Molecular electrostatic potentials and hydrogen bonding in alpha-, beta-, and gamma-cyclodextrins

Cyclodextrins (CDs) are cyclic oligomers of glucose having the toroid of sugars elaborating a central cavity of varying size depending on the number of glucoses. The central hydrophobic cavity of CD shows a binding affinity toward different guest molecules, which include small substituted benzenes to long chain surfactant molecules leading to a variety of inclusion complexes when the size and shape complementarity of host and guest are compatible. Further, interaction of guest molecules with the outer surface of alpha-CD has also been observed. Primarily it is the electrostatic interactions that essentially constitute a driving force for the formation of inclusion complexes. To gain insights for these interactions, the electronic structure and the molecular electrostatic potentials in alpha-, beta-, and gamma-CDs are derived using the hybrid density functional theory employing the three-parameter exchange correlation functional due to Becke, Lee, Yang, and Parr (B3LYP). The present work demonstrates how the topography of the molecular electrostatic potential (MESP) provides a measure of the cavity dimensions and understanding of the hydrogen-bonded interactions involving primary and secondary hydroxyl groups. In alpha-CD, hydrogen-bonded interactions between primary -OH groups engender a "cone-like" structure, while in beta- or gamma-CD the interactions from the primary -OH with ether oxygen in glucose ring facilitates a "barrel-like" structure. Further, the strength of hydrogen-bonded interactions of primary -OH groups follows the rank order alpha-CD > beta-CD > gamma-CD, while the secondary hydrogen-bonded interactions exhibit a reverse trend. Thus weak hydrogen-bonded interactions prevalent in gamma-CD manifest in shallow MESP minima near hydroxyl oxygens compared to those in alpha- or beta-CD. Furthermore, electrostatic potential topography reveals that the guest molecule tends to penetrate inside the cavity forming the inclusion complex in beta- or gamma-CD.     

In silico engineering of tailored ink-binding ability at molecular printboards.

Molecular recognition between guest ink molecules and beta-cyclodextrin (beta-CD) cavities at self-assembled monolayers provides a molecular printboard for nanopatterning applications. We recently used molecular dynamics (MD) simulations to describe the specificity of ink-printboard binding and here extend the simulations to include charged cyclodextrin hosts, necessary to broaden the chemistry of molecular printboards and bind charged inks such as the ferrocenium cation. Shifting to high pH, or alternatively grafting a charged sidearm onto beta-CD, created three distinct types of anionic beta-CD cavity and we used electronic structure calculations and MD simulations to measure host-guest charge transfer and binding strengths. We find that steric recognition of uncharged organic molecules is retained at the charged printboards, and that improved guest-host electrostatic contacts can strengthen binding of larger inks while penalising small inks, enhancing the level of discrimination. A prudent choice of complementary host-guest shape and charge states thus provides a means of tuning both ink binding strength and specificity at molecular printboards.     

Cyclodextrin-assisted capillary electrophoretic resolution of 1,1'-bi-2-naphthol atropisomers.

Native beta- and gamma-cyclodextrin (CD), neutral beta-CD derivatives and ethylcarbonate derivatives of beta- and gamma-CD were used as stereoselective additives for CD-capillary zone electrophoresis (CZE) resolution of atropisomers of 1,1'-bi-(2-naphthol) (BN). CZE experiments at variable CD concentration allowed calculating binding constants from electrophoretic mobility data, corrected for electroosmotic flow (EOF) and running buffer viscosity variations. The CDs were chosen on the basis of geometric examination of molecular models of BN and CDs that suggested the possibility of inclusion complexes formation. Optimum concentrations, with aqueous 25 mM phosphate running buffer at pH 10.5, 36 cm x 50 microm capillary and 10 kV applied potential, were 3.6, 3.9, 2.1, 2.2, 1.9 mM for beta-CD, gamma-CD, ethylcarbonate-beta-CD, methyl-beta-CD and hydroxypropyl-beta-CD, respectively.     

Complex formation of cyclomaltononaose delta-cyclodextrin (delta-CD) with macrocyclic compounds

The complex forming ability of delta-cyclodextrin delta-CD with 7 kinds of macrocyclic compounds (MCCs) with 8-15 carbon atoms in the ring as models of large guest molecules was studied in aqueous solution and compared with the complexation properties of alpha-, beta- and gamma-CD. Both alpha- and beta-CD formed relatively stable complexes with small MCCs, while gamma- and delta-CD were more efficient in binding larger MCCs. The solid MCC/delta-CD complexes were precipitated with the larger MCCs with 11-15 carbon atoms in the ring, while no such precipitates were obtained with smaller MCCs with only 8-10 carbon atoms in the ring. The formation of the solid complexes was confirmed by powder X-ray diffractometry and differential scanning calorimetry. The cell dimensions of cycloundecanone (11 carbon atoms in the ring)/delta-CD complex were determined by X-ray crystallography. The preliminary crystal data were: Monoclinic, P21, a=32.50 (2)A, b=19.02 (3)A, c=16.60 (1) A, beta3=98.37 (5)degrees, V=10148 (16) A3.     

Modeling competitive guest binding to beta-cyclodextrin molecular printboards

Anchoring of functionalized guest molecules to self-assembled monolayers (SAMs) is key to the development of molecular printboards for nanopatterning. One very promising system involves guest binding to immobilized beta-cyclodextrin (beta-CD) hosts, with guest:host recognition facilitated by a hydrophobic interaction between uncharged anchor groups on the guest molecule and beta-CD hosts self-assembled at gold surfaces. We use molecular dynamics free energy (MDFE) simulations to describe the specificity of guest:beta-CD association. We find good agreement with experimental thermodynamic measurements for binding enthalpy differences between three commonly used phenyl guests: benzene, toluene, and t-butylbenzene. van der Waals interaction with the inside of the host cavity accounts for almost all of the net stabilization of the larger phenyl guests in beta-CD. Partial and full methylation of the secondary rim of beta-CD decreases host rigidity and significantly impairs binding of both phenyl and larger adamantane guest molecules. The beta-CD cavity is also very intolerant of guest charging, penalizing the oxidized state of ferrocene by at least 7 kcal/mol. beta-CD hence expresses moderate specificity toward uncharged organic guest molecules by van der Waals recognition, with a much higher specificity calculated for electrostatic recognition of organometallic guests.     

A spectroscopic study of the inclusion of azulene by beta- and gamma-cyclodextrins

The inclusion of azulene (AZ) inside the cavities of beta-cyclodextrin (beta-CD) and gamma-cyclodextrin (gamma-CD) was studied using absorption, fluorescence and induced-circular dichroism spectroscopy. The inclusion of AZ into the cavity of beta-CD has a stoichiometry of 1:1, whereas that of AZ/gamma-CD complex is 1:2. The equilibrium constants for the formation of the two complexes were calculated to be 780+/-150 M(-1) for AZ:beta-CD and (4.5+/-0.86)x10(5) M(-2) for AZ:(gamma-CD)(2). The latter is due to a stepwise equilibrium mechanism in which a 1:1 complex is formed with a binding constant of 775 M(-1), followed by the formation of a 1:2 complex with a binding constant of 580 M(-1). The difference between the two binding constant values is slight, indicating an almost equal contribution from each of the gamma-CD molecules to the overall binding in AZ:(gamma-CD)(2). From the induced-circular dichroism spectra, the inclusion of AZ was found to be axial in AZ:beta-CD and nearly axial in AZ:(gamma-CD)(2).     

Can the anomalous aqueous solubility of beta-cyclodextrin be explained by its hydration free energy alone?

The well-documented anomalous solubility of beta-cyclodextrin (beta-CD), relative to alpha- and gamma-CD, has been examined by Naidoo et al. (J. Phys. Chem. B, 2004, 108, 4236-4238.) from the perspective of water organization and internal motion of the macrocyclic rings. Whether modulation in the hydration patterns and in the rigidity of the molecular scaffold can be reconciled with the hydration free energy of beta-CD to rationalize its notorious low solubility remains open to further investigation. In this contribution, multi-nanosecond molecular dynamics (MD) simulations have been carried out to investigate the hydration process of alpha-, beta- and gamma-CD. The distribution of water molecules involved in this process and the linearity of intramolecular hydrogen bonds have been analyzed. The results reported here demonstrate that the anomalous solubility for beta-CD can be essentially rationalized by its greater rigidity conferred by the participating intramolecular hydrogen bonds and the higher density of water molecules of lesser mobility. The hydration free energy of alpha-, beta- and gamma-CD was computed using the free energy perturbation method. This quantity is shown to increase with the number of glucose units, thereby suggesting that the anomalous solubility of beta-CD cannot be explained by its free energy of hydration alone.     

Organic anion recognition of naphthalenesulfonates by steroid-modified beta-cyclodextrins: enhanced molecular binding ability and molecular selectivity

Two beta-cyclodextrin (beta-CD) derivatives bearing steroid groups (1 and 2) were synthesized by the condensation of mono(6-aminoethylamino-6-deoxy)-beta-CD with cholic acid and deoxycholic acid, respectively, and their original conformations and binding behavior to the organic anion of naphthalenesulfonate derivatives were investigated by using 1H NMR spectroscopy and spectrofluorometric titration in combination with computational methods. The 2D NMR experiments reveal that the steroid groups attached to the beta-CD rim could be deeply embedded in the beta-CD cavity to form the intramolecular (for 1) or intermolecular (for 2) inclusion complexes in aqueous solution. Upon complexation with naphthalenesulfonate derivatives, modified beta-CDs display two obviously different binding modes, that is, the competitive inclusion mode and the induced-fit inclusion mode, which is consistent with the results of molecular modeling study. The two modes and the strict size/shape fitting relationship between the hosts and guests reasonably explain the different binding behaviors and molecular selectivity of host beta-CDs 1 and 2 toward the naphthalenesulfonate guests. Therefore, the cholic acid- or deoxycholic acid-modified beta-CDs could effectively recognize the size/shape of guest molecules as compared with the parent beta-CD, giving good molecular selectivity up to 24.9 for the disodium 2,6-naphthalenedisulfonate/disodium 1,5-naphthalenedisulfonate pair by the host 1.     

Cyclodextrin effect on solvolysis of substituted benzoyl chlorides

A kinetic study was carried out on the solvolysis of substituted benzoyl chlorides in the presence of alpha-, beta- and gamma-CD. Combination of the substituent dependent mechanism for solvolysis of benzoyl chlorides and the complexation ability of the cyclodextrin yields the following experimental behavior: (i) catalysis by beta- and gamma-CD for solvolysis of electron-attracting substituted benzoyl chlorides due to the reaction with its hydroxyl group C(6); (ii) absence of alpha-CD influence on solvolysis of benzoyl chlorides with electron withdrawing substituents; (iii) inhibition of solvolysis of benzoyl chlorides with electron-donating groups. This behavior is observed for solvolysis of meta/para substituted substrates in the presence of beta-CD, solvolysis of meta-substituted benzoyl chlorides in the presence of alpha-CD and solvolysis of para-substituted benzoyl chlorides in the presence of gamma-CD. This decrease in the rate constant is a consequence of the complexation of the substrate in the cyclodextrin cavity and its low solvation ability, causing the rate of solvolysis in its interior to be negligible. (iv) The solvolysis of meta-substituted benzoyl chlorides in the presence of gamma-CD yields a new behavior where the reaction of the complexed substrate is not negligible in the interior of the cyclodextrin cavity, which has been interpreted as a consequence of incomplete expulsion of hydration water from its cavity when the complexation takes place. (v) The experimental results obtained in the presence of alpha-CD show that meta-substituted benzoyl chlorides give rise to host : guest complexes with 1 : 1 stoichiometries, whereas those which are para-substituted cause a 2 : 1 stoichiometry to be formed. This difference in behavior has been interpreted taking into account the size of the different benzoyl chlorides and their accommodation in the alpha-CD cavity.     

Enantioseparation of phenothiazines in cyclodextrin-modified capillary zone electrophoresis: reversal of migration order

Enantioseparations of phenothiazines with gamma-cyclodextrin (gamma-CD) as a chiral selector were investigated using citrate and phosphate buffer electrolytes at pH 3.0. Reversal of the enantiomer migration order of promethazine, ethopropazine, and trimeprazine was observed by varying gamma-CD concentration in the range of 5-9 mM, 2.5-4.5 mM and 1.5-2.8 mM, respectively, using 100 mM citrate buffer at pH 3.0. As in the case of beta-CD, the (+)-enantiomers of phenothiazines possess greater binding strength to gamma-CD than the (-)-enantiomers. The evaluation of the binding constants and limiting mobility of the complexes formed between the enantiomers of phenothiazines and gamma-CD reveals that the binding strength of phenothiazines to gamma-CD and the differences in the binding constants and limiting mobility of the complexes are responsible for the enantiomer migration reversal. Both the binding constants and limiting mobility of the complexes between the (+)-enantiomers of phenothiazine and gamma-CD are greater than those of the corresponding (-)-enantiomers in a citrate buffer, while the binding constants of the complexes primarily determined the migration order of the enantiomers in a phosphate buffer. Compared with the results obtained using a phosphate buffer, we may conclude that citrate buffer which involves competitive complexation with chiral selector plays a significant role in the enantiomer migration reversal.     

CoMFA-based comparison of two models of binding site on adenosine A1 receptor

A set of 32 N6-substituted adenosines and 22 8-substituted xanthines with affinity for adenosine A1 receptors was subjected to three-dimensional quantitative structure-affinity relationship analysis using comparative molecular field analysis (CoMFA). The aim was to compare two modes of binding to the receptor – `N6-C8' and `N6-N7'. Good models with high predictive power and stability were obtained. A comparison of these models gives the following results: (a) Inclusion of both steric and electrostatic fields in CoMFA generates better predictive models compared to models based on steric or electrostatic fields alone. (b) The `N6-N7' CoMFA models are slightly better than the `N6-C8' ones. (c) Steric restriction exists around the N6-H in the `N6-N7' steric field map, which is absent in the `N6-C8' steric field map. This report demonstrates that the `N6-N7' mode of binding is a further development of the `N6-C8' model with a slightly better predictive ability and more accurate steric and electrostatic overlaps between agonists and antagonists.     

应用量化参数和CoMFA法研究苯甲酸类化合物的结构和其pKa值的相关性

人工神经网;应用量化参数和CoMFA法研究苯甲酸类化合物的结构和其pKa值的相关性     

Inclusion complexes of Fe(III) tetrakis(4-sulfonatophenyl)porphyrin with cyclodextrins in aqueous solutions

In aqueous solutions, inclusion complexation of Fe(III) tetrakis(4-sulfonatophenyl)porphyrin (FeTSPP) with alpha-cyclodextrin (alpha-CD), beta-CD, gamma-CD, and heptakis(2,3,6-tri-O-methyl)-beta-CD (TM-beta-CD) has been examined by means of absorption and induced circular dichroism spectroscopy. FeTSPP has been found to form inclusion complexes with beta-CD, gamma-CD, and TM-beta-CD in pH 3.2 buffers. At pH 10.1, where FeTSPP self-associates to form an oxo-bridged dimer, FeTSPP also forms inclusion complexes with alpha-CD, beta-CD, gamma-CD, and TM-beta-CD. The stoichiometries of the CD-FeTSPP inclusion complexes are 1:1, except for TM-beta-CD in pH 10.1 buffers where its 1:1 inclusion complex associates with TM-beta-CD to form a 2:1 inclusion complex at high TM-beta-CD concentrations. Equilibrium constants of FeTSPP for the formation of the 1:1 inclusion complexes have been evaluated for beta-CD, gamma-CD, and TM-beta-CD. Induced circular dichroism spectra of FeTSPP in alpha-CD and beta-CD solutions exhibit a signal pattern (a negative sign) that is different from those in acidic and basic solutions containing gamma-CD and that in basic solution containing TM-beta-CD, suggesting different inclusion modes towards FeTSPP.     

Experimental (NMR) and Computational (MD) Studies on the Inclusion Complexes of 1-Bromoadamantane with alpha-, beta-, and gamma-Cyclodextrin

The inclusion complexes between the most commonly used cyclodextrins (alpha-, beta-, and gamma-CD) and 1-bromoadamantane were prepared and studied experimentally by NMR methods and by molecular dynamics simulations (AMBER force field) with solvation. The NMR results suggest host/guest ratios of 2:1, 1:1, and 1:1 for the complexes with alpha-, beta-, and gamma-cyclodextrin, respectively, as well as defined geometries for the complexes. Averaged geometrical data from the molecular dynamics simulations agree with the complexation geometries deduced experimentally.     

A computational study of regioselectivity in a cyclodextrin-mediated Diels-Alder reaction: revelation of site selectivity and the importance of shallow binding and multiple binding modes

The use of a cyclodextrin.Diels-Alder transition structure complex (CD.TS) as a model in molecular dynamics simulations has enabled us to gain insight into the controlling factors in the cyclodextrin-mediated Diels-Alder reaction of methyl-p-benzoquinone with isoprene. MD simulations were carried out with multiple binding configurations of the CD.TS (TS=meta-TS, para-TS) complexes at the top and bottom rims of beta-CD. We discovered that i) only shallow binding with the CD is necessary for the regioselectivity, and multiple binding geometries are possible; ii) the narrow bottom rim, with the primary hydroxyl groups, of the CD binds both regio-TSs better than at the wider top rim (secondary hydroxyl groups), which was unexpected from the perspective of shape complementarity that governs the stability of most CD.guest complexes. Overall, the bottom rim of the CD exhibits higher regioisomer discrimination for the meta-TS; iii) structural clustering analyses of the CD.TS configurations (sampled during MD simulations) have enabled us to evaluate the binding energies of the different binding configurations. The result indicates that there is a direct correlation between meta-product selectivity and a higher number of binding configurations favoring the formation of the CD.meta-TS complex. The main forces of stabilization in the CD.TS complexes are the van der Waals interactions when the TS is bound at the top rim. At the bottom rim, closer contacts between polar functional groups of the TS and CD have increased the importance of electrostatic interactions. We found that van der Waals, solvation, and torsional forces are less favorable for complexation at the bottom rim; however, this is compensated by large favorable electrostatic interactions. With insights obtained from the study of CD.TS complexes and MD simulations of the modified heptakis-[6-O-(2-hydroxy)propyl]-beta-CD, we were able to explain why a low selectivity was observed when the Diels-Alder reaction was carried out in this modified CD. Two types of search method [Monte Carlo and multiple minimum (MCMM) and molecular dynamics (MD)] to explore and evaluate the different possible binding geometries of the TS within beta-CD, were discussed.     

Dynamic study of interaction between beta-cyclodextrin and aspirin by the ultrasonic relaxation method

A single ultrasonic relaxational phenomenon was observed in aqueous solutions containing both beta-cyclodextrin (beta-CD) as host and nonionized or ionized acetylsalicylic acid (aspirin) as guest. The observed relaxation was responsible for a dynamic complexation reaction between beta-CD and aspirin molecules, concomitant with a volume change during the reaction. The kinetic and equilibrium constants for the complexation in the acid (nonionized) form of the aspirin system were derived from the guest concentration dependence of the relaxation frequency. The equilibrium constant for the carboxylate (ionized) form of aspirin was determined from the concentration dependence of a maximum absorption per wavelength, and the rate constants were calculated by using the determined equilibrium constant and the observed relaxation frequencies, which remained nearly almost constant over the concentration range studied. The results showed that the effect of charge on the aspirin molecule was reflected only in the dissociation process from the beta-CD cavity, while no remarkable change was seen in the association process whose rate was diffusion controlled. The results could be explained on the basis of the difference of the hydrophobic moieties in the two guests that were included in the host cavity. The results of the standard volume change for the complexation reaction were closely related to the number of expelled water molecules originally located in the beta-CD cavity and the volume of the aspirin molecule incorporated into the beta-CD cavity.     

胆甾类分子钳对氨基酸衍生物的对映选择性识别

用差紫外光谱滴定法考察了以脱氧胆酸作spacer的手性分子钳1～3对一系列α-氨基酸甲酯的对映选择性识别性能。结果表明,分子钳1和2与客体氨基酸甲酯形成1:1型超分子配合物,并显示较好的手性识别能力。分钳3对所考察的氨基酸甲酯均没有明显的识别作用。讨论了主-客体间尺寸/形状匹配、几何互补等因素对形成超分子配合物的影响,并利用计算机模拟作辅助手段对实验结果和现象进行了解释。     

Complexation behavior of alpha-, beta-, and gamma-cyclodextrin in modulating and constructing polymer networks

A systematic study of the host-guest complexation by alpha-, beta-, and gamma-cyclodextrin (CD) in either the free state or as substituents of poly(acrylic acid) (PAA) with the hydrophobic n-octadecyl groups, C18, substituted onto PAA (HMPAA) and its effect on polymer aggregation and network formation is reported. Free alpha-CD, beta-CD, and gamma-CD mask hydrophobic associations between the C18 substituent of HMPAA in aqueous solution and form host-guest complexes with a 1:1 or CD:C18 substituent stoichiometry at 0.5 wt % polymer concentration. For alpha-CD this host-guest stoichiometry changes to 2:1 or 2alpha-CD:C18 at > or =1 wt % polymer concentrations but not for beta-CD and gamma-CD. Shear-thickening occurs when gamma-CD complexes C18 HMPAA substituents. Upon addition of sodium dodecyl sulfate, SDS (SDS:CD = 1:1), the hydrophobic associations between C18 diminished by alpha-CD masking were fully restored, were only partly restored in the case of beta-CD, and not restored for gamma-CD. When alpha- and beta-CD substituted PAA (alpha-CDPAA and beta-CDPAA) were mixed with HMPAA polymer, networks formed. As for free beta-CD, the beta-CD substituents of beta-CDPAA also formed 1:1 or beta-CD:C18 stoichiometry host-guest complexes with the C18 substituents of HMPAA. The alpha-CD substituents of alpha-CDPAA also formed 1:1 or alpha-CD:C18 stoichiometry host-guest complexes with some indication of the formation of 2:1 or 2alpha-CD:C18 stoichiometry host-guest complexes at polymer concentrations > or =1 wt %. The polymer networks formed by beta-CDPAA with HMPAA are less viscous than those formed by alpha-CDPAA, for which shear-thickening occurs at polymer concentrations > or =2 wt %. It is evident that the difference in CD annular size and its match with the C18 of HMPAA control the diversity of the interactions of alpha-CD, beta-CD, gamma-CD, alpha-CDPAA, and beta-CDPAA with HMPAA.