4P101
シクロデキストリンと 胆汁酸・胆汁塩の複合体についての理論的研究（お茶大院人間文化創成科学）姚 嵐、森 幸恵、鷹野 景子

Theoretical study on complexes of cyclodextrins with bile acids
and bile salts(Ochanomizu Univ.) Lan Yao, Yukie Mori, Keiko Takano
Introduction
Cyclodextrins (-CD, -CD, and-CD) are cyclic oligosaccharides consisting of six,seven and eight -(1,4)-linked D-glucose units, and they are good host molecules toaccommodate hydrophobic guest molecules inside their cavity. According to the previous
calculation in the gas phase, the lowest energy conformation is the closed conformation (Fig.
1a), while another energy minimum is the open conformation, which resembles the structures
observed in the solid state (Fig. 1b).1 It is reported that CDs form 1:1 inclusion complexes
with bile salts such as cholate (CA-) and deoxycholate (DCA-) in aqueous solution. In thisstudy, the intermolecular interactions have been investigated for 1:1 complexes of CDs withcholic acid (CA, Fig. 2a), deoxycholic acid (DCA, Fig. 2b) and their anions (CA-, DCA-) inthe gas phase and in aqueous solution by means of the DFT calculations.

(a)

(b)

(a) CA(b) DCA

Fig. 1. Top and side views of -CD in the open

Fig. 2. The structural formulas of cholic acid(a) and closed (b) conformations.

(CA) and deoxycholic acid (DCA)

Computational methods
The geometries of the CD/CA inclusion complexes were optimized by the DFT-D(B97-D) and DFT (M06-2X) methods with the standard 6-31G(d) basis set. The strengths ofinteractions were quantified by the basis set superposition error (BSSE)-corrected binding
energies (Ebinding) both in the gas phase and in aqueous solution. The polarizable continuum
model (PCM) was applied for the aqueous solution. The strain energy (Estrain) was alsoevaluated. The intermolecular hydrogen bonds and van der Waals interactions between CAand CD were investigated by inspection of the optimized geometries

Results and Discussion
According to the results of the calculations by the B97-D and M06-2X methods, theopen/top1 and the open/mid2 are energetically favored configurations for the -CD/CAcomplex in the gas phase, while open/bottom1 and open/top1 are favorable for the -CD/CAcomplex. The structures are schematically shown in Fig.3, in which the arrow indicates thedirection from the carboxylic group toward the A-ring of CA (defined as direction 1,otherwise is direction 2). The diameter of-CD (dup =7.13Å, ddown = 6.71 Å in the openconformation) prohibits the steroid skeleton of the bile acid or bile salt (width = 6.20 Å forCA) from entering into the cavity of -CD, and only the side chain can enter into it. Suchgeometrical features are in good agreement with those suggested by the experimental study.2

Fig. 3. Schematic drawings of the stable configurations of the CD/CA complexes.
(Top, mid, and bottom are defined by the complexed position of the main part of guest molecule.)

Three hydrogen bonds are seen between -CD and CA, suggesting that the H-bonds andvan der Waals interactions play a decisive role in the complexation in the gas phase.
The BSSE-corrected binding enthalpies were calculated by the M06-2X/6-31G(d) method
for the -CD complexes in aqueous solution (Table 1). The present calculations overestimate
the absolute values of Hbinding, but the difference between CA- and DCA- is quite small, which
agrees with the experimental observation. Such small difference between CA- and DCAsuggests that the hydroxyl group at C7 only slightly affects the complexation with -CD.
Table 1. BSSE-corrected binding energies and binding enthalpies /kcal·mol-1 in aqueous solution
Guest

Ebinding

Hbinding

Experimental Hbinding2

CA-22.5-19.8-------25.0

-22.9

-5.5

DCA-22.9-21.1-------25.0

-22.5

-6.2

CADCA

1. Karpfen et al. Monatsh. Chem. 2008, 139, 363.
2. Liu Y et al. J. Org. Chem. 2007, 72, 8227.