Computational Investigation of Enthalpy–Entropy Compensation in Complexation of Glycoconjugated Bile Salts with β-Cyclodextrin and Analogs

Abstract

The inclusion complexes of glycoconjugated bile salts with β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrins (HP-β-CD) in aqueous solution were investigated by molecular dynamics simulations to provide a molecular explanation of the experimentally observed destabilizing effect of the HP substituents. Good agreement with experimental data was found with respect to penetration depths of CDs. An increased degree of HP substitution (DS) resulted in an increased probability of blocking the cavity opening, thereby hindering the bile salt from entering CD. Further, the residence time of water molecules in the cavity increased with the DS. Release of water from the cavity resulted in a positive enthalpy change, which correlates qualitatively with the experimentally determined increase in complexation enthalpy and contributes to the enthalpy-entropy compensation. The positive change in complexation entropy with DS was not able to compensate for this unfavorable change in enthalpy induced by the HP substituents, resulting in a destabilizing effect. This was found to originate from fixation of the HP substituents and decreased free rotation of the bile salts within the CD cavities.

Binding Thermodynamics and Kinetics Calculations Using Chemical Host and Guest: A Comprehensive Picture of Molecular Recognition

“…Both force field parameters allow the sugar ring to flip in the free states, and β -CD can easily adjust to an open cavity conformation when forming a complex with a guest. Therefore, unlike existing study showing that substituents attached to decorated β -CDs block a guest from binding, 70 the ring flipping itself in our study did not hinder guest binding. However, more flipped sugar rings modeled by GAFF-CD allow the formation of more H bonds between waters and β -CD and a more structured H-bond network as compared with conformations modeled by q4MD-CD.…”

Rapid Ion Mobility Separations of Bile Acid Isomers Using Cyclodextrin Adducts and Structures for Lossless Ion Manipulations

“…Cyclodextrins show promise for these separations as previous condensed phase studies have demonstrated their ability to form host-guest inclusion complexes with BAs. 31–38 In these complexes, the aliphatic side chain of the BA can easily slip inside the hydrophobic cavity of the cyclodextrin, and the more bulky steroid portion fits between the hydrophilic exterior and hydrophobic interior. 31–38 This hydrophobic cavity is created by the hydrogen atoms on H3 and H5 of the glucose moieties facing inward, with the hydrophilic rims being created from the primary and secondary hydroxyls (see the Supporting Information and refs 39–41).…”

“…31–38 In these complexes, the aliphatic side chain of the BA can easily slip inside the hydrophobic cavity of the cyclodextrin, and the more bulky steroid portion fits between the hydrophilic exterior and hydrophobic interior. 31–38 This hydrophobic cavity is created by the hydrogen atoms on H3 and H5 of the glucose moieties facing inward, with the hydrophilic rims being created from the primary and secondary hydroxyls (see the Supporting Information and refs 39–41). Based on this information, we hypothesized that the potential interactions between the cyclodextrin and tauro-BAs would result in gas phase host–guest inclusion ion complexes of varying size and shape after electrospray ionization (ESI), enabling separation with SLIM SUPER IM–MS.…”

Thermodynamic investigation of the interaction between cyclodextrins and preservatives — Application and verification in a mathematical model to determine the needed preservative surplus in aqueous cyclodextrin formulations

“…This can partly explain why the HPβCD generally form weaker complexes than mβCD, since the hydroxyl group positioned on the propyl chain is hydrophilic and therefore disturbing the hydrophobic interactions between the preservative molecule and CD substituent. However, dehydration of the hydrophobic surface area in general have also been demonstrated to influence the interaction Tidemand et al, 2014), hence, some of the differences may also be due to the dissimilarity in energy from the dehydration of a hydrophobic moiety.…”