1P131
DFT と ab initio FMO 法によるシクロデキストリンと胆汁酸の包接錯体の相互作用に関する理論研究（お茶大院人間文化創成科学）姚 嵐、森 幸恵、鷹野 景子

Theoretical Study on Intermolecular Interactions in Complexes ofCyclodextrins with Bile Acids:
DFT and ab initio Fragment Molecular Orbital Calculations(Ochanomizu Univ.) Lan Yao, Yukie Mori, Keiko Takano
Introduction Cyclodextrins (-, -, and-CD), which are cyclic oligosaccharides consistingof six, seven and eight -(1,4)-linked D-glucose units (Fig.1), are good host molecules toaccommodate hydrophobic guest molecules inside their cavity. It is reported that CDs form
1:1 inclusion complexes with bile salts such as cholate and deoxycholate, and the binding
mode is proposed from the NMR experiments.1 In the present study, the intermolecularinteractions have been investigated for 1:1 complexes of CDs with cholic acid (CA, Fig. 2),
deoxycholic acid (DCA), and their anions in the gas phase and in aqueous solution by DFTand ab initio MO calculations in order to clarify causative factors for stabilization of thecomplexes.
OX
C25
H3C
OH
C12C

CH3(a)(b)

Fig. 1. -CD in open (a) and closed (b) conformations.

C3OHAO

CH3DB
C7

R=OH, X=H: cholic acid (CA)
R=H, X=H: deoxycholic acid (DCA)
R=OH, X=- : cholate (CA-)
R=H, X=- : deoxycholate (DCA-)

RFig. 2. Structural formulas of guest molecules.

Computational Methods Eight stable structures (Fig. 3) were obtained in our previous study
by the B97-D/6-31G(d) calculation.2 In the present study, geometries were optimized both ingas phase and in aqueous phase by DFT (B97-D, M06-2X, and B3LYP functionals) with the6-31G(d) basis set. IEF-PCM was employed for aqueous phase. Association energies werecomputed with correction for basis set superposition error. Single-point energy calculations bythe fragment molecular orbital (FMO)-MP23/6-31G(d) method were carried out for thegeometries optimized in aqueous phase with B97-D.
Results and Discussion The association energies of -CD/CA and -CD/CA are morenegative than that of -CD/CA in the gas phase. The open/top1 configuration was the moststable for -CD/CA. The structures of -CD/CA optimized with B97-D and M06-2X inaqueous phase resembled the structure proposed from the NMR experiments1 whereas they
were rather different from that with B3LYP, which is likely because B97-D and M06-2X are
known to exhibit better performance than B3LYP on evaluation of dispersion interaction.
Formation of intermolecular hydrogen bonds (H-bonds) may be a significant driving force
for complexation of a guest by CDs. The numbers of intermolecular H-bonds were examined
for the -CD complexes with different guests or orientations in aqueous phase. In the case of
-CD/CA, the open/top1 and closed/mid1 configurations involve six intermolecular H-bonds
whereas the open/mid2 involves only three. The -CD/DCA complex in the open/top1
configuration involves four intermolecular H-bonds. In spite of the difference in the numberof H-bonds, the association energies are almost the same for -CD/CA and -CD/DCA,
suggesting that another factor also contributes to the stabilization.
Dispersion interaction may be another important driving force in the CD/bile acids
complexes. Pair interaction energy decomposition analyses with FMO-MP2 method revealed
that both the electrostatic (Ees) and dispersion (Edisp) terms significantly contribute to the totalinteraction energies (Etotal) as shown in Fig. 4. The most stable configuration, open/top1, of
-CD/CA exhibits the most negative total and electrostatic interaction energies. Thedispersion term in -CD/CAis more negative than that in -CD/CA. In summary, both theintermolecular H-bonds and dispersion interactions have significant contribution to thestabilization of the CD/bile acid complexes.
In the poster, results of preliminary MD simulation of the complexes in aqueous solution
with explicit water molecules will be also presented.
CD (closed)

Blue: -CD open/top1
Red: -CD open/mid2
Green: -CD open/top1
Purple: -CD open/bottom1

kcal mol-1
120
99.3
90

a. CD (closed) mid1

78.7
72.6
71.7

b. CD (closed) top2

60CD (open)

300
c. CD (open) bottom1

d. CD (open) mid1

e. CD (open) mid2

-30-33.5 -31.6
-35.2
-41.6
-60

-54.2

-60.0
-58.9
-70.2
-71.4

-69.6 -68.3
-90

-80.4
-93.3

f. CD (open) top1

g. CD (open) top2

Fig. 3. Schematic drawings of eightstable structures of CD/CA complexes.

-86.3 -80.8-93.1-120
EtotalEes

Eex

Ect+mix

Edisp

Fig. 4. Interaction energies for -CD/CA and -CD/CA
at the B97-D-optimized geometry.

1. P. R. Cabrer et al. Langmuir 1999, 15, 5489. 2. L. Yao et al. 第６回分子科学討論会 (2012, 4P101). 3.
D. G. Fedorov et al. J. Chem. Phys. 2004, 120, 6832; D. G. Fedorov et al. J. Chem. Phys. 2004, 121, 2483.