Structural and energetic investigation on the host/guest inclusion process of benzyl isothiocyanate into β-cyclodextrin using dispersion-corrected DFT calculations (original) (raw)
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Structural Chemistry
The proposed study concerns the inclusion complexation of dimethoate (DMT) in the β-cyclodextrin (β-CD) molecule cage using a 1:1 stoichiometry. The interactions between DMT and-CD were evaluated using PM7 and DFT in water and gas with base 6-31G(d,p); using the CAMB3LYP functional. All approaches agree with the optimal 3D structure, which includes full DMT inclusion in the CD cavity. Complexation, LUMO, and HOMO energies were computed. The natural bond orbital (NBO) and UV-visible calculations were determined and discussed. Additionally, the non-covalent intermolecular interactions between dimethoate and β-cyclodextrin are investigated through: reduced density gradient (RDG), non-covalent interaction (NCI) and independent gradient model (IGM) that the main forces stabilizing the examined inclusion complex are H-bond and Van Der Waals interactions. Furthermore, the energy decomposition analysis (EDA) emphasizes the importance of the H-bond as attractive interactions.
Molecular modeling methodology of β-cyclodextrin inclusion complexes
Journal of Molecular Structure: THEOCHEM, 1996
A docking approach for molecular mechanics optimization of P-cyclodextrin complexes is described. Because of the specific geometry of the cyclodextrins and the class of guests (relatives of tert-butyl benzene), the guest molecule is moved along a vector going through the middle of the cavity. This vector is perpendicular to the mean plane of the a&al oxygen atoms that link the glucose units. At each step along this vector, the geometry of the bimolecular assembly was optimized to give a minimum in the molecular mechanics steric energy. As expected, the energy decreases as the guest molecule enters the cyclodextrin cavity, and again increases as the guest exits from the other side of the cavity. Rotation of the guest within the cavity prior to energy minimization did not result in lower energies; the minimization process found the best rotational orientation of the guest. On the other hand, it was necessary to drive the guest along the vector; the energy minimization process did not pull the guest into an optimal depth of penetration into the cavity. The binding energies calculated at two different dielectric constants were almost identical, indicating that the complex formation is stabilized by dispersive or Van der Waals forces and not electrostatic (dipole-dipole or hydrogen bonding) forces.
Supramolecular Chemistry, 2009
Molecular dynamics (MD) simulations have been conducted to explore time-resolved guest-host interactions involving inclusion complex formation between b-cyclodextrin and organic molecules bearing two peripheral benzene rings in aqueous solution. Moreover, free energy perturbation (FEP) and thermodynamic integration (TI) methods at different simulation times have been employed to estimate the relative free energy of complexation. Also, the less computer-time demanding molecular mechanics/Poisson -Boltzmann surface area (MM/PBSA) method was used to estimate the free energy of complexation based on only 1-ns MD simulation. Results showed that both FEP and TI methods were able to reasonably reproduce the experimental thermodynamic quantities. However, long simulation times (e.g. 15 ns) were needed for benzoin mutating to benzanilide (BAN), while moderately shorter times were sufficient for BAN mutating to phenyl benzoate and for benzilic acid mutating to diphenylacetic acid. The results have been discussed in the light of the differences in the chemical structural and conformational features of the guest molecules. In general, it was apparent that the TI method requires less time for convergence of results than the FEP method. However, the less expensive MM/PBSA method proved capable of producing results that are in agreement with those of the more expensive TI and FEP methods.
Journal of Molecular Modeling
Forming complexes with cyclodextrins can protect nicotinic acid (vitamin B3) from premature metabolism and enhance the solubility and stability of this drug. In this work, the formation of the inclusion complex of the neutral form of nicotinic acid and β-cyclodextrin was achieved. The complex is modeled using PM3, PM6-D4H3, and PM7, by considering two orientations of the guest: A and B, one is from wide to narrow rim, and the second is from narrow to the wide rim, respectively. The global minima positions were re-optimized using three density function methods: MN-15, B3LYP, and PW6B95-D3 with polarized Pople basis set 6-31G(d) in gas and aqueous phase. Orientation A showed the minimum complexation energy where the carboxylic functional group of nicotinic acid is located on the primary hydroxyl rim of β-cyclodextrin and the pyridine ring is totally embedded in the cavity. To further our study on the nature of complexation and the interactions of this host-guest system, different calculations were done. The reactivity indices showed that orientation A is harder than B and more electrophilic; the charge transfer occurred from the host to the guest and was confirmed by the natural population analysis (NPA). The natural bond orbitals (NBO) reveal the delocalization of orbitals between the host and the guest, quantum theory of atoms in molecules (QTAIM) analysis, and non-covalent interaction (NCI) analysis based on a reduced density gradient (RDG) give a detailed description of the nature of interactions between the host and the guest such as the hydrogen bonding and van der Waals interaction, and confirmed the stability of the complex given by the orientation A.
Calculation of a β-cyclodextrin-binaphthyl inclusion complex using density functional theory
Phase Transitions, 2004
We investigated the interaction of the host-guest β-cyclodextrin-2,2'-Dihydroxy-1,1'-binaphthyl complex by means of molecular dynamics simulation using a density functional based tight-binding code. We focused in particular on the investigation of the most stable conformation of this complex by investigating some of the structural properties that change with the time. This includes the hydrogen bonding formation of the active agent guest molecule with the torus-like macro ring of the host β-cyclodextrin leading to the formation of the stable adduct in the lipophilic cavity of the biopolimeric matrix. The role of solvent, water in stabilizing the complex was also discussed. We relate our results of the final stable optimized geometry of the complex to the UV/Vis and circular dichroism spectral study.
Journal of Molecular Structure: THEOCHEM, 2008
Molecular dynamics (MD) simulations using the Amber force field have been applied to obtain detailed information on inclusion complex formation between natural cyclodextrins (CDs) and organic molecules (1-alkanols, substituted phenols, and substituted imidazoles). The obtained MD trajectories were used to estimate the binding free energy of each guest/CD complex using the molecular mechanics/Poisson Boltzmann surface area (MM-PBSA) method. The calculated relative binding free energies of the inclusion complexes of some organic compounds with a-and b-CDs were in good agreement with the experimental data though the absolute values were not. Inspection of the binding free energy components revealed the dominant contribution of van der Waals interactions to inclusion complex stability. Both guest-host electrostatic interactions and the hydrophobic effect do also contribute to complex stability. It was also apparent from the calculations that the flexibility of the guest molecule has a significant contribution to complex stability.
The Journal of Physical Chemistry B, 2009
A theoretical and experimental study about the formation and structure of the inclusion complex (-)-menthyl-O--D-glucopyranoside 1 with -cyclodextrin ( -CD) 2 is presented as paradigmatic case study to test the results of molecular dynamics (MD) simulations. The customary methodological approachsthe use of experimental geometrical parameters as restraints for MD runssis logically reversed and the calculated structures are a posteriori compared with those obtained from NMR spectroscopy in D 2 O solution and single crystal X-ray diffraction so as to validate the simulation procedure. The guest molecule 1 allows for a broad repertoire of intermolecular interactions (dipolar, hydrophobic, hydrogen bonds) concurring to stabilize the host-guest complex, thus providing the general applicability of the simulation procedure to cyclodextrin physical chemistry. Many starting geometries of the host-guest association were chosen, not assuming any a priori inclusion. The simulation protocol, involving energy minimization and MD runs in explicit water, yielded four possible inclusion geometries, ruling out higher-energy outer adducts. By analysis of the average energy at room temperature, the most stable geometry in solution was eventually obtained, while the kinetics of formation showed that it is also kinetically favored. The reliability of such geometry was thoroughly checked against the NOE distances via the pair distribution functions, that is, the statistical distribution of intermolecular distances among selected diagnostic atoms calculated from the MD trajectories at room temperature. An analogous procedure was adopted both with implicit solvent and in Vacuo. The most stable geometry matched that found with explicit solvent but major differences were observed in the relative stability of the metastable complexes as a consequence of the lack of hydration on the polar moiety of the guest. Finally, a control set of geometrical parameters of the thermodynamically favored complex matched the corresponding one obtained from the X-ray structure, while local conformational differences were indicative of packing effects.
2008
Molecular dynamics (MD) simulations using the Amber force field have been applied to obtain detailed information on inclusion complex formation between natural cyclodextrins (CDs) and organic molecules (1-alkanols, substituted phenols, and substituted imidazoles). The obtained MD trajectories were used to estimate the binding free energy of each guest/CD complex using the molecular mechanics/Poisson Boltzmann surface area (MM-PBSA) method. The calculated relative binding free energies of the inclusion complexes of some organic compounds with a-and b-CDs were in good agreement with the experimental data though the absolute values were not. Inspection of the binding free energy components revealed the dominant contribution of van der Waals interactions to inclusion complex stability. Both guest-host electrostatic interactions and the hydrophobic effect do also contribute to complex stability. It was also apparent from the calculations that the flexibility of the guest molecule has a significant contribution to complex stability.
An in-depth theoretical analysis of two monosubstituted cyclodextrins (CDs) has been performed in order to find the appropriate level of theory capable of the correct qualitative description of their experimentally evidenced self-inclusion phenomenon. The correct increased stability of conformations with substituents included into the cavity ('IN' conformations) compared with those in which sub-stituents point outside the cavity ('OUT' conformations) is qualitatively predicted by molecular mechanics , the dispersion-corrected self-consistent-charge density-functional tight-binding (SCC-DFTB-D), dispersion-corrected density-functional theory (DFT-D), single-point second-order MøllerePlesset (MP2), and domain based local pair natural orbital coupled cluster (DLPNO-CCSD(T)) computations. The latter four approaches provide also quantitative insights into the relative stability of the 'IN' and 'OUT' conformations. The method of choice for the fast evaluation of the stability order of the CD conforma-tions is the SCC-DFTB-D that yields relative energies with nearly DFT-D and MP2 accuracy.