Article

# Simulations of docking C 60 in β-Cyclodextrin

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## Abstract

Inclusion complex MM+, Amber 99 Monte Carlo simulation We simulated the docking of the fullerene C 60 in β-Cyclodextrin using two models. We considered in this study complexes formed by 1:1 and 1:2 guest–host stoichiometries in vacuum and aqueous phase. We investigated three orientations for β-CDs in 1:2 complexes, Head to Head (HH), Head to Tail (HT) and Tail to Tail (TT). Both models agree on energetic of the inclusion process, optimum 3D structure complex, inclusion mode and stoichiometry of most stable structure. In both media, we predicted the possibility of formation of 1:1 complexes, where the most stable structure corresponds to the location of C 60 at the wider rim of β-CD with a partial inclusion. In vacuum, for 1:2 stoichiometry, the most stable complex was in HH orientation with a "V" shaped structure which favored some intermolecular hydrogen bonds, but in water both TT and HH orientations were equally stable within the calculations errors. Over all, we found that the complex with 1:2 stoichiometry is more stable than that with 1:1 stoichiometry. Our results are in agreement with the experimental spectroscopic data. We found that the driving forces for complexation in both environments were non bonded Van der Waals interaction between the host and the guest molecule for both stoichiometries. Also, we noticed that the presence of water molecules caused a relative destabilization of all complexes in both stoichiometries except for TT orientation.

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... To model the molecular docking process, we followed the method described in references [27][28][29][30][31]. The coordinate system for the complexation process is shown in Fig. 2a. ...
... The structure generated at each step is optimized, in vacuum, using PM3 method without imposing any symmetrical restriction. As reported in our previous papers [28][29][30][31], our computing strategy is a compromise between computing cost and accuracy of the results. These tasks are computationally expensive at the ab-initio or DFT level for such large system, so we choose to use PM3 method, which has proven its efficiency for CD chemistry and was proved powerful in the conformational study of supramolecular systems as well as cyclodextrin inclusion complexes [27,32,33]. ...
... Evidently, the lowest negative value corresponds to the most stable complex. It is calculated according to the following equation [28][29][30][31]: ...
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... Cyclodextrins and their inclusion complexes have been studied using different computational methods, such as molecular dynamics and Monte Carlo simulations [105][106][107]. Alvira [102] performed a theoretical study aiming to evaluate the formation of the inclusion complex between the β-cyclodextrin (β-CD) and eugenol in water using molecular dynamics simulations. ...
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... Therefore, the key characteristic of fullerene derivatives in this work is that they have quite similar solubility to CD, that is to say they can dissolve well in both DMF to form cosolution with CD. Furthermore, based on some simulation reports 28,33 , we think that complex exists as the molecular structure illustration in Scheme 1. Notably, the product is formed almost at the same time when water is added, which shows that the process of the inclusion is instantaneous and efficient. We directly proved the successful synthesis of complex by ESI-MS test. ...
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We developed a novel pathway to highly efficiently synthesize the [60]Fullerene (C$_{60}$)-Cyclodextrin (CD) complex, which is termed as solvent-induced reversible recognition. Three kinds of typical complexes, namely, C$_{60}$-2GUA$^+$-$\alpha$-CD, C$_{60}$-2GUA$^+$-$\beta$-CD and C$_{60}$-4OH-$\beta$-CD, were synthesized. The chemical structure of all complexes was fully confirmed by Fourier transform infrared spectroscopy, Nuclear magnetic resonance (NMR), UV-Vis spectroscopy and the solubility test. Furthermore, crystalline status and thermal degradation were recorded by X-ray diffraction and Thermogravimetric analysis, respectively. Both the NMR and ESI-MS results clearly confirmed the 1:1 complex of C$_{60}$ derivatives with CD. The pathway overcame the preparation limitation of traditional complex, and was extended to the prepare $\alpha$-CD containing complex. To the best of our knowledge, it is the first time to report $\alpha$-CD related complex. The geometric relation between C$_{60}$ and CD for all the three kinds of complexes were analyzed. We can achieve high efficiency to obtain solid-state complex products, which lays the foundation for the widely practical application of complex and provides enough experimental basis for the advanced application of C$_{60}$ and CD in supramolecular assembly. Notably, the solvent-induced reversibility and ionic instability of the complex provides a new possibility for the molecular recognition-based sensing.
... The computing procedure is obtained with the following factors: the number of atoms in the complex (311 atoms), the available computer power and the desired level of computation for full geometry optimization calculations. Because these tasks are computationally costly at the ab-initio or Density Functional Theory method (DFT) for such large systems, HF/STO-3 G for optimizing conformer possibilities and PM3 method for modeling the molecular docking process were purchased [49,50]. The coordinate systempurchaced for definition the complexation process has been illustrated in Fig. 1. ...
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... There are certain general characteristics for the type of molecules capable of being included totally or partially inside the cavity of CDs, but each case must be analyzed individually. CDs and their inclusion complexes have been theoretically studied using several computational methods: molecular mechanics (MM) [8,9], molecular dynamics (MD) [6,10], and Monte Carlo simulations (MC) [11,12]. ...
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... A well-known experimental finding is the existence of an appropriate size of the guest to reach maximum binding affinity in each CD [4][5][6][7], but there is no theoretical justification for this result and the factors influencing this affinity are not known. CDs and their inclusion complexes have been theoretically studied using different computational methods: molecular mechanics (MM) [8,9], molecular dynamics (MD) [6,10], and Monte Carlo simulations (MC) [11,12], where all the atoms of both CDs and guest molecules have been described. ...
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... Calculated bicoordinate CD/C 60 complexes are shown in Scheme 2, with both the space-filling and hybrid ball-and-stick structures shown for clarity. The MM+ molecular mechanics calculations followed that described by Seridi for the interactions of C 60 and β-CD, 36 but modified for the γ-CD structure. These calculated energy-minimized structures, along with literature data for the association of CD and C 60 in solution, suggest that C 60 can stabilize network formation and integrity through bicoordinate or bicapping associations with CD's. ...
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Article
An improved force field for molecular mechanics calculations of the structures and energies of hydrocarbons is presented. The problem of simultaneously obtaining a sufficiently large gauche butane interaction energy while keeping the hydrogens small enough for good structural predictions was solved with the aid of onefold and twofold rotational barriers. The structural results are competitive with the best of currently available force fields, while the energy calculations are superior to any previously reported. For a list of 42 selected diverse types of hydrocarbons, the standard deviation between the calculated and experimental heats of formation is 0.42 kcal/mol, compared with an average reported experimental error for the same group of compounds of 0.40 kcal/mol.
Article
Molecular mechanics calculations were applied to monomers and dimers of cyanine dyes (3,3′-diethyloxacarbocyanine iodide (DOC), 3,3′-diethyloxadicarbocyanine iodide (DODC), and 3,3′-diethyloxatricarbocyanine iodide (DOTC)) in β- and γ-cyclodextrin (CD) cavities, to explain the experimental findings that DODC and DOTC dimers are included both in β-and γ-CD cavities and that the DOC dimer is included only in a γ-CD cavity. The calculations show that the inclusion of dye dimers into cyclodextrin leads to stabilization of the total system; however, the (DOC)2-β-CD system is much less stable than the others, in agreement with experimental findings. Except for DOC and β-CD, the dimer dye (D2)-CD systems are found to be more stable than the corresponding monomer dye (D)-CD systems. This seemingly puzzling result can be rationalized in terms of the important role of the van der Waals stabilization energy in the inclusion compounds. The present study shows the usefulness of molecular mechanics calculations in the investigation of inclusion compounds.
Article
The ability of C[sub 60] fullerene ([open quotes]Bucky Ball[close quotes]) derivatives to interact with the active site of HIV-1 protease (HIVP) has been examined through model building and simple physical chemical analysis. The model complexes generated via the program DOCK3 suggest that C[sub 60] derivatives will fit snugly in the active site, thereby removing 298 A[sup 2] of primarily nonpolar surface from solvent exposure and driving ligand/protein association. The prediction that these compounds should bind to the active site and thereby act as inhibitors has been borne out by the experimental evidence. Kinetic analysis of HIVP in the presence of a water-soluble C[sub 60] derivative, bis(phenethylamino-succinate) C[sub 60], suggests a competitive mode of inhibition. This is consistent with and supports the predicted binding mode. Diamino C[sub 60] has been proposed as a [open quotes]second-generation[close quotes] C[sub 60] derivative that will be able to form salt bridges with the catalytic aspartic acids in addition to Van der Waals contacts with the nonpolar HIVP surface, thereby improving the binding relative to the tested compound. 15 refs., 6 figs., 1 tab.
Article
A simple method of preparing water-soluble C-60 at room temperature has been developed by complexing it with gamma-cyclodextrin. By this method concentrations as high as 1.0 X 10(-4) mol dm(-3) of C-60 can be solubilized in water. The complex is characterized by thermogravimetric, optical absorption, and powder X-ray diffraction analysis. The optical absorption spectrum, extinction coefficient, and equilibrium constant for a 2:1 (CD:C-60) complex of C-60 With gamma-cyclodextrin are reported. With the help of picosecond and nanosecond laser photolysis techniques, the triplet characteristics of the CD-C-60 complex are determined.
Article
We investigated the inclusion process of Lamotrigine (LMN) in beta cyclodextrin (β-CD) with 1:1 stoichiometry using empirical, semi-empirical and quantum mechanical calculations models. We have found that the quantum and hybrid ONIOM2 methods gave the most favorable orientation in which the guest molecule is totally sequestered in the hydrophobic cavity of the cyclodextrin with the tiazine ring located near the primary hydroxyls of the β-CD and the dichloro phenyl moiety near the secondary hydroxyls with no hydrogen bonding formation. Moreover, the statistical thermodynamic calculations at 1 atm and 298.15 K demonstrate that 1:1 LMN/β-CD complexation is an exothermic process, enthalpically favorable in nature and that non bonded Van der Waals interactions represent the mainly driving forces leading to complex stability. While, HOMO and LUMO orbital investigations confirm on one hand the better stability of ‘A’ orientation and on the other hand prove that no significant change will be observed in the electronic structure of LMN after complexation.
Article
A water-soluble complex between C70 and γ—cyclodextrin has been prepared by boiling a conc. solution of γ—cyclodextrin (0.8M) in water with solid C70 suspended in water. The complex has been characterised by its UV/VIS spectrum and by photophysical methods.
Article
A novel supramolecular inclusion complex of α-CD/C60 was synthesized using anionic C60. The reaction progress was monitored in situ by visible and near-IR spectroscopy. The obtained complex was characterized by UV–vis, 13C NMR, MALDI-TOF, and cyclic voltammetry. The induction and dispersion forces are considered to be the major driving forces for the formation of a resulting α-CD/C60- inclusion complex.
Article
Molecular modeling was used to investigate factors influencing complex formation between cyclodextrins and guest molecules and predict their stability through a theoretical model based on the search for a correlation between experimental stability constants (K s) and some theoretical parameters describing complexation (docking energy, host– guest contact surfaces, intermolecular interaction fields) calculated from complex structures at a minimum confor-mational energy, obtained through stochastic methods based on molecular dynamic simulations. Naproxen, ibuprofen, ketoprofen and ibuproxam were used as model drug molecules. Multiple Regression Analysis allowed identification of the significant factors for the complex stability. A mathematical model (r ¼ 0:897) related log K s with complex docking energy and lipophilic molecular fields of cyclodextrin and drug. Ó 2002 Elsevier Science B.V. All rights reserved.
Article
Cyclodextrins (CDs) are useful functional excipients, which are being used to camouflage undesirable pharmaceutical characteristics, especially poor aqueous solubility, through the inclusion complexation process with insoluble drugs. The selection of more efficient cyclodextrin is important to improve the bioavailability of drugs. In this study, the complexing and solubilizing abilities toward poorly water-soluble monocyclic molecules of natural CDs (α-CD, β-CD, and γ-CD) were investigated using Monte Carlo (MC) docking simulations studies. These theoretical results closely agree with the experimental observation of the complex stability in water of the various guests–CD complexes. Host preferences, based on the experimentally determined stability constants between host CDs and guest molecules, show excellent correlation with the calculated interaction energies of corresponding complexes. The inclusion complex with the lower MC docking interaction energy shows a higher value of stability constant than that of the other complex, and the prediction accuracy of the preferred complex for 21 host–guest pairs is 100%. This result indicates that the MC docking interaction energy could be employed as a useful parameter to select more efficient cyclodextrin as a host for the bioavailability of insoluble drugs. In this study, β-CD shows greater solubilizing efficacies toward guest molecules than those of α-CD and γ-CD, with the exception of one case due to the structure of a guest molecule containing one lipophilic cyclic moiety. The surface area change of CDs and hydrogen bonding between the host and guest also work as major factors for the formation of the stable complex.
Article
We present an all atom potential energy function for the simulation of proteins and nucleic acids. This work is an extension of the CH united atom function recently presented by S.J. Weiner et al. J. Amer. Chem. Soc., 106, 765 (1984). The parameters of our function are based on calculations on ethane, propane, n−butane, dimethyl ether, methyl ethyl ether, tetrahydrofuran, imidazole, indole, deoxyadenosine, base paired dinucleoside phosphates, adenine, guanine, uracil, cytosine, thymine, insulin, and myoglobin. We have also used these parameters to carry out the first general vibrational analysis of all five nucleic acid bases with a molecular mechanics potential approach.
Article
We present the derivation of a new molecular mechanical force field for simulating the structures, conformational energies, and interaction energies of proteins, nucleic acids, and many related organic molecules in condensed phases. This effective two-body force field is the successor to the Weiner et al, force field and was developed with some of the same philosophies, such as the use of a simple diagonal potential function and electrostatic potential fit atom centered charges. The need for a 10-12 function for representing hydrogen bonds is no longer necessary due to the improved performance of the new charge model and new van der Waals parameters. These new charges are determined using a 6-31G basis set and restrained electrostatic potential (RESP) fitting and have been shown to reproduce interaction energies, free energies of solvation, and conformational energies of simple small molecules to a good degree of accuracy. Furthermore, the new RESP charges exhibit less variability as a function of the molecular conformation used in the charge determination. The new van der Waals parameters have been derived from liquid simulations and include hydrogen parameters which take into account the effects of any geminal electronegative atoms. The bonded parameters developed by Weiner et al. were modified as necessary to reproduce experimental vibrational frequencies and structures. Most of the simple dihedral parameters have been retained from Weiner et. al., but a complex set of phi and psi parameters which do a good job of reproducing the energies of the low-energy conformations of glycyl and alanyl dipeptides has been developed for the peptide backbone.
Article
We present the development of a force field for simulation of nucleic acids and proteins. Our approach began by obtaining equilibrium bond lengths and angles from microwave, neutron diffraction, and prior molecular mechanical calculations, torsional constants from microwave, NMR, and molecular mechanical studies, nonbonded parameters from crystal packing calculations, and atomic charges from the fit of a partial charge model to electrostatic potentials calculated by ab initio quantum mechanical theory. The parameters were then refined with molecular mechanical studies on the structures and energies of model compounds. For nucleic acids, we focused on methyl ethyl ether, tetrahydrofuran, deoxyadenosine, dimethyl phosphate, 9-methylguanine-1-methylcytosine hydrogen-bonded complex, 9-methyladenine-1-methylthymine hydrogen-bonded complex, and 1,3-dimethyluracil base-stacked dimer. Bond, angle, torsional, nonbonded, and hydrogen-bond parameters were varied to optimize the agreement between calculated and experimental values for sugar pucker energies and structures, vibrational frequencies of dimethyl phosphate and tetrahydrofuran, and energies for base pairing and base stacking. For proteins, we focused on Φ,Ψ maps of glycyl and alanyl dipeptides, hydrogen-bonding interactions involving the various protein polar groups, and energy refinement calculations on insulin. Unlike the models for hydrogen bonding involving nitrogen and oxygen electron donors, an adequate description of sulfur hydrogen bonding required explicit inclusion of lone pairs.
Article
Azobenzene derivatives in solution present thermal cis–trans isomerization through the double bond –NN–. Experimental results showed that β-cyclodextrin inhibited the isomerization process for some azoderivatives while others were not affected. As previous model studies on the inclusion complexation of cyclodextrins with various guests, offered significant insights into the non-covalent intermolecular interactions and theoretical calculations helped to illustrate the driving forces for the complexation, here we have undertaken a theoretical study of the entire process of the formation of 1:1 stoichiometry azobenzene/β-cyclodextrin structures, in order to contribute to the understanding and rationalization of the experimental results reported before. With this purpose, we first searched for a possible way of formation of each substituted azobenzene/β-cyclodextrin inclusion complex and then we have performed an analysis of the strain energy changes involved and we have also analyzed the interaction forces driving towards the different kinds of stable structures yielded by the calculation procedure.
Article
Two local anaesthetics, Bupivacaine (BVC) and Lidocaine (LDC), were studied by experimental as well as theoretical methods. These compounds were associated with a drug delivery system of cyclodextrins (CDs). We used Differential Scanning Calorimetry (DSC) for experimental measurements. We calculated enthalpy change for the process of association between drug and CD. Calculations were performed using Molecular Mechanics (MM) with MM+ and OPLS Forced Fields. Both 1:1 and 1:2 stoichiometries were studied. DSC result indicates formation of stable inclusion compounds for all cases. A difference between physical mixture and inclusion compound was observed. The OPLS GB/SA (OPLSw) results show that the difference of enthalpy change between 1:1 and 1:2 stoichiometries is ca. ±1 kcal mol−1 for BVC. For LDC, the corresponding difference is ca. 10 kcal mol−1. This indicates that ring out type of docking is stable for the 1:1 stoichiometry. Head-to-head alignment was predicted to be stable in 1:2 stoichiometries. 1:1 and 1:2 associations coexist and establish a dynamic equilibrium.
Article
The strongly hydrophobic C(60) fullerene is a carbon allotrope of huge interest in materials science and in pharmaceutical chemistry that can be solubilized in water either by extensive chemical functionalization or by inclusion in appropriate carriers such as the cyclodextrins with formation of host-guest complexes. Here we report a molecular dynamics study of the complexes formed in solution by C(60) with gamma- and delta-cyclodextrins. The most stable host-guest complex stoichiometry is determined to be 2:1 through simulations in vacuo and in explicit water by the stepwise addition of the cyclodextrins to C(60). No a priori assumption about the inclusion stoichiometry and geometry is made. The equilibrium fluctuations of the complexes that can affect the system stability are also investigated within the molecular dynamics runs.
Article
The molecular basis for the remarkable enhancement of the solubility of paclitaxel by O-dimethylcyclomaltoheptaose (DM-beta-CD) over cyclomaltoheptaose (beta-cyclodextrin, beta-CD) was investigated with Monte Carlo docking-minimization simulation. As possible guests of inclusion complexation for the host cyclic oligosaccharides, two functional moieties of the suggested solution structure of paclitaxel were used where one is the C-3'N benzoyl moiety (B-ring) and the other is a hydrophobic (HP) cluster site among the C-3' phenyl (C-ring), C-2 benzoate (A-ring), and C-4 acetoxy moieties. The energetic preference of inclusion complexation of DM-beta-CD over beta-CD was analyzed on the basis of more efficient partitioning process of DM-beta-CD into the hydrophobic cluster site of the paclitaxel.
Article
The fullerene family, and especially C60, has very appealing photo-, electro-chemical and physical properties, which can be exploited in many and different biological fields. Fullerene is able to fit inside the hydrophobic cavity of HIV proteases, inhibiting the access of substrates to the catalytic site of the enzyme. It can be used as radical scavenger; in fact some water-soluble derivatives are able to reduce ROS concentrations. At the same time, if exposed to light, fullerene can produce singlet oxygen in high quantum yields. This action, together with the direct electron transfer from excited state of fullerene and DNA bases, can be used to cleave DNA. In this review we report the most recent aspects of fullerene biological applications.
Article
In all nitrogen-fixation processes known so far--including the industrial Haber-Bosch process, biological fixation by nitrogenase enzymes and previously described homogeneous synthetic systems--the direct transformation of the stable, inert dinitrogen molecule (N2) into ammonia (NH3) relies on the powerful redox properties of metals. Here we show that nitrogen fixation can also be achieved by using a non-metallic buckminsterfullerene (C60) molecule, in the form of a water-soluble C60:gamma-cyclodextrin (1:2) complex, and light under nitrogen at atmospheric pressure. This metal-free system efficiently fixes nitrogen under mild conditions by making use of the redox properties of the fullerene derivative.
Article
Different from C60 dianion which readily reacts with electrophiles, supramolecular C60 dianion (2) generated from gamma-cyclodextrin-bicapped C60 (1) and NaBH4 (or diborate) in DMSO-H2O (9:1, v/v) is able to reduce N-N+, C=C-EWG and C=O bonds to provide the respective dihydro derivatives; 1-mediated reduction of acetophenone with NaBH4 in the presence of (Me2N)2CH2 and EtONa gives turn over frequency (TOF)/h of 400.
Article
Caveolin is a major component of caveolae which is a plasma membrane microdomain. The emerging role of caveolin in tumorigenesis was based mainly on in vitro experiments with cancer cell lines. We performed semi-quantitative RT-PCR for caveolin, Akt and EGFR to understand the role of caveolins in colorectal tumor biology. Cancer tissue samples and the neighboring normal colon mucosa were obtained from 95 colorectal cancer patients who underwent operations at Ewha Womans University Mokdong Hospital. With these fresh tissues, semi-quantitative RT-PCR was performed by coamplification of the gene for caveolin-1, EGFR and Akt-1 with beta-actin. The average age was 60.21+/-13.33 years old, and sex ratio was 1.44:1. Caveolin-1 is more expressed in tumors than normal mucosa (P=0.025). The expression of caveolin-1 and Akt-1 had a definitive positive relationship (P=0.002). But, the expression of caveolin-1 and EGFR was not significantly related. We could not find correlations between caveolin-1 expression and clinical factors. In conclusion, caveolin-1 is more expressed in cancer tissues than normal colon and related with Akt-1, not with EGFR expression in colorectal cancer tissues, which suggests that signaling for caveolin-1 affects Akt-1 activation, but this reaction is not initiated by EGFR stimulation in colon cancer.
Article
The water soluble inclusion complex [C(60):(gamma-cyclodextrin)(2)] has been characterized using electrospray tandem mass spectrometry and collision induced dissociation. [C(60):(gamma-cyclodextrin)(2)] ions were detected in the gas phase as doubly deprotonated, doubly protonated and doubly sodiated ions. The absence of monocharged complex ions following electronebulization is a likely consequence of the dimeric nature and structural symmetry of the inclusion complex. The collision induced dissociation of positive ions led exclusively to the observation of the protonated and sodiated cyclodextrin ions as well as their fragments. In negative ion mode the closed shell anion C(60)H(-) was the dominant fragment detected at low collision energies whereas at higher collision energies the signal corresponding to deprotonated cyclodextrin units becomes significant. Since C(60) (2-) has been reported to have a nonnegligible basicity compared to C(60) and C(60) (-), it is likely that the proton transfer involved in the formation of the C(60)H(-) anion occurs following transfer of the two electrons from the deprotonated gamma-cyclodextrins to the fullerene. Finally, the charge state of the inclusion complex ions is also shown to affect the interaction strengths between its subunits. The relative stabilities of the three ionic species studied in gas phase following electronebulization are as follows: [C(60):(gamma-cyclodextrin)(2) + 2H](2+) < [C(60):(gamma-cyclodextrin)(2)- 2H](2-) < [C(60):(gamma-cyclodextrin)(2) + 2Na](2+).