jp1c03916_si_001.pdf (3.36 MB)
Measurement of Single-Molecule Forces in Cholesterol and Cyclodextrin Host–Guest Complexes
journal contribution
posted on 2021-09-15, 14:06 authored by Shankar Pandey, Yuan Xiang, Dilanka V. D. Walpita Kankanamalage, Janarthanan Jayawickramarajah, Yongsheng Leng, Hanbin MaoBiological host molecules such as
β-cyclodextrins (β-CDs)
have been used to remove cholesterol guests from membranes and artery
plaques. In this work, we calibrated the host–guest intermolecular
mechanical forces (IMMFs) between cholesterol and cyclodextrin complexes
by combining single-molecule force spectroscopy in optical tweezers
and computational molecular simulations for the first time. Compared
to native β-CD, methylated beta cyclodextrins complexed with
cholesterols demonstrated higher mechanical stabilities due to the
loss of more high-energy water molecules inside the methylated β-CD
cavities. This result is consistent with the finding that methylated
β-CD is more potent at solubilizing cholesterols than β-CD,
suggesting that the IMMF can serve as a novel indicator to evaluate
the solubility of small molecules such as cholesterols. Importantly,
we found that the force spectroscopy measured in such biological host–guest
complexes is direction-dependent: pulling from the alkyl end of the
cholesterol molecule resulted in a larger IMMF than that from the
hydroxyl end of the cholesterol molecule. Molecular dynamics coupled
with umbrella sampling simulations further revealed that cholesterol
molecules tend to enter or leave from the wide opening of cyclodextrins.
Such an orientation rationalizes that cyclodextrins are rather efficient
at extracting cholesterols from the phospholipid bilayer in which
hydroxyl groups of cholesterols are readily exposed to the hydrophobic
cavities of cyclodextrins. We anticipate that the IMMF measured by
both experimental and computational force spectroscopy measurements
help elucidate solubility mechanisms not only for cholesterols in
different environments but also to host–guest systems in general,
which have been widely exploited for their solubilization properties
in drug delivery, for example.
History
Usage metrics
Categories
Keywords
umbrella sampling simulationsmolecular dynamics coupledcomputational molecular simulationsmolecule force spectroscopyforce spectroscopy measuredremove cholesterol guestscholesterol molecules tendcholesterol molecule resultedcholesterol moleculesmall moleculesmolecule forcesimmf measuredwidely exploitedwide openingsolubilization propertiesreadily exposedrather efficientphospholipid bilayerorientation rationalizesoptical tweezersnovel indicatorhydroxyl groupshydroxyl endhydrophobic cavitiesfirst timedrug deliverydifferent environmentscyclodextrin complexesartery plaquesalkyl end