and discussions 3.1 Energy and geometries of the minima The graphical representation of the energy changes involved during the inclusion process of CENS-prolinate in β-CD cavity at different Z positions for both orientations are illustrated in (Fig. 3).
step 1
step 2
-30
complexation energy ( Kcal mol-1)
-40 -50 -60 -70 -80 -90
Orientation 1
-100 -110 -120 -6
-5
-4
-3
-2
-1
0
1
2
3
4
5
6
Z coordinate (Å)
step 1
step 2
complexation energy ( Kcal mol-1)
-30 -40 -50 -60 -70 -80 -90
-100
Orientation 2
-110 -120 -130 -6
-5
-4
-3
-2
-1
0
1
2
3
4
5
6
Z coordinate (Å)
Fig. 3. Complexation energies profile of CENS-proline /β-CD complex at different positions Z (PM7 calculations).
Stepe 1: The complexation energy of both orientations is negative at each distance from -6 A˚ to
6 A˚, which indicates that the inclusion process of the CENS-prolinate in the β –CD
cavity is energetically favorable and has a good agreement with experimental data. The variation of the complexation energy during the inclusion process indicated that the complexes adopt inclusion geometry in which the CENS-prolinate structure fully embedded inside the β-CD cavity. Step 2: To maximize the electrostatic and hydrophobic interaction between the host and the guest molecules of both orientations, we have focused our Conformational analysis from –2 to +1A°. As we can see from (Fig. 3 step 2), the energies of the minima for both configurations stretch over a range of -55.81 to -121.27kcal mol-1and from -61.96 to -107.45 kcal mol-1 for orientation 2 and orientation1 respectively. On the other hand, the most stable structure is obtained at Z = -2 Å for orientation2 and Z is equal to 0 Å for the orientation 1. The main results obtained for the CENS-prolinate /β-CD complex are compiled in Table 1.Our calculations show that Orientation 2 is significantly more favorable than orientation 1 by an energy difference of -13.825kcal mol-1. Table 1 Complexation and deformation energies (kcal mol-1) measured by PM7 method of the optimal conformations for both orientations. Orientation 1
Orientation2
∆E
Ecompl (kcal mol-1)(PM7)
-107.453
-121.278
-13.825
DEF guest(kcal mol-1)
19.255
20.183
DEF host(kcal mol-1)
43.991
51.599
In addition, the results indicate that the deformation energy of the β-CD molecule is higher than that of CENS-prolinate in both orientations. he β-CD molecule in Orientation2 needs more energy than in the Orientation1. This can prove the fact that the flexibility of the host structure is an important structural requirement for the complexation. CENS-prolinate molecule in Orientation2 complex needs a little more energy than for Orientation1 in order to adapt its structure to bind inside the β-CD cavity. It can be seen, from the favorable structures proposed with PM7 method for both orientations depicted in the (Fig. 4). The CENS-prolinate is totally embedded in host cavity and we could notice the formation of a considerable number of hydrogen bonds , defined as N=O···H and S=O···H , C=O···H H-bonds, with bond lengths inferior than .5 A˚ and the angle at hydrogen atom is greater than 90°.
Fig. 4. Energy-minimized structures (PM7) of the 1: 1 CENS-prolinate /β-CD complexes; Side view (a) Top view (b).
3.2 HOMO-LUMO parameters The energy levels of frontier molecular orbitals is an important value, which can used as an indicator of stability and chemical reactivity of the host /guest systems. Therefore, we can discover that how host/guest molecules interact and where is the active sites in reaction. The energies of the frontier molecular orbitals EHOMO and ELUMO, HOMO–LUMO gap, electronegativity(X), electronic potential (μ), hardness (η) and global electrophilicity index (ω) for the title compound calculated using the PM7 semiempirical method are presented in Table 2. Table 2 Frontier molecular orbital energies, HOMO–LUMO gap and global reactivity descriptors for CENS-prolinate /β-CD complex calculated at PM7method. β-CD
CENS-prolinate Orientation 1 Orientation2
HF(kcal mol-1)
-1580.16917
-169.24106
-1793.61756
-1798.90675
EHOMO (ev)
-10.286
-10.154
-10.061
-10.032
ELUMO (ev)
0.676
-0.980
-1.402
-1.053
EHOMO - ELUMO (ev)
-10.962
-9.174
-8.659
-8.979
Chemical potential,
µ (ev)
-4.805
-5.567
-5.7315
-5.542
Chemical hardness,
η (ev)
5.481
4.587
4.329
4.489
2.106
3.378
3.793
3.421
Global electrophilicity index,
ω(ev)
It is clearly mentioned in Table 2, that the HOMO–LUMO energy gap value is of 8.659eV for orientation1 and -8.979 eV for orientation 2, which advocates that this complex is more stable than the last one. This value explains the partial charge transfer of electron from the HOMO to the LUMO orbital , which influences the biological activity (the electronic structures) of the guest molecule. The relatively high value of HOMO–LUMO indicates that the title compound presents high chemical stability and it has low reactivity. This result was in good agreement with the complexation energy, and the chemical potential (μ˂0) which means the encapsulation spontaneous. Further large global electrophilicity index (ω= .4 1 eV) explains its encapsulation within β-CD cavity is favoured. The Electrostatic potential contour map are helpful in understanding the effective localization of electron density in the CENS-prolinate /β-CD supramolecular systems, The ESP maps for both orientation are shown in (Fig. 5).
Fig. 5. Structure of a) orientation 1 b) orientation 2 and c) free β-CD giving 2D contours of Electrostatic surface potential (ESP) showing the concentration of negative charges in the center of the cavity
3.3 ONIOM calculation In order to confirm our results obtained by PM7 calculations, a variety of ONIOM2 combinations have been proposed [DFT : DFT] and [MP2 : DFT] approaches. The geometries were also compared to the standard method full DFT [B3LYP6-311G*], with the aim to perform a more precise inspection on the geometry and electronic structure of the CENSprolinate /β-CD complex. For that, we choose the following levels of ONIOM2 calculations: The mixed model [MP2/6-31(g,d) : B3LYP/3-21(g,d) ] uses the second order of Møller–Presset perturbation theory (MP2) to model the guest and density functional theory (DFT) to describe the host
geometry. A non-mixed model is that in which density functional theory (DFT) applied to both molecules, but with different basis set. The ONIOM2 results reported in Table 3 follow the same trend as the PM7 optimizations. Regarding the ONIOM2 methods, we can point out that both combinations, ONIOM(MP2/631G*: B3LYP /3-21G*) and ONIOM(B3LYP /6-31G*:B3LYP/3-21G*), give relatively acceptable values relative to target value, being equal respectively to -26.831 and -13.137kcal mol-1; In hybrid [MP2:DFT] calculations smaller H-bond lengths appear compared to the DFT/ DFT and full DFT methods. Table 3
The Ecompl (kcal mol-1) complexation energies computed with ONIOM and full DFT method of CENS-prolinate /β-CD complex calculated for both orientations Not Mixed Scheme with
Mixed Scheme with
ONIOM(QM/6-31G*:B3LYP/3-21G*)
ONIOM(MP2/6-31G*: B3LYP /3-21G*)
Full B3LYP6-311G*
B3PW91
ωB97X-D
M05-2X
B3LYP
Orientation 1
-74.895
-74.071
-74.074
-60.931
-74.728
-13.553
Orientation2
-87.281
-86.652
-86.748
-87.762
-87.865
-23.388
-12.386
-12.58
-12.674
-26.831
-13.137
-9.835
ΔE(kcal
mol-1)
MP2-FC
The ONIOM2 (MP2/6-31G*: B3LYP /3-21G*) optimized structures of both complexes are presented in (Fig. 6).
Fig. 6. The intermolecular hydrogen bond at each energy minimum obtained by the ONIOM2 (MP2/6-31G*: B3LYP /3-21G*) calculations for both orientations.
Geometrical analysis of The preferred penetration mode displayed in (Fig. 6) suggest that using MP2 method as a high level describes considerably better the geometry of the system than other DFT methods.
We could notice that the stability of orientation 2 is governed by the presence of three intermolecular H-bonds in the structure. For both structures the N=O bond is located in the hydrophobic environment attached to the β-CD cavity with several hydrogen bonds .The results also agree well with the experimental data of these complexes. Figure. 7 illustrates the frontier molecular orbital HOMO and LUMO energy pictures for orientation 2.
Fig. 7. Plot of the highest occupied molecular orbitals and lowest vacant MOs of CENSprolinate /β-CD complex (for orientation 2)
4. Hydrogen binding investigation The structure of the complex obtained with ONIOM2 (MP2/6-31G*: B3LYP /3-21G*) method for both orientations shows the presence of several strong intermolecular Hydrogen bonds which are denoted by dashed lines, and the corresponding H···O distances are labeled in (Fig. 6). In order to analyze the intermolecular hydrogen bond interactions, two methodologies were used: the topological analysis of the electron density within the AIM method and the Natural Bond Orbital (NBO). In the AIM approach, the presence/absence of an interatomic BCP determines the existence/non-existence of a HB interaction [27, 28]. In contrast, in the
NBO method, a numerical value is obtained for the interaction of the lone pair of the oxygen atom with the σ*
−
orbital [29]. The AIM and NBO analysis will be discussed separately
first and then compared. 4.1.The topological properties of interactions :AIM study Geometrical as well as topological parameters are handy tool to characterize the strength of hydrogen bond [30] . The geometrical criteria for the existence of hydrogen bond are as follows:
The proton H···A acceptor distance should be less than the sum of the Van der Waal’s radii of these atoms.
The angle between proton (H) donor and acceptor (A) should be greater than 90°.
The theory of atoms in molecules (AIM) mainly based on electron density ρ(r) [31] :
The presence of (3,-1) bond critical point (BCP) for the proton H···A acceptor contact as a confirmation of the existence of hydrogen bonding interaction.
The electron density (ρ ...A) value must be within the range ,from 0.002 to 0.04 a.u.
The corresponding Laplacian - ∇2ρ (rBCP) should be within the range 0.024–0.139 a.u.
he topological parameters of analyzed hydrogen bonds such as ρBCP, -∇2ρBCP, λ1, λ2, λ3 and ε bond ellipticity have been gathered in the following table.
Table 4 Summary of AIM analysis for the compounds under study using MP2/6-31G*: B3LYP /31G* method. he selected topological parameters are the electron density (ρBCP), its Laplacian (-∇2ρBCP) and eigenvalues (λi) of Hessian (a.u).
ρ(r)
-∇2ρ
λ1
λ2
λ3
ε*
Interactions
Bond length
O 60···H 172
2.1
0.0208 -0.0214 -0.0294 -0.0283 0.1434 0.03886
O157···H 133
1.9
0.0227 -0.0236 -0.0347 -0.0343 0.1635 0.01166
O 74···H 174
1.9
0.0360 -0.0263 -0.0547 -0.0534 0.2133 0.02434
O 155···H 138
1.8
0.0314 -0.0259 -0.0501 -0.0498 0.2039 0.00602
O 161···H 145
1.8
0.0400 -0.0280 -0.0676 -0.0652 0.2448 0.03680
*ε = (λ1/ λ2) -1.
Interaction O (161) ---H (145)
Interaction O (157) ---H (133)
Interaction O (155) ---H (138)
Fig. 8. Molecular graph of CENS-prolinate /β-CD complex. The graph was obtained at the MP2/6-31G*: B3LYP /3-21G* level. Geometrical parameters such as distance between interacting atoms ( … ) and bond angle (D― … ) are in agreement with the hydrogen-bonding criteria.
In the current study all the values of ρBCP and -∇ 2ρBCP fall within the proposed typical range of the H-bonds. Positive values of Laplacian ∇ 2ρBCP in Table 4 are indicative of depletion of electronic charge along the bond path, which is characteristic of closed shell interactions such as hydrogen bonds; are on the high side of the requirements to define a hydrogen bond and thus a strong interaction maybe concluded. The molecular graphs illustrated in (Fig. 8) include the critical points and bond paths of the most interactions previously discussed in this section as obtained from AIM analysis. The intermolecular hydrogen bonding predicted by the large values of electronic density ρBCP and Laplacian-∇ 2ρBCP of N160 O161···H145, S156O157····H133and C153O155···H138 are consistent with the short distances of their hydrogen bonds, showing a clear relationship between the topological properties of the charge density in hydrogen-bonded systems and the inter-nuclear distances of the systems. Such results suggest that the stability of the favorable complex could be attributed to the above stronger H-bonds interaction. he sum of negative curvatures (λ1 H···
λ2) as well as the positive ones (λ3) decreases with
distances, where λ1 < λ2 < 0 < λ3 are the Hessian eigenvalues of the electron density at
BCP.This indicates that depletion of electron density along the bond path is accompanied with accumulation of electron density in the plane perpendicular to the bond path. The lower values of ellipticity index confirm that there is electron delocalization through the corresponding atoms. 4.2.Natural Bond order analysis (NBO) The aim of this section is to discern the extent of hydrogen bonding contacts using NBO analysis results. The NBO analysis was performed at MP2/6-31G*: B3LYP /3-21G*level of theory, the stabilization energy (E
(2)
) is used to characterize the interaction between occupied
Lewis-type NBO orbitals and formally unoccupied non-Lewis NBO orbitals which act the
delocalization trend of electrons from the bonding (BD) or nonbonding orbitals (LP) to the anti-bonding orbitals (BD*) [32]. Stabilization energy (E (2)) associated as a result of electron delocalization between donor NBO (i) and acceptor NBO (j), is estimated by following equation:
Where
is the donor orbital occupancy; E (i) and E (j) are orbital energies of donor and
acceptor NBO orbitals and Fij is the off-diagonal Fock matrix. The most important delocalization of electron densities are those arise from electron lone pairs (LP) of oxygen atoms as donors and OH bonds as acceptors. Their corresponding energies collected in (Table 5) show that the E(2) values are increased with shortening hydrogen bonds distance d(O. . .H). All the HBs predicted by the AIM method are confirmed by the NBO analysis In the most stable complex CENS-prolinate /β-CD generated from Orientation 2, when the CENS-proline is regarded as a donor, the important H-bonds observed are:
The first interaction localized between the LP (O161) and the BD* (H145) of the O73–H145 bond is positioned at 1.8 Å with an O16⋯H73–O145 angle of 165.7°. The corresponding energy is estimated to 9.27kcal mol-1.
The second one is between the LP (O157) and the BD* (H133) of the O53 –H133 bond; positioned at 1.9 Å with an O157⋯H133–O53 angle of 162.5°. The energy of this H-bond is estimated to 5.15kcal mol-1.
The third one is located between the LP (O155) and the BD* (H138) of the O62–H138 bond; positioned at 1.8 Å with an O155⋯ H138– O62 angle of 162.7°. The estimated energy is 5.23kcal mol-1.
Table 5 Some donor–acceptor interactions in CENS-prolinate /β-CD complex and their second order perturbation stabilization energies, E(2) (kcal mol-1) ,distances and angles for orientation
Donor NBO (i)
Acceptor NBO (j)
ONIOM2 (MP2/6-31G*: B3LYP /3-21G*) d(Å)
Angle(°)
E(2) (kcal/mol)
β-CD proton donor and guest proton acceptor
LP O 60
BD*C 152 - H 172
2.1
172.5
3.65
LP O 74
BD*C 162 - H 174
1.9
154.8
2.75
LP O 74
BD*C 162 - H 174
1.9
154.8
6.49
Guest proton donor and β-CD proton acceptor
LP O 155
BD*O 62 - H 138
1.8
162.7
5.23
LP O 155
BD*O 62 - H 138
/
/
2.57
LP O 157
BD*O 53 - H 133
1.9
162.5
5.15
LP O 161
BD*C
2.1
140.4
1.55
LP O 161
BD*O 73 - H 145
1.8
165.7
9.27
LP O 161
BD*O 73 - H 145
/
/
4.19
3 - H 80
In the case where β-CD is regarded as a donor, the important interaction is observed between the oxygen atom (O74) and the hydrogen atom (H174) of the C162–H174 bond. The energy of this H-bond is estimated to 6.49kcal/mol (1.9Å, 154.8°). According to generated NBO results, we can say that the intermolecular hydrogen interactions in the CENS-prolinate /β- CD inclusion complexes play an essential role with regard to the stability of these complexes. The data of AIM analysis leads to conclusions, which are in agreement with the data of NBO analysis.
5. Conclusion A complete structural, thermodynamic, and electronic investigation along with NBO analysis and AIM approach of the supramolecular interaction of CENS-prolinate with β-CD
have been carried out with ("parametrized model seven") PM7 and ONIOM and DFT (B3LYP/6-311G(d))method. The results obtained by employing PM7 method provide important insights into the geometry and the interactions between CENS-prolinate and β-CD molecules. The relatively high value of ∆EHOMO–LUMO energy gap indicates that the title compound presents high chemical stability. In the second part of this research, calculations performed at ONIOM method clearly show that orientation 2 is more favorable than orientation 1, in good agreement with PM7 results. The best results are obtained with the ONIOM (MP2/6-31G*: B3LYP /3-21G*) combination. The CENS-proline (N=O)bond is located in the hydrophobic environment attached to the β-CD cavity with several hydrogen bonds .The results also agree well with the experimental
data of these complexes. The obtained simulation results indicating that [MP2/6-31(g,d) : B3LYP/3-21(g,d) ] hybrid method is suitable for the proposed study. Finally, the AIM and NBO methodologies were used in order to discuss the origin of conformational preference and hydrogen bond strength. It has been concluded from the obtained results that the hydrogen bonding is the major factor contributing to the overall stability of the complexation. Acknowledgements This study was supported by the Algerian Ministry of Higher Education and Scientific Research and the General Direction of Scientific Research, the General Direction of Scientific Research and Technological Development (DGRSDT) and the National Research Fund (FNR). REFERENCES [1] B. Ivanova, M. Spiteller, Macromolecular ensembles of cyclodextrin crystallohydrates and clathrates experimental and theoretical gas and condense phase study, Int. J. Biol. Macromol. 64 (2014) 383–391.
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Highlights
N-Nitroso-N-(2-chloroethyl)-N’-sulfamoylproline (CENS-proline) Alkylating agent is a class of antineoplastic or anticancer drugs.
Theoretical study of CENS-proline /β-cyclodextrin inclusion complex using PM7 docking and hybrid QM:QM and MP2:QM calculation.
Thermodynamic parameters of complexation process are verified by PM7 calculation.
Strong hydrogen bonds are formed between host and guest moleculs
NBO and AIM analysis is used to study host/guest intramolecular interactions.
S2210-271X(16)30490-X http://dx.doi.org/10.1016/j.comptc.2016.12.004 COMPTC 2321
To appear in:
Computational & Theoretical Chemistry
Received Date: Revised Date: Accepted Date:
11 June 2016 20 September 2016 2 December 2016
Please cite this article as: Amel. Bouzitouna, Djameleddine. Khatmi, Ouassila. Attoui-Yahia, A hybrid MP2/DFT scheme for N-Nitroso-N-(2-chloroethyl)-N’-sulfamoylprolinate/β-Cyclodextrin supramolecular structure: AIM, NBO analysis, Computational & Theoretical Chemistry (2016), doi: http://dx.doi.org/10.1016/j.comptc. 2016.12.004
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A hybrid MP2/DFT scheme for N-Nitroso-N-(2-chloroethyl)-N’sulfamoylprolinate/β-Cyclodextrin supramolecular structure: AIM, NBO analysis Amel. BOUZITOUNAa, Djameleddine. KHATMIb , Ouassila. ATTOUI-YAHIAc, a. Department of chemistry, Badji-Mokhtar University, Annaba, Algeria b. Laboratory of computational chemistry and nanostructures BP: 401, University of Guelma, Algeria c. Applied Organic Chemistry Laboratory, Department of Chemistry, Faculty of Science, BadjiMokhtar University, BP 12 Annaba, Algeria
[email protected]
graphical abstract
Abstract: N-Nitroso-N-(2-chloroethyl)-N’-sulfamoylprolinate (CENS-proline) is a poorly water soluble antineoplastic drug, and to improve its solubility and bioavailability it was experimentally complexed with β -cyclodextrin. To predict the 3-dimensional arrangement of host-guest systems, a complete conformational analysis has been done using PM7 and ONIOM2 hybrid calculations. Both PM7 and ONIOM2 result have revealed that CENS-prolinate drug is totally encapsulated inside the β -cyclodextrin cavity, in consistency with experimental observation. Our calculations reasonably illustrated that using (MP2/6-31G*: B3LYP /3-21G*) combination describe considerably better the geometry of the system than other DFT methods. To highlight the nature of supramolecular interactions and their impacts to the encapsulation process phenomena, the NBO analysis demonstrates that the hydrogen bonds interactions are of type N=O···H and S=O···H with stabilization energies greater than 9 and 5 kcal mol-1 respectively. Based on our AIM results, the acceptable ρ, λ1, λ2, λ3 and positive ∇2ρ values confirmed efficient and non-covalent interaction between CENS-prolinate and β-CD.
Key words: 'β-Cyclodextrin', 'HOMO-LUMO Analysis', 'ONIOM', 'PM7', MP2', 'AIM'.
1. Introduction The frontiers of modern medicinal chemistry largely involved macromolecular host–guest systems in the molecular drugs design of novel effective therapeutics [1]. The vital role of CDs in many key chemical and biological processes, and the complexity of their structural and physical phenomena lead to increasing interest on CDs supramolecular ensembles, stimulating more and more research efforts [1]. Cyclodextrins (CDs) are biodegradable cyclic oligosaccharides classified by the number of D-(+) - glucopyranose subunits which typically numbers six (α–cyclodextrin), seven (β– cyclodextrin) and eight (γ–cyclodextrin) arranged in a truncated cone shape structure, shown in (Fig. 1a).
Fig. 1. Optimized geometrical structures of (a) β -CD and (b) CENS-prolinate calculated at B3LYP/6-31G* level of theory.
Many hydroxyl groups delineate the outside part of the ring, which make the cyclodextrin both hydrophilic and soluble in water [2]. In terms of lipophilic micro-environment cavity, cyclodextrin can host a large variety of organic and inorganic compounds of suitable size [3] with biological activity might be embedded. The specific structure of the cyclodextrine present remarkable properties in improving aqueous solubility, chemical stability, and bioavailability of drugs, nevertheless, the inclusion complexes can exhibit considerable thermodynamic stability [4]. The binding forces between host and guest molecule belong to weak interactions such as van der Waals and hydrophobic interactions and non-covalent hydrogen bonding interactions [5]. 2-Chloroethylnitrosoureas (CENU) are recognized as bifunctional alkylation agents, which have important clinical applications for the treatment variety of hematological and solid tumors. However, their clinical usefulness has been limited by toxic and carcinogenic side effect [6]. N-nitroso-N-(2-chloroethyl)-N’-sulfamoylprolinate (CENS-prolinate) is a new component presented very promising anticancer properties against a variety of tumors, which was synthesized
from
the
2-Chloroethylnitrosoureas
(CENU)
structure,
without
any
carbamoylating activity. See (Fig. 1b) [7]. Most of the chemotherapeutic agents discarded due to their poor aqueous solubility, these molecules are associated with poor physicochemical and biopharmaceutical properties that hinder the effectiveness of chemotherapy. An important approach in this regard is the use of combination of β-cyclodextrin and nanotechnology in delivery system. A systematic experimental study carried out by M. Kadri et al. [8] investigated the physicochemical property of the host/guest complex and evaluated the complexation ability of β-cyclodextrin with CENS-prolinate drug using UV–visible spectroscopy and 1H, 13C and
15N NMR techniques; they reported that CENS-prolinate molecule has some instability and poor water solubility. These properties clearly improved by the formation of inclusion complexe with β-CD [9].The 1HNMR spectra Analysis confirmed the formation of a 1:1 [host:guest] stoichiometric complex. In general, the experimental approaches provide indirect information on the complex geometries and their encapsulation process; it is often difficult to obtain detailed host–guest interaction mechanisms [10]. To overcome these drawbacks, we suggest in the current paper a systematic computational methodology to describe complexation energy of the CENS-prolinate /β-CD system with the aim to have some structural information about the geometry, electronic properties and the driving forces governing the formation of the inclusion complex. The present work is organized as follows.
First, to examine in detail the insertion
pathways we have investigated the docking processes of CENS-prolinate with the β-CD molecule using the parameterized model seven PM7 quantum semiempirical method [11, 12]. In the second part of work, we extend our investigation with an ONIOM (Our Own Nlayer Integrated molecular Orbital and molecular Mechanics Mechanics) [13, 14] hybrid calculation. More specifically, we have used (DFT/DFT) and (MP2/DFT) combinations. Finally, for more information about the nature of the nonbonding interactions occuring between host and guest molecules, the study was completed using natural bond orbital (NBO) [15] and topology analysis technique proposed by Bader for analyzing electron charge density in "atoms in molecules" (AIM) theory [16, 17]. 2. Structure entry and computational methods
The quantum chemical investigation of host–guest inclusion complex were performed with MOPAC 2012 (Molecular Orbital Package, version12.301W) [18] and GAUSSIAN 09 [19] software package, The input files for both programs were prepared and visualized by GaussView 5.0 [20] and Gabidit (version 2.4.5) [21] programs respectively. The individual CENS-prolinate structure sketched using Chem3D Ultra Cambridge soft (version 10.0), and the β-CD crystallographic structure was taken from its Cambridge Structural Database (CSD). Starting host and guest geometries were fully optimized using the density functional theory (DFT) method with B3LYP hybrid exchange-correlation functional using standard split valence 6-31G* basis set. See (Fig. 2).
Fig. 2. Schematic illustration of the CENS-prolinate binding mode inside β-CD cavity forming both orientations.
The Different conformers of CENS-prolinate/β-CD complex constructed following the procedure described in reference [22]. Shown in (Fig. 2) .Briefly; the β-CD center defined as the origin of the coordinate system, then their glycosidic oxygen atoms positioned onto the plane, afterwards the -
and -
groups were pro ected into
space.
he
N
guest bond initially placed along the Z-axis and the guest position determined by the Zcoordinate of the sulfur atom. Two possible orientations of the guest molecule in the complex: Orientation 1: the alkyl group point toward the secondary hydroxyl of β–CD. Orientation 2: the proline cycle points toward the secondary hydroxyl of β–CD. he docking was started by keeping β-CD molecule at a fixed position (center) and moving the guest molecule along the Z-axis from +6 to –6, at 1Å intervals by steps. To attain optimized structure, the conformational searches evaluated in two steps. at the first step, the guest molecule was rotated around the
N bond by 30° from 0° to
360°.The resulting geometries were converted into a MOPAC input file. In order to maximize the electrostatic and hydrophobic interaction between the host and the guest molecules, a second step is then achieved along the Z-axis from +1 to –2 with a stepwise of 1 A°. The CENS-prolinate molecule rotated around the Z-axis from 0° to 360° at 10° interval. It is worth mentioning that the initial structures studied at the second step are the most stables complexes obtained in the first step. The resulting geometry at both steps completely optimized using the semi-empirical quantum mechanics PM7method implemented in the MOPAC 2012 software package. The complexation and deformation energy was calculated for the minimum energy structures by the following equation Eq. (1) and Eq. (2): Ecomplexation=Ecomplex
(Eguest+Ehost)
DEF[component]= E[component]spopt
(1) E[component]opt
(2)
Where Ecomplex, Eguest and Ehost represent respectively the relative energies of complex, free CENS-proline and free β-CD molecules. Besides The deformation energy for each component, the guest or the host molecule, throughout the formation of the complex, was defined as the difference in the energy of the total optimized component compared to its energy in the complex. In order to understand the nature of electronic transitions within CENS-prolinate /β-CD complex, Using the molecular properties such as the orbital energies, HOMO the ionization potential (I) can be expressed as: I = -EHOMO and LUMO electron affinity (A) can be expressed as: A = -ELUMO, we can calculate the molecular properties such as Eq. (3) [23]: χ= (I+A)/2
(3)
μ = -χ
(4)
η = (I-A)/2
(5)
ω = μ2 / η
(6)
he electronic potential (μ) which is Eq. (4):
he hardness (η) Eq. (5):
And global electrophilicity index (ω) Eq. (6):
To improve the precision of the conformational analysis results, both CENS-prolinate /β-CD complexes were also completely optimized using the two-layered ONIOM-2 method. The full system called ‘‘real’’ is treated with an inexpensive model chemistry (low level of theory) and is divided into two layers is termed “models”:
Outer layer (β-CD) can be modeled with low level of theory using DFT/B3LYP calculation.
Inner layer (CENS-prolinate) is treated at the high level of theory with four DFT functional (B3LYP, M05-
, ωB97 -D and B3PW91) and the second order Møller-
Plesset method (MP2). Herein, the medium 6-31G(d) basis set was applied to CENS-prolinate model , the most important part, and the small 3-21G(d) basis set to cyclodextrin molecule which is considered as environment. The total ONIOM energy EONIOM is given by Eq. (7): EONIOM = E (high; model) + E (low; real) E (low; model)
(7)
Where E (high, model) is the energy of the guest, E (low, real) is the energy of the complex, and E (low, model) is the energy of the host. In order to understand the structure-property relationship, The second-order Fock matrix was used to evaluate the donor–acceptor interactions at the B3LYP/6-311G(d,p) level employing the NBO 3.1 program [24] implemented in the Gaussian 09 package. Finally, The wave function generated from the previously single point calculation (B3LYP/611G(d,p)), was used for calculated the topological properties such as electron density ρ, Laplacian of electron density ∇2ρ and eigenvalues (λ) of the
essian matrix at the bond
critical points BCPs, employing the Bader’s theory of ‘Atoms in Molecules’ implemented in AIM 2000 software [25, 26] . 3. Results and discussions 3.1 Energy and geometries of the minima The graphical representation of the energy changes involved during the inclusion process of CENS-prolinate in β-CD cavity at different Z positions for both orientations are illustrated in (Fig. 3).
step 1
step 2
-30
complexation energy ( Kcal mol-1)
-40 -50 -60 -70 -80 -90
Orientation 1
-100 -110 -120 -6
-5
-4
-3
-2
-1
0
1
2
3
4
5
6
Z coordinate (Å)
step 1
step 2
complexation energy ( Kcal mol-1)
-30 -40 -50 -60 -70 -80 -90
-100
Orientation 2
-110 -120 -130 -6
-5
-4
-3
-2
-1
0
1
2
3
4
5
6
Z coordinate (Å)
Fig. 3. Complexation energies profile of CENS-proline /β-CD complex at different positions Z (PM7 calculations).
Stepe 1: The complexation energy of both orientations is negative at each distance from -6 A˚ to
6 A˚, which indicates that the inclusion process of the CENS-prolinate in the β –CD
cavity is energetically favorable and has a good agreement with experimental data. The variation of the complexation energy during the inclusion process indicated that the complexes adopt inclusion geometry in which the CENS-prolinate structure fully embedded inside the β-CD cavity. Step 2: To maximize the electrostatic and hydrophobic interaction between the host and the guest molecules of both orientations, we have focused our Conformational analysis from –2 to +1A°. As we can see from (Fig. 3 step 2), the energies of the minima for both configurations stretch over a range of -55.81 to -121.27kcal mol-1and from -61.96 to -107.45 kcal mol-1 for orientation 2 and orientation1 respectively. On the other hand, the most stable structure is obtained at Z = -2 Å for orientation2 and Z is equal to 0 Å for the orientation 1. The main results obtained for the CENS-prolinate /β-CD complex are compiled in Table 1.Our calculations show that Orientation 2 is significantly more favorable than orientation 1 by an energy difference of -13.825kcal mol-1. Table 1 Complexation and deformation energies (kcal mol-1) measured by PM7 method of the optimal conformations for both orientations. Orientation 1
Orientation2
∆E
Ecompl (kcal mol-1)(PM7)
-107.453
-121.278
-13.825
DEF guest(kcal mol-1)
19.255
20.183
DEF host(kcal mol-1)
43.991
51.599
In addition, the results indicate that the deformation energy of the β-CD molecule is higher than that of CENS-prolinate in both orientations. he β-CD molecule in Orientation2 needs more energy than in the Orientation1. This can prove the fact that the flexibility of the host structure is an important structural requirement for the complexation. CENS-prolinate molecule in Orientation2 complex needs a little more energy than for Orientation1 in order to adapt its structure to bind inside the β-CD cavity. It can be seen, from the favorable structures proposed with PM7 method for both orientations depicted in the (Fig. 4). The CENS-prolinate is totally embedded in host cavity and we could notice the formation of a considerable number of hydrogen bonds , defined as N=O···H and S=O···H , C=O···H H-bonds, with bond lengths inferior than .5 A˚ and the angle at hydrogen atom is greater than 90°.
Fig. 4. Energy-minimized structures (PM7) of the 1: 1 CENS-prolinate /β-CD complexes; Side view (a) Top view (b).
3.2 HOMO-LUMO parameters The energy levels of frontier molecular orbitals is an important value, which can used as an indicator of stability and chemical reactivity of the host /guest systems. Therefore, we can discover that how host/guest molecules interact and where is the active sites in reaction. The energies of the frontier molecular orbitals EHOMO and ELUMO, HOMO–LUMO gap, electronegativity(X), electronic potential (μ), hardness (η) and global electrophilicity index (ω) for the title compound calculated using the PM7 semiempirical method are presented in Table 2. Table 2 Frontier molecular orbital energies, HOMO–LUMO gap and global reactivity descriptors for CENS-prolinate /β-CD complex calculated at PM7method. β-CD
CENS-prolinate Orientation 1 Orientation2
HF(kcal mol-1)
-1580.16917
-169.24106
-1793.61756
-1798.90675
EHOMO (ev)
-10.286
-10.154
-10.061
-10.032
ELUMO (ev)
0.676
-0.980
-1.402
-1.053
EHOMO - ELUMO (ev)
-10.962
-9.174
-8.659
-8.979
Chemical potential,
µ (ev)
-4.805
-5.567
-5.7315
-5.542
Chemical hardness,
η (ev)
5.481
4.587
4.329
4.489
2.106
3.378
3.793
3.421
Global electrophilicity index,
ω(ev)
It is clearly mentioned in Table 2, that the HOMO–LUMO energy gap value is of 8.659eV for orientation1 and -8.979 eV for orientation 2, which advocates that this complex is more stable than the last one. This value explains the partial charge transfer of electron from the HOMO to the LUMO orbital , which influences the biological activity (the electronic structures) of the guest molecule. The relatively high value of HOMO–LUMO indicates that the title compound presents high chemical stability and it has low reactivity. This result was in good agreement with the complexation energy, and the chemical potential (μ˂0) which means the encapsulation spontaneous. Further large global electrophilicity index (ω= .4 1 eV) explains its encapsulation within β-CD cavity is favoured. The Electrostatic potential contour map are helpful in understanding the effective localization of electron density in the CENS-prolinate /β-CD supramolecular systems, The ESP maps for both orientation are shown in (Fig. 5).
Fig. 5. Structure of a) orientation 1 b) orientation 2 and c) free β-CD giving 2D contours of Electrostatic surface potential (ESP) showing the concentration of negative charges in the center of the cavity
3.3 ONIOM calculation In order to confirm our results obtained by PM7 calculations, a variety of ONIOM2 combinations have been proposed [DFT : DFT] and [MP2 : DFT] approaches. The geometries were also compared to the standard method full DFT [B3LYP6-311G*], with the aim to perform a more precise inspection on the geometry and electronic structure of the CENSprolinate /β-CD complex. For that, we choose the following levels of ONIOM2 calculations: The mixed model [MP2/6-31(g,d) : B3LYP/3-21(g,d) ] uses the second order of Møller–Presset perturbation theory (MP2) to model the guest and density functional theory (DFT) to describe the host
geometry. A non-mixed model is that in which density functional theory (DFT) applied to both molecules, but with different basis set. The ONIOM2 results reported in Table 3 follow the same trend as the PM7 optimizations. Regarding the ONIOM2 methods, we can point out that both combinations, ONIOM(MP2/631G*: B3LYP /3-21G*) and ONIOM(B3LYP /6-31G*:B3LYP/3-21G*), give relatively acceptable values relative to target value, being equal respectively to -26.831 and -13.137kcal mol-1; In hybrid [MP2:DFT] calculations smaller H-bond lengths appear compared to the DFT/ DFT and full DFT methods. Table 3
The Ecompl (kcal mol-1) complexation energies computed with ONIOM and full DFT method of CENS-prolinate /β-CD complex calculated for both orientations Not Mixed Scheme with
Mixed Scheme with
ONIOM(QM/6-31G*:B3LYP/3-21G*)
ONIOM(MP2/6-31G*: B3LYP /3-21G*)
Full B3LYP6-311G*
B3PW91
ωB97X-D
M05-2X
B3LYP
Orientation 1
-74.895
-74.071
-74.074
-60.931
-74.728
-13.553
Orientation2
-87.281
-86.652
-86.748
-87.762
-87.865
-23.388
-12.386
-12.58
-12.674
-26.831
-13.137
-9.835
ΔE(kcal
mol-1)
MP2-FC
The ONIOM2 (MP2/6-31G*: B3LYP /3-21G*) optimized structures of both complexes are presented in (Fig. 6).
Fig. 6. The intermolecular hydrogen bond at each energy minimum obtained by the ONIOM2 (MP2/6-31G*: B3LYP /3-21G*) calculations for both orientations.
Geometrical analysis of The preferred penetration mode displayed in (Fig. 6) suggest that using MP2 method as a high level describes considerably better the geometry of the system than other DFT methods.
We could notice that the stability of orientation 2 is governed by the presence of three intermolecular H-bonds in the structure. For both structures the N=O bond is located in the hydrophobic environment attached to the β-CD cavity with several hydrogen bonds .The results also agree well with the experimental data of these complexes. Figure. 7 illustrates the frontier molecular orbital HOMO and LUMO energy pictures for orientation 2.
Fig. 7. Plot of the highest occupied molecular orbitals and lowest vacant MOs of CENSprolinate /β-CD complex (for orientation 2)
4. Hydrogen binding investigation The structure of the complex obtained with ONIOM2 (MP2/6-31G*: B3LYP /3-21G*) method for both orientations shows the presence of several strong intermolecular Hydrogen bonds which are denoted by dashed lines, and the corresponding H···O distances are labeled in (Fig. 6). In order to analyze the intermolecular hydrogen bond interactions, two methodologies were used: the topological analysis of the electron density within the AIM method and the Natural Bond Orbital (NBO). In the AIM approach, the presence/absence of an interatomic BCP determines the existence/non-existence of a HB interaction [27, 28]. In contrast, in the
NBO method, a numerical value is obtained for the interaction of the lone pair of the oxygen atom with the σ*
−
orbital [29]. The AIM and NBO analysis will be discussed separately
first and then compared. 4.1.The topological properties of interactions :AIM study Geometrical as well as topological parameters are handy tool to characterize the strength of hydrogen bond [30] . The geometrical criteria for the existence of hydrogen bond are as follows:
The proton H···A acceptor distance should be less than the sum of the Van der Waal’s radii of these atoms.
The angle between proton (H) donor and acceptor (A) should be greater than 90°.
The theory of atoms in molecules (AIM) mainly based on electron density ρ(r) [31] :
The presence of (3,-1) bond critical point (BCP) for the proton H···A acceptor contact as a confirmation of the existence of hydrogen bonding interaction.
The electron density (ρ ...A) value must be within the range ,from 0.002 to 0.04 a.u.
The corresponding Laplacian - ∇2ρ (rBCP) should be within the range 0.024–0.139 a.u.
he topological parameters of analyzed hydrogen bonds such as ρBCP, -∇2ρBCP, λ1, λ2, λ3 and ε bond ellipticity have been gathered in the following table.
Table 4 Summary of AIM analysis for the compounds under study using MP2/6-31G*: B3LYP /31G* method. he selected topological parameters are the electron density (ρBCP), its Laplacian (-∇2ρBCP) and eigenvalues (λi) of Hessian (a.u).
ρ(r)
-∇2ρ
λ1
λ2
λ3
ε*
Interactions
Bond length
O 60···H 172
2.1
0.0208 -0.0214 -0.0294 -0.0283 0.1434 0.03886
O157···H 133
1.9
0.0227 -0.0236 -0.0347 -0.0343 0.1635 0.01166
O 74···H 174
1.9
0.0360 -0.0263 -0.0547 -0.0534 0.2133 0.02434
O 155···H 138
1.8
0.0314 -0.0259 -0.0501 -0.0498 0.2039 0.00602
O 161···H 145
1.8
0.0400 -0.0280 -0.0676 -0.0652 0.2448 0.03680
*ε = (λ1/ λ2) -1.
Interaction O (161) ---H (145)
Interaction O (157) ---H (133)
Interaction O (155) ---H (138)
Fig. 8. Molecular graph of CENS-prolinate /β-CD complex. The graph was obtained at the MP2/6-31G*: B3LYP /3-21G* level. Geometrical parameters such as distance between interacting atoms ( … ) and bond angle (D― … ) are in agreement with the hydrogen-bonding criteria.
In the current study all the values of ρBCP and -∇ 2ρBCP fall within the proposed typical range of the H-bonds. Positive values of Laplacian ∇ 2ρBCP in Table 4 are indicative of depletion of electronic charge along the bond path, which is characteristic of closed shell interactions such as hydrogen bonds; are on the high side of the requirements to define a hydrogen bond and thus a strong interaction maybe concluded. The molecular graphs illustrated in (Fig. 8) include the critical points and bond paths of the most interactions previously discussed in this section as obtained from AIM analysis. The intermolecular hydrogen bonding predicted by the large values of electronic density ρBCP and Laplacian-∇ 2ρBCP of N160 O161···H145, S156O157····H133and C153O155···H138 are consistent with the short distances of their hydrogen bonds, showing a clear relationship between the topological properties of the charge density in hydrogen-bonded systems and the inter-nuclear distances of the systems. Such results suggest that the stability of the favorable complex could be attributed to the above stronger H-bonds interaction. he sum of negative curvatures (λ1 H···
λ2) as well as the positive ones (λ3) decreases with
distances, where λ1 < λ2 < 0 < λ3 are the Hessian eigenvalues of the electron density at
BCP.This indicates that depletion of electron density along the bond path is accompanied with accumulation of electron density in the plane perpendicular to the bond path. The lower values of ellipticity index confirm that there is electron delocalization through the corresponding atoms. 4.2.Natural Bond order analysis (NBO) The aim of this section is to discern the extent of hydrogen bonding contacts using NBO analysis results. The NBO analysis was performed at MP2/6-31G*: B3LYP /3-21G*level of theory, the stabilization energy (E
(2)
) is used to characterize the interaction between occupied
Lewis-type NBO orbitals and formally unoccupied non-Lewis NBO orbitals which act the
delocalization trend of electrons from the bonding (BD) or nonbonding orbitals (LP) to the anti-bonding orbitals (BD*) [32]. Stabilization energy (E (2)) associated as a result of electron delocalization between donor NBO (i) and acceptor NBO (j), is estimated by following equation:
Where
is the donor orbital occupancy; E (i) and E (j) are orbital energies of donor and
acceptor NBO orbitals and Fij is the off-diagonal Fock matrix. The most important delocalization of electron densities are those arise from electron lone pairs (LP) of oxygen atoms as donors and OH bonds as acceptors. Their corresponding energies collected in (Table 5) show that the E(2) values are increased with shortening hydrogen bonds distance d(O. . .H). All the HBs predicted by the AIM method are confirmed by the NBO analysis In the most stable complex CENS-prolinate /β-CD generated from Orientation 2, when the CENS-proline is regarded as a donor, the important H-bonds observed are:
The first interaction localized between the LP (O161) and the BD* (H145) of the O73–H145 bond is positioned at 1.8 Å with an O16⋯H73–O145 angle of 165.7°. The corresponding energy is estimated to 9.27kcal mol-1.
The second one is between the LP (O157) and the BD* (H133) of the O53 –H133 bond; positioned at 1.9 Å with an O157⋯H133–O53 angle of 162.5°. The energy of this H-bond is estimated to 5.15kcal mol-1.
The third one is located between the LP (O155) and the BD* (H138) of the O62–H138 bond; positioned at 1.8 Å with an O155⋯ H138– O62 angle of 162.7°. The estimated energy is 5.23kcal mol-1.
Table 5 Some donor–acceptor interactions in CENS-prolinate /β-CD complex and their second order perturbation stabilization energies, E(2) (kcal mol-1) ,distances and angles for orientation
Donor NBO (i)
Acceptor NBO (j)
ONIOM2 (MP2/6-31G*: B3LYP /3-21G*) d(Å)
Angle(°)
E(2) (kcal/mol)
β-CD proton donor and guest proton acceptor
LP O 60
BD*C 152 - H 172
2.1
172.5
3.65
LP O 74
BD*C 162 - H 174
1.9
154.8
2.75
LP O 74
BD*C 162 - H 174
1.9
154.8
6.49
Guest proton donor and β-CD proton acceptor
LP O 155
BD*O 62 - H 138
1.8
162.7
5.23
LP O 155
BD*O 62 - H 138
/
/
2.57
LP O 157
BD*O 53 - H 133
1.9
162.5
5.15
LP O 161
BD*C
2.1
140.4
1.55
LP O 161
BD*O 73 - H 145
1.8
165.7
9.27
LP O 161
BD*O 73 - H 145
/
/
4.19
3 - H 80
In the case where β-CD is regarded as a donor, the important interaction is observed between the oxygen atom (O74) and the hydrogen atom (H174) of the C162–H174 bond. The energy of this H-bond is estimated to 6.49kcal/mol (1.9Å, 154.8°). According to generated NBO results, we can say that the intermolecular hydrogen interactions in the CENS-prolinate /β- CD inclusion complexes play an essential role with regard to the stability of these complexes. The data of AIM analysis leads to conclusions, which are in agreement with the data of NBO analysis.
5. Conclusion A complete structural, thermodynamic, and electronic investigation along with NBO analysis and AIM approach of the supramolecular interaction of CENS-prolinate with β-CD
have been carried out with ("parametrized model seven") PM7 and ONIOM and DFT (B3LYP/6-311G(d))method. The results obtained by employing PM7 method provide important insights into the geometry and the interactions between CENS-prolinate and β-CD molecules. The relatively high value of ∆EHOMO–LUMO energy gap indicates that the title compound presents high chemical stability. In the second part of this research, calculations performed at ONIOM method clearly show that orientation 2 is more favorable than orientation 1, in good agreement with PM7 results. The best results are obtained with the ONIOM (MP2/6-31G*: B3LYP /3-21G*) combination. The CENS-proline (N=O)bond is located in the hydrophobic environment attached to the β-CD cavity with several hydrogen bonds .The results also agree well with the experimental
data of these complexes. The obtained simulation results indicating that [MP2/6-31(g,d) : B3LYP/3-21(g,d) ] hybrid method is suitable for the proposed study. Finally, the AIM and NBO methodologies were used in order to discuss the origin of conformational preference and hydrogen bond strength. It has been concluded from the obtained results that the hydrogen bonding is the major factor contributing to the overall stability of the complexation. Acknowledgements This study was supported by the Algerian Ministry of Higher Education and Scientific Research and the General Direction of Scientific Research, the General Direction of Scientific Research and Technological Development (DGRSDT) and the National Research Fund (FNR). REFERENCES [1] B. Ivanova, M. Spiteller, Macromolecular ensembles of cyclodextrin crystallohydrates and clathrates experimental and theoretical gas and condense phase study, Int. J. Biol. Macromol. 64 (2014) 383–391.
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Highlights
N-Nitroso-N-(2-chloroethyl)-N’-sulfamoylproline (CENS-proline) Alkylating agent is a class of antineoplastic or anticancer drugs.
Theoretical study of CENS-proline /β-cyclodextrin inclusion complex using PM7 docking and hybrid QM:QM and MP2:QM calculation.
Thermodynamic parameters of complexation process are verified by PM7 calculation.
Strong hydrogen bonds are formed between host and guest moleculs
NBO and AIM analysis is used to study host/guest intramolecular interactions.