Computational microscopy of cyclodextrin mediated cholesterol extraction from lipid model membranes

Abstract

Beta-cyclodextrins (β-CDs) can form inclusion complexes with cholesterol, and are commonly used to manipulate cholesterol levels of biomembranes. In this work, we have used multiscale molecular dynamics simulations to provide a detailed view on the interaction between β-CDs and lipid model membranes. We show that cholesterol can be extracted efficiently upon adsorption of β-CD dimers at the membrane/water interface. However, extraction is only observed to occur spontaneously in membranes with high cholesterol levels. Free energy calculations reveal the presence of a kinetic barrier for cholesterol extraction in the case of low cholesterol content. Cholesterol uptake is facilitated in case of (poly)unsaturated lipid membranes, which increases the free energy of the membrane bound state of cholesterol. Comparing lipid/cholesterol compositions typical of liquid-disordered (Ld) and liquid-order (Lo) domains, we furthermore show that cholesterol is preferentially extracted from the disordered regions, in line with recent experimental data.

Cyclodextrins as Emerging Therapeutic Tools in the Treatment of Cholesterol-Associated Vascular and Neurodegenerative Diseases

“…Such an observed extraction phenomenon has been described to depend on the cell surface distribution of the CDs at least for the cholesterol whose membrane extraction is preferentially achieved by β-CDs [28][29][30]. This suggests a passive diffusion of the CDs into the lipid bilayer by directing their opened secondary rim towards the lipidic polar groups while remaining anchored to the glycerol-ester groups and phosphate by hydrogen bond formation.…”

“…Phospholipids, acting as acetylcholine precursor, would counteract the loss of cholinergic neurons responsible for impaired cognition in AD patients. The chitosan/phospholipid/β-CD microspheres were tested in vivo in rats modeling AD following Aβ [25][26][27][28][29][30][31][32][33][34][35] injection into the hippocampus. In these animals, learning and memory were improved according to Morris water maze test data compared to untreated littermates.…”

Effect of Cyclodextrins on Morphology and Barrier Characteristics of Isolated Rabbit Corneas

“…Savolainen et al studied toxicity/irritation caused by CDs on human corneal epithelial cell lines and observed that the cytotoxic effect was in the order of αCD > dimethyl-βCD > SBEβCD = HPβCD > γCD (9). In another study, Lopez et al performed a computational simulation of CDs interacting with cholesterol (8). It was reported that within 10 ns of the initial interaction, CDs orient in a perpendicular direction to the surface of the phospholipid monolayer and the hydroxyl groups of membrane cholesterol penetrate into the inner core of the CD.…”

Lipofuscin Accumulation into and Clearance from Retinal Pigment Epithelium Lysosomes: Physiopathology and Emerging Therapeutics

“…In normal cells, cholesterol is more abundantly present in plasma membrane, common recycling endosome and trans-Golgi complex [117]. Removal of cholesterol from these membranes, requires high concentrations (5-10 mM) and prolonged times because βCDs, which have an ~8 Ǻ deep cavity, must form stacked dimers (improbable event) to remove 18 Ǻ long cholesterols out of the lipid bilayer and shelter them from the water [118].…”

“…In normal cells, cholesterol is more abundantly present in plasma membrane, common recycling endosome and trans-Golgi complex [117]. Removal of cholesterol from these membranes, requires high concentrations (5-10 mM) and prolonged times because βCDs, which have an ~8 Ǻ deep cavity, must form stacked dimers (improbable event) to remove 18 Ǻ long cholesterols out of the lipid bilayer and shelter them from the water [118].In cells with Niemann Pick Type-C defect, i.e., with inactivating mutations in either NPC1 or NPC2 genes, that code for two intra-lysosomal lipid transporter proteins, cholesterol is, also, aberrantly accumulated within lysosomes. Removal of lysosomal cholesterol buildups requires lower concentrations (0.1-1.0 mM) and shorter incubation times with βCD [119].…”