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

Abstract

This study presents a comprehensive analysis of the cholesterol binding mechanism and conformational changes in cyclodextrin (CD) carriers, namely βCD, 2HPβCD, and MβCD. 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/βCD and cholesterol/MβCD complexes was lower compared to cholesterol/2HPβCD 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 2HPβCD occurred perpendicularly and solely through positioning cholesterol's oxygen toward the primary hydroxyl rim (PHR), the mechanism of cholesterol binding to βCD and MβCD 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 (κ2) and asphericity parameter (b) in cyclodextrins were investigated. βCD exhibited a spherical structure regardless of cholesterol presence, while 2HPβCD and MβCD displayed more pronounced non-sphericity in the absence of cholesterol. Loading cholesterol transformed 2HPβCD and MβCD into more spherical shapes, with increased probabilities of higher κ2. MβCD showed a higher maximum peak of κ2 compared to 2HPβCD after cholesterol loading, while 2HPβCD maintained a significant maximum peak at 0.2 for b.

Unveiling the dynamic and thermodynamic interactions of hydrocortisone with β-cyclodextrin and its methylated derivatives through insights from molecular dynamics simulations

“…It appears that methylation causes the internal part of the cavities of the derivatives to become highly non-polar, leading to intramolecular attraction in this region. Such an event has previously been observed in some βCD derivatives, accompanied by a significant outflow of water from the center of the cavity 46 . However, the loading of HC into the cavities leads to an increase in the A MID values, which are almost the same for all derivatives as for βCD.…”

“…The Bennett acceptance ratio method (BAR) 44 was employed to assess variations in free energy across different λ values in Hamiltonians. A thermodynamic cycle utilizing alchemical www.nature.com/scientificreports/ free energy computations 45,46 was utilized to ascertain binding free energy. The computation involved gradually reducing the potential energy of interaction between HC and its surroundings using a λ parameter spanning 0 to 1 47,48 .…”

“…Initially, Coulombic solute-solvent interactions were disabled at higher λ values compared to vdW terms to prevent unstable Coulombic interactions, which could yield unreliable energies and configurations 46,49 . Soft-core potentials with specific parameters (α = 0.5, σ = 0.3, and p = 1) were integrated to prevent atom overlap between solute and solvent at low λ values [46][47][48] . Free energy calculations commenced from the final configuration of each simulated system, with each simulation lasting 5 ns.…”

Hydroxypropyl-Beta Cyclodextrin Barrier Prevents Respiratory Viral Infections: A Preclinical Study

“…HPBCD (up to 10% w/v) has been historically administered in clinical patients six times a day for 4 days [58]. Lastly, based on the proposed mechanism of action of cholesterol sequestration, frequent intranasal dosing may cause cytotoxic effects long term by depleting cholesterol on the mucosal cell surface [59]. Compared to alpha CDs and methylated CDs, modified beta cyclodextrins exhibit reduced cell toxicity [5,60].…”