Deciphering the mechanism of γ-cyclodextrin's hydrophobic cavity hydration: an integrated experimental and theoretical study

Abstract

Cyclodextrins (CDs) are host systems with inherent capability for inclusion complex formation with various molecular entities, mostly hydrophobic substances. Host CDs are highly accommodative to water molecules as well and usually contain water in the native state. There is still an ongoing discussion on both the total number of water molecules and their preferred binding position inside the cavities of the CDs. To understand the hydration/dehydration properties of γ-CD (the largest of the three most abundant native CDs), the main experimental methods applied in this study were differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). By coupling these techniques with density functional theory (DFT) calculations we try to shed some light on the mechanism of the γ-CD hydration and to address some unanswered questions: (i) what are the preferable locations for water molecules in the macrocyclic cavity ("hot spots"); (ii) what are the major factors contributing to the stability of the water cluster in the CD interior; (iii) what type of interactions (i.e., water-water and/or water-CD walls) contribute to the stability of the water assemble; (iv) how does the mechanism of the γ-CD hydration compare with those of its α-CD and β-CD counterparts.

Keywords: DFT calculation; DSC/TG; cyclodextrin; hydration; thermodynamic characteristic.

Figure 1

Chemical structure of γ-CD (A); M062X/6-31G(d,p) optimized conformers of nonhydrated γ-CD in two projections – side view (B) and top view from O6 side of the truncated cone (C). The "closed" conformation is with oppositely oriented intramolecular hydrogen bonds on the two edges: viewed from above (the narrow rim side; O6 side), the orientation of the hydrogen bonds on the wide rim (O2/O3 side of the truncated cone) is clockwise (CW), while the orientation of the hydrogen bonds on the narrow rim is counterclockwise (CCW).

Figure 2

Schematic representation of γ-CD–nH₂O complexes (where n = 1–7) with water molecules/clusters located at different positions, and M062X/6-311++G(d,p)//M062X/6-31G(d,p) calculated relative enthalpies (ΔH⁷⁸) of the respective complexes, in kcal mol⁻¹.

Figure 3

M062X/6-31G(d,p) optimized structures of the most stable (a/b structures from Figure 2) γ-CD–nH₂O (n = 1–7) complexes with water molecules trapped in the CD cavity and not protruding out.

Figure 4

DSC curve (A) and TG analysis for γ-CD (B). Compared to our previous studies, the hydrated γ-cyclodextrin (with 7 H₂O molecules) is placed in the middle between α-CD (with 6) and β-CD (with 10).