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The Hydrophobic Properties of Cyclodextrins and Some Non-Glucose Cyclooligosaccharides, and Their Properties in Aqueous Solution

Stefan Immel

3rd Domestic Meeting on "Bioactive Carbohydrates", hosted by Prof. Dr. N. Kashimura and Prof. Dr. S. Kitamura at Kyoto Prefectural University, Japan, November 7, 1998, Abstract 3-10.

Molecular dynamics simulations of α-cyclodextrin (1) in water were used to analyze hydrogen-bonding, hydration properties, and water exchange phenomena in detail (Figs. 1 and 2). Of the approx. 105-115 water molecules contained in the first hydration sphere of α-CD, an average of 34.2+-2.5 are engaged into 37.3+-2.8 hydrogen bonding interactions with the solute; the cavity itself is filled with an average of 6.2 H2O molecules.

CD6 water densities
CD6 water densities
CD6 water trajectories
Fig. 1: MD-derived relative water densities around α-CD in solution: dark shading indicates enhanced water probabilities, whereas light areas correspond to low or bulk phase water densities (left: front view perpendicular to the CD macrocycle, right: side view). Fig. 2: 120 ps partial MD trajectory of the diffusion of a single water molecule through the CD cavity.

All hydroxyl groups are engaged in extensive H-bonding interactions with the surrounding solvent. Preferred are interresidue interactions of the 2-O - O-3' type between adjacent glucose units, but water-mediated hydrogen bond bridges (i.e. water molecules H-bonded to two hydroxyl groups simultaneously, cf. Fig. 3) were also found to persist with high significance.

Fig. 3: In α-CD interresidue hydrogen bonds of the 2-O - O-3' type occur with high probability and long life-spans of around 30 ps, whereas the intra-residue interaction is disfavored. Water-mediated H-bond bridges are observed with probabilities of around 10-20 %.
CD6 hydrogen bonds
CD6 water bridges

The hydrophobic characteristics of small- and large-ring CDs (cf. ribbon models shown below) were studied by molecular modeling and color-coded projection of the molecular lipophilicity patterns onto the solvent-accessible surfaces of the cyclodextrins[1].

CD6 ribbon model
CD10 ribbon model
CD14 ribbon model
CD26 ribbon model
V-Amylose ribbon model
CD6 (α-CD, 1)

Non-Glucose Cyclooligosaccharides
cyclo[D-Glcp α(1→4)]n
cyclo[D-Manp α(1→4)]n
cyclo[D-Allp α(1→4)]n
cyclo[D-Altp α(1→4)]n

Out of the large number of cyclooligosaccharides consisting of other sugar units than glucose, the cyclomannins, cycloallins, and in particular the cycloaltrins appear most interesting. In α-cycloaltrin (α-CA 2, i.e. cyclo[D-Altp α(1→4)]6) inversion of the configuration at C-2 and C-3 is likely not only to introduce additional strain into the macrocycle, but it also renders the monosaccharide units with considerable flexibility.

α-Cycloaltrin (2) adopts in the solid-state[2] a unique C3 symmetrical conformation with nearly perfect 4C1 and 1C4 chairs in an alternating sequence (2a). 1H and 13C NMR data in D2O at 30°C and 4°C indicate a dynamic conformational equilibrium of at least two different altrose geometries with almost equal energies in the macrocycle. Unlike the conformation 2a (Fig. 4) which features side-on indentations only, the intermediate all-OS2 structure 2b in the 4C1<-> OS2<-> 1C4 equilibrium features a "through-going" central cavity (Fig. 4). We have investigated the dynamic processes in 2 by means of molecular dynamics (MD) simulations in aqueous solution.

CA6 (4C1/1C4) formula
CA6 (4C1/1C4) cross-section cut
CA6 (4C1/1C4) hydration shell
CA6 (all-OS2) formula
CA6 (all-OS2) cross-section cut
CA6 (all-OS2) hydration shell
Fig. 4: Superimposed surface cross section cuts (center) of the alternating 4C1 / 1C4 (2a) and all-OS2 conformation (2b) of α-cycloaltrin with approximate molecular dimensions in Å. On the right, typical MD derived snap-shot geometries of the first hydration shell of both geometries with 31 and 41 water molecules hydrogen bonded to 2a and 2b are displayed.

[1] On the hydrophobic characteristics of cyclodextrins: computer-aided visualization of molecular lipophilicity patterns.
F. W. Lichtenthaler and S. Immel, Liebigs Ann. Chem. 1996, 27-37.
[2] Synthesis, structure, and conformational features of α-cycloaltrin: a cyclooligosaccharide with alternating 4C1/1C4pyranoid chairs.
Y. Nogami, K. Nasu, T. Koga, K. Ohta, K. Fujita, S. Immel, H. J. Lindner, G. E. Schmitt, and F. W. Lichtenthaler, Angew. Chem. Int. Ed. Engl. 1997, 36, 1899-1902.

Additional Graphics: Cyclodextrins

© Copyright PD Dr. S. Immel