Exploring the role of cyclodextrins as a cholesterol scavenger: a molecular dynamics investigation of conformational changes and thermodynamics

This study presents a comprehensive analysis of the cholesterol binding mechanism and conformational changes in cyclodextrin (CD) carriers, namely beta CD, 2HP beta CD, and M beta CD. The results revealed that the binding of cholesterol to CDs was spontaneous and thermodynamically favorable, with van der Waals interactions playing a dominant role, while Coulombic interactions have a negligible contribution. The solubility of cholesterol/beta CD and cholesterol/M beta CD complexes was lower compared to cholesterol/2HP beta CD complex due to stronger vdW and Coulombic repulsion between water and CDs. Hydrogen bonding was found to have a minor role in the binding process. The investigation of mechanisms and kinetics of binding demonstrated that cholesterol permeates into the CD cavities completely. Replicas consideration indicated that while the binding to 2HP beta CD occurred perpendicularly and solely through positioning cholesterol's oxygen toward the primary hydroxyl rim (PHR), the mechanism of cholesterol binding to beta CD and M beta CD could take place with the orientation of oxygen towards both rims. Functionalization resulted in decreased cavity polarity, increased constriction tendency, and altered solubility and configuration of the carrier. Upon cholesterol binding, the CDs expanded, increasing the cavity volume in cholesterol-containing systems. The effects of cholesterol on the relative shape anisotropy (kappa 2) and asphericity parameter (b) in cyclodextrins were investigated. beta CD exhibited a spherical structure regardless of cholesterol presence, while 2HP beta CD and M beta CD displayed more pronounced non-sphericity in the absence of cholesterol. Loading cholesterol transformed 2HP beta CD and M beta CD into more spherical shapes, with increased probabilities of higher kappa 2. M beta CD showed a higher maximum peak of kappa 2 compared to 2HP beta CD after cholesterol loading, while 2HP beta CD maintained a significant maximum peak at 0.2 for b.