Cooperative Binding of Cyclodextrin Dimers to Isoflavone Analogues Elucidated by Free Energy Calculations

Abstract

Dimerization of cyclodextrin (CD) molecules is an elementary step in the construction of CD-based nanostructured materials. Cooperative binding of CD cavities to guest molecules facilitates the dimerization process and, consequently, the overall stability and assembly of CD nanostructures. In the present study, all three dimerization modes (head-to-head, head-to-tail, and tail-to-tail) of β-CD molecules and their binding to three isoflavone drug analogues (puerarin, daidzin, and daidzein) were investigated in explicit water surrounding using molecular dynamics simulations. Total and individual contributions from the binding partners and solvent environment to the thermodynamics of these binding reactions are quantified in detail using free energy calculations. Cooperative drug binding to two CD cavities gives an enhanced binding strength for daidzin and daidzein, whereas for puerarin no obvious enhancement is observed. Head-to-head dimerization yields the most stable complexes for inclusion of the tested isoflavones (templates) and may be a promising building block for construction of template-stabilized CD nanostructures. Compared to the case of CD monomers, the desolvation of CD dimers and entropy changes upon complexation prove to be influential factors of cooperative binding. Our results shed light on key points of the design of CD-based supramolecular assemblies. We also show that structure-based calculation of binding thermodynamics can quantify stabilization caused by cooperative effects in building blocks of nanostructured materials.

Aggregation of Cyclodextrins: Fundamental Issues and Applications

“…It was demonstrated that the cooperative binding of CD cavities to guest molecules favors the dimerization process and, consequently, the overall stability and assembly of the CD nanostructures. It was also proved that the desolvation of CD dimers and entropy changes upon complexation cooperatively contributes to the binding process [78].…”

“…Computer simulations have been used to rationalize the experimental findings concerning recognition [77], inclusion [36,[77][78][79], and aggregation [34,35,37,39,80]. The cooperative binding of at least two CD monomers to a guest molecule has been considered the driving force responsible for self-assembly processes in the construction of CD-based nanoarchitectures [78].…”

“…The cooperative binding of at least two CD monomers to a guest molecule has been considered the driving force responsible for self-assembly processes in the construction of CD-based nanoarchitectures [78]. For aggregation processes without using guests, the assembly is usually driven by the hydrophilic portals (in native CDs) and by interactions between substituent chains of CD derivatives with the neighboring cavities of other CDs [78].…”

Modeling Soft Supramolecular Nanostructures by Molecular Simulations

“…The feasibility of the estimated binding free-energy depends on the correct estimation of thermodynamic quantities and the concerted interaction components (enthalpy, entropy and solvent contributions) [15,47]. For instance, the quantification of these interaction components have been directed at inclusion complexes between cyclodextrins and its derivatives and different model drugs (see Refs.…”

What causes tumbling of altro-α-CD derivatives? Insight from computer simulations

“…20) with the CHARMM 36 force eld. 23,24 However, owing to possible inconsistencies between the CHARMM36 and the q4md-CD force elds-arising from distinct parameterization philosophies, the CHARMM force eld for carbohydrates, 25,26 which has proven suitable for the study of CDs, 19,21 was employed in this work to describe the pyranose monosaccharides and glycosidic linkages of the altro-a-CD. 21 The q4md-CD force eld, 22 an Amber-derived force eld, has been shown to perform remarkably well for the modeling of CDs.…”