Molecular Mechanism of Cyclodextrin Mediated Cholesterol Extraction

Abstract

The depletion of cholesterol from membranes, mediated by β-cyclodextrin ( β-CD) is well known and documented, but the molecular details of this process are largely unknown. Using molecular dynamics simulations, we have been able to study the CD mediated extraction of cholesterol from model membranes, in particular from a pure cholesterol monolayer, at atomic resolution. Our results show that efficient cholesterol extraction depends on the structural distribution of the CDs on the surface of the monolayer. With a suitably oriented dimer, cholesterol is extracted spontaneously on a nanosecond time scale. Additional free energy calculations reveal that the CDs have a strong affinity to bind to the membrane surface, and, by doing so, destabilize the local packing of cholesterol molecules making their extraction favorable. Our results have implications for the interpretation of experimental measurements, and may help in the rational design of efficient CD based nano-carriers.

Author Summary

The ability of certain molecules to capture other molecules forming so-called inclusion complexes has a range of potential important applications in e.g. drug delivery and chemical sensing. Here we study the complexation of cholesterol by small oligosaccharide rings named cyclodextrins (CDs). Cholesterol is an essential lipid in the plasma cell membrane, and the ability of CDs to extract cholesterol is widely used in the biomedical field to control the level of cholesterol in the membrane. The molecular mechanism of this process, however, is still not resolved. Using a detailed computational model of cholesterol and CD, we have succeeded to simulate this extraction process. We observe that the CDs are rapidly binding to the membrane surface in a dimeric form, and, provided that the CD dimers are in a suitable orientation, cholesterol molecules are being extracted spontaneously. The cholesterol/CD inclusion complex remains adsorbed on the surface; our simulations predict that the rate limiting step for the actual transport of cholesterol is the desorption of the complex from the membrane. With a clearer understanding of the basic molecular mechanism of the CD mediated process of cholesterol extraction, we can begin to rationalize the design of more efficient CDs in numerous applications.