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Measurement of Single-Molecule Forces in Cholesterol and Cyclodextrin Host-Guest Complexes.
Shankar Pandey1, Yuan Xiang2, Dilanka V D Walpita Kankanamalage3
1Department of Chemistry and Biochemistry, and Advanced Materials and Liquid Crystal Institute, Kent State University, Kent, Ohio 44242, United States.
The Journal of Physical Chemistry. B
|September 15, 2021
Summary
Intermolecular mechanical forces (IMMFs) between cyclodextrins and cholesterol were measured for the first time. Methylated cyclodextrins show higher mechanical stability and cholesterol solubilization, indicating IMMF as a novel solubility indicator.
Area of Science:
- Biophysics
- Supramolecular Chemistry
- Nanotechnology
Background:
- Biological host molecules like beta-cyclodextrins (β-CDs) are utilized to remove cholesterol from biological membranes and arterial plaques.
- Understanding the mechanical forces governing host-guest interactions is crucial for applications in solubilization and drug delivery.
Purpose of the Study:
- To calibrate intermolecular mechanical forces (IMMFs) between cholesterol and cyclodextrin complexes using a combination of single-molecule force spectroscopy and computational simulations.
- To investigate the influence of cyclodextrin modifications (e.g., methylation) on the mechanical stability and solubilization of cholesterol.
- To elucidate the orientation-dependent nature of these forces and the preferred binding/unbinding pathways of cholesterol within cyclodextrins.
Main Methods:
- Single-molecule force spectroscopy employing optical tweezers to measure mechanical forces.
- Computational molecular simulations, including molecular dynamics and umbrella sampling, to complement experimental data.
- Calibration of host-guest intermolecular mechanical forces (IMMFs) between cholesterol and cyclodextrin complexes.
Main Results:
- Methylated beta cyclodextrins exhibited higher mechanical stabilities with cholesterol compared to native β-CDs, attributed to the loss of water molecules.
- The IMMF was found to be direction-dependent, with greater force required when pulling from the alkyl end of cholesterol versus the hydroxyl end.
- Molecular dynamics simulations revealed that cholesterol molecules preferentially enter/exit cyclodextrins through their wide opening, rationalizing efficient extraction from lipid bilayers.
Conclusions:
- IMMF can serve as a novel indicator for evaluating the solubility of small molecules like cholesterol.
- The orientation-dependent force spectroscopy provides insights into the mechanism of cholesterol extraction by cyclodextrins from phospholipid bilayers.
- This work provides a foundation for understanding host-guest interactions and their application in areas like drug delivery.
