CoChat
Sign Up
Cited by 198

The DOI matches its Crossref record.

Molecular Mechanism of Cyclodextrin Mediated Cholesterol Extraction

López, Cesar A., de Vries, Alex H., Marrink, Siewert J.·2011·PLoS Computational Biology
DOI 10.1371/journal.pcbi.1002020PMC PMC3063748
Open this paper in CoChat — free account

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1371/journal.pcbi.1002020

Cites

Statistics

Figures

Figure 1 Spontaneous extraction of cholesterol by a cyclodextrin dimer. Panels (A,B) show the initial system set-up with four CD dimers sitting on top of a pure cholesterol monolayer, panels C–F show the time evolution of the extraction of cholesterol by one of the CD dimers. At 0 ns the cholesterol is still inside the monolayer (C), at 10 ns the upper part is sucked in (D), and after 25 ns the cholesterol is almost fully inside apart from the tail (E). Tilting of the complex after 100 ns completes the extraction process (F). Color code; cholesterol body: grey, cholesterol head: red-white, CDs: white and red, water: blue (In panel A the level of the water layer is only depicted by a blue line).
Figure 1 Spontaneous extraction of cholesterol by a cyclodextrin dimer. Panels (A,B) show the initial system set-up with four CD dimers sitting on top of a pure cholesterol monolayer, panels C–F show the time evolution of the extraction of cholesterol by one of the CD dimers. At 0 ns the cholesterol is still inside the monolayer (C), at 10 ns the upper part is sucked in (D), and after 25 ns the cholesterol is almost fully inside apart from the tail (E). Tilting of the complex after 100 ns completes the extraction process (F). Color code; cholesterol body: grey, cholesterol head: red-white, CDs: white and red, water: blue (In panel A the level of the water layer is only depicted by a blue line).CC BY · PubMed Central
Figure 2 Collective binding of cyclodextrins and subsequent cholesterol extraction. Panels (A,B) show the initial system set-up with 16 CD dimers in aqueous solution next to a cholesterol monolayer. Panels (C,D) show the final configuration of the systems after 200 ns. The CDs adopt a number of configurations, either stacked (red arrow), or as single layer in either a tilted or untilted orientation with respect to the surface normal. Dimers present in the untilted orientation (white arrows) are capable of extraction cholesterol. A close up of a CD/cholesterol complex, stabilized in an upright position by a cluster of stacked CDs, is shown in panel E. Color code; cholesterol body: dark grey, cholesterol head: red-white, CDs: light grey. Water is not depicted for clarity.
Figure 2 Collective binding of cyclodextrins and subsequent cholesterol extraction. Panels (A,B) show the initial system set-up with 16 CD dimers in aqueous solution next to a cholesterol monolayer. Panels (C,D) show the final configuration of the systems after 200 ns. The CDs adopt a number of configurations, either stacked (red arrow), or as single layer in either a tilted or untilted orientation with respect to the surface normal. Dimers present in the untilted orientation (white arrows) are capable of extraction cholesterol. A close up of a CD/cholesterol complex, stabilized in an upright position by a cluster of stacked CDs, is shown in panel E. Color code; cholesterol body: dark grey, cholesterol head: red-white, CDs: light grey. Water is not depicted for clarity.CC BY · PubMed Central
Figure 3 Free energies of sub-steps of the cholesterol desorption process. (A) Association of CD dimer, (B) Binding of cholesterol to a CD monomer, (C) Binding of cholesterol to a CD dimer, (D) Extraction of cholesterol from cholesterol monolayer, (E) Extraction of cholesterol mediated by a -CD dimer, (F) Desorption of tilted CD dimer from cholesterol monolayer. The values of the associated free energies are given for each sub-step.
Figure 3 Free energies of sub-steps of the cholesterol desorption process. (A) Association of CD dimer, (B) Binding of cholesterol to a CD monomer, (C) Binding of cholesterol to a CD dimer, (D) Extraction of cholesterol from cholesterol monolayer, (E) Extraction of cholesterol mediated by a -CD dimer, (F) Desorption of tilted CD dimer from cholesterol monolayer. The values of the associated free energies are given for each sub-step.CC BY · PubMed Central
Figure 4 Potential of mean force for CD mediated cholesterol extraction. Using the umbrella sampling method, cholesterol was slowly extracted into a CD dimer adsorbed on the cholesterol monolayer. The reaction coordinate represents the distance between the centers of mass of the cholesterol and the cholesterol monolayer. A small activation barrier at the beginning of the process is noticeable (state A). As the reaction coordinate increases, the free energy is lowered by the encapsulation of cholesterol inside the CD dimer. Beyond a distance of 0.7 nm, the energy drops even further due to the tilting of the whole complex. The lowest free energy (−28 kJ ) is found for the complex laying parallel to the surface (state B). Pulling cholesterol further away from the monolayer forces the complex back toward an upright orientation (state C) with an associated increase of the free energy by 11 kJ . The energy difference between state A and C, corresponding to the direct extraction of cholesterol, is −17 kJ .
Figure 4 Potential of mean force for CD mediated cholesterol extraction. Using the umbrella sampling method, cholesterol was slowly extracted into a CD dimer adsorbed on the cholesterol monolayer. The reaction coordinate represents the distance between the centers of mass of the cholesterol and the cholesterol monolayer. A small activation barrier at the beginning of the process is noticeable (state A). As the reaction coordinate increases, the free energy is lowered by the encapsulation of cholesterol inside the CD dimer. Beyond a distance of 0.7 nm, the energy drops even further due to the tilting of the whole complex. The lowest free energy (−28 kJ ) is found for the complex laying parallel to the surface (state B). Pulling cholesterol further away from the monolayer forces the complex back toward an upright orientation (state C) with an associated increase of the free energy by 11 kJ . The energy difference between state A and C, corresponding to the direct extraction of cholesterol, is −17 kJ .CC BY · PubMed Central
Figure 5 Molecular model for cyclodextrin mediated cholesterol extraction. (A) Association of CDs in aqueous solution leads to the formation of dimers (B), which bind to the membrane surface assuming either a tilted or untilted configuration (C). The latter configuration is suitable to extract cholesterol, allowing the formation of a membrane-bound complex (D). Desorption of the complex brings cholesterol in solution (E), facilitating its transfer to other membranes (F). Direct desorption of cholesterol is energetically much more costly (G) (Energy values are in kJ ).
Figure 5 Molecular model for cyclodextrin mediated cholesterol extraction. (A) Association of CDs in aqueous solution leads to the formation of dimers (B), which bind to the membrane surface assuming either a tilted or untilted configuration (C). The latter configuration is suitable to extract cholesterol, allowing the formation of a membrane-bound complex (D). Desorption of the complex brings cholesterol in solution (E), facilitating its transfer to other membranes (F). Direct desorption of cholesterol is energetically much more costly (G) (Energy values are in kJ ).CC BY · PubMed Central
Figure 6 Comparison of surface mediated and solvent mediated cholesterol-CD complexation. Schematic overview of the energetic steps involved in the unassisted desolvation of cholesterol (black) versus the CD mediated desolvation (blue) of cholesterol from the membrane. The unassisted pathway involves a large energy barrier of 30–35 kT to put cholesterol in solution before it complexes with CD, whereas the surface mediated route only involves a barrier of 10–15 kT required to dissociate the cholesterol/CD complex from the membrane surface.
Figure 6 Comparison of surface mediated and solvent mediated cholesterol-CD complexation. Schematic overview of the energetic steps involved in the unassisted desolvation of cholesterol (black) versus the CD mediated desolvation (blue) of cholesterol from the membrane. The unassisted pathway involves a large energy barrier of 30–35 kT to put cholesterol in solution before it complexes with CD, whereas the surface mediated route only involves a barrier of 10–15 kT required to dissociate the cholesterol/CD complex from the membrane surface.CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

No references could be resolved yet.

Research works printed but not linked: 47

  1. ED Valle, 2004, Cyclodextrins and their uses: a review., Process Biochem, 39, 1033, 10.1016/S0032-9592(03)00258-9 · DOI · Paper page
  2. VJ Stella, 2008, Cyclodextrins., Toxicol Pathol, 36, 30, 10.1177/0192623307310945 · DOI
  3. A Vyas, 2008, Cyclodextrin based novel drug delivery systems., J Inclusion Phenom Macrocyclic Chem, 62, 23, 10.1007/s10847-008-9456-y · DOI · Paper page
  4. ME Davis, 2004, Cyclodextrin-based pharmaceutics: past, present and future., Nat Rev Drug Discov, 3, 1023, 10.1038/nrd1576 · DOI
  5. Y Yu, 2008, Solubility of beta-cyclodextrin in different mixed solvents., Pet Sci, 5, 263, 10.1007/s12182-008-0044-y · DOI
  6. T Ogoshi, 2008, Chemical sensors based on cyclodextrin derivatives., Sensors, 8, 4961, 10.3390/s8084961 · DOI
  7. F van de Manakker, 2009, Cyclodextrin-based polymeric materials: synthesis, properties, and pharmaceutical/biomedical applications., Biomacromolecules, 10, 3157, 10.1021/bm901065f · DOI
  8. A Harada, 2009, Cyclodextrin-based supramolecular polymers., Chem Soc Rev, 38, 875, 10.1039/b705458k · DOI
  9. E Bilensoy, 2009, Recent advances and future directions in amphiphilic cyclodextrin nanoparticles., Expert Opin Drug Deliv, 6, 1161, 10.1517/17425240903222218 · DOI
  10. M Messner, 2010, Self-assembled cyclodextrin aggregates and nanoparticles., Int J Pharm, 387, 199, 10.1016/j.ijpharm.2009.11.035 · DOI
  11. R Zidovetzki, 2007, Use of cyclodextrins to manipulate plasma membrane cholesterol content: evidence, misconceptions and control strategies., Biochim Biophys Acta, 1768, 1311, 10.1016/j.bbamem.2007.03.026 · DOI
  12. VM Atger, 1997, Cyclodextrins as catalysts for the removal of cholesterol from macrophage foam cells., J Clin Invest, 99, 773, 10.1172/JCI119223 · DOI
  13. R Leventis, 2001, Use of cyclodextrins to monitor transbilayer movement and differential lipid affinities of cholesterol., Biophys J, 81, 2257, 10.1016/S0006-3495(01)75873-0 · DOI · Paper page
  14. J Mascetti, 2008, Organization of beta-cyclodextrin under pure cholesterol, dmpc, or dmpg and mixed cholesterol/phospholipid monolayers., Langmuir, 24, 9616, 10.1021/la8004294 · DOI
  15. H Ohvo, 1996, Cyclodextrin-mediated removal of sterols from monolayers: effects of sterol structure and phospholipids on desorption rate., Biochemistry, 35, 8018, 10.1021/bi9528816 · DOI
  16. PG Yancey, 1996, Cellular cholesterol efflux mediated by cyclodextrins demonstration of kinetic pools and mechanism of efflux., J Biol Chem, 271, 16026, 10.1074/jbc.271.27.16026 · DOI
  17. Y Ohtani, 1989, Differential effects of alpha-, beta- and gamma-cyclodextrins on human erythrocytes., Eur J Biochem, 186, 17, 10.1111/j.1432-1033.1989.tb15171.x · DOI
  18. R Ravichandran, 1998, Inclusion of ring a of cholesterol inside the beta-cyclodextrin cavity: Evidence from oxidation reactions and structural studies., J Incl Phenom Macrocyclic Chem, 30, 253, 10.1023/A:1007912809965 · DOI
  19. C Betzel, 1984, Topography of cyclodextrin inclusion complexes, part 20 circular and ip-op hydrogen bonding in beta-cyclodextrin undecahydrate: a neutron diffraction study., J Am Chem Soc, 106, 7545, 10.1021/ja00336a039 · DOI
  20. MP Besenicar, 2008, Kinetics of cholesterol extraction from lipid membranes by methyl-beta-cyclodextrin-a surface plasmon resonance approach., Biochim Biophys Acta, 1778, 175, 10.1016/j.bbamem.2007.09.022 · DOI
  21. H Ohvo-Rekilä, 2000, Cyclodextrin-catalyzed extraction of unresent sterols from monolayer membranes and small unilamellar vesicles., Chem Phys Lipids, 105, 167, 10.1016/S0009-3084(00)00122-5 · DOI
  22. D Castagne, 2009, Study of the cholesterol extraction capacity of beta-cyclodextrin and its derivatives, relationships with their effects on endothelial cell viability and on membrane models., J Incl Phenom Macrocyclic Chem, 63, 225, 10.1007/s10847-008-9510-9 · DOI
  23. YH Choi, 2001, Molecular modeling studies of the beta-cyclodextrin in monomer and dimer form as hosts for the complexation of cholesterol., J Incl Phenom Macrocyclic Chem, 39, 71, 10.1023/A:1008196029391 · DOI
  24. Y Yu, 2006, Molecular dynamics study of the inclusion of cholesterol into cyclodextrins., J Phys Chem B, 110, 6372, 10.1021/jp056751a · DOI
  25. J Hernández-Pascacio, 2007, Cyclodextrinbased self-assembled nanotubes at the water/air interface., J Phys Chem B, 111, 12625, 10.1021/jp076576t · DOI
  26. P Weinzinger, 2007, Molecular dynamics simulations and quantum chemical calculations on beta-cyclodextrin spironolactone complex., J Incl Phenom Macrocyclic Chem, 57, 29, 10.1007/s10847-006-9165-3 · DOI
  27. A Piñeiro, 2007, On the characterization of host-guest complexes: surface tension, calorimetry, and molecular dynamics of cyclodextrins with a non-ionic surfactant., J Phys Chem B, 111, 4383, 10.1021/jp0688815 · DOI
  28. A Tsamaloukas, 2005, Interactions of cholesterol with lipid membranes and cyclodextrin characterized by calorimetry., Biophys J, 89, 1109, 10.1529/biophysj.105.061846 · DOI
  29. RO Williams, 1998, Characterization of an inclusion complex of cholesterol and hydroxypropyl-beta-cyclodextrin., Eur J Pharm Biopharm, 46, 355, 10.1016/S0939-6411(98)00033-2 · DOI
  30. J Hernández-Pascacio, 2008, A small molecular size system giving unexpected surface effects: alpha-cyclodextrin+sodium dodecyl sulfate in water., J Colloid Interface Sci, 328, 391, 10.1016/j.jcis.2008.09.002 · DOI
  31. Y He, 2008, Cyclodextrin-based aggregates and characterization by microscopy., Micron, 39, 495, 10.1016/j.micron.2007.06.017 · DOI
  32. P Bonnet, 2002, Structure and thermodynamics of alpha-, beta-, and gamma-cyclodextrin dimers. molecular dynamics studies of the solvent effect and free binding energies., J Org Chem, 67, 8602, 10.1021/jo026166v · DOI
  33. HW Frijlink, 1991, The effect of parenterally administered cyclodextrins on cholesterol levels in the rat., Pharm Res, 8, 9, 10.1023/A:1015861719134 · DOI
  34. R Breslow, 1996, Cholesterol recognition and binding by cyclodextrin dimers., J Am Chem Soc, 118, 8495, 10.1021/ja961567b · DOI
  35. J Nishijo, 2003, Interactions of cholesterol with cyclodextrins in aqueous solution., Chem Pharm Bull (Tokyo), 51, 1253, 10.1248/cpb.51.1253 · DOI
  36. WF Bennett, 2009, Molecular view of cholesterol ip-op and chemical potential in different membrane environments., J Am Chem Soc, 131, 12714, 10.1021/ja903529f · DOI
  37. PO Montiel, 2000, Soluble carbohydrates (trehalose in particular) and cryoprotection in polar biota., Cryo Letters, 21, 83
  38. B Hess, 2008, Gromacs 4: Algorithms for highly efficient, load-balanced, and scalable molecular simulation., J Chem Theory Comput, 4, 435, 10.1021/ct700301q · DOI
  39. RD Lins, 2005, A new gromos force field for hexopyranose-based carbohydrates., J Comput Chem, 26, 1400, 10.1002/jcc.20275 · DOI
  40. M Höltje, 2001, Molecular dynamics simulations of stratum corneum lipid models: fatty acids and cholesterol., Biochim Biophys Acta, 1511, 156, 10.1016/S0005-2736(01)00270-X · DOI
  41. B Hess, 1997, Lincs: A linear constraint solver for molecular simulations., J Comput Chem, 18, 1463, 10.1002/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H · DOI
  42. WF van Gunsteren, 1990, Computer simulation of molecular dynamics: Methodology, applications, and perspectives in chemistry., Angew Chem Int Ed, 29, 992, 10.1002/anie.199009921 · DOI
  43. I Tironi, 1995, A generalized reaction field method for molecular dynamics simulations., J Chem Phys, 102, 5451, 10.1063/1.469273 · DOI
  44. HJC Berendsen, 1984, Molecular dynamics with coupling to an external bath., J Chem Phys, 81, 3684, 10.1063/1.448118 · DOI
  45. G Torrie, 1977, Nonphysical sampling distributions in monte carlo free-energy estimation: Umbrella sampling., J Comput Phys, 23, 187, 10.1016/0021-9991(77)90121-8 · DOI · Paper page
  46. S Kumar, 1992, The weighted histogram analysis method for free-energy calculations on biomolecules. i. the method., J Comput Chem, 13, 1011, 10.1002/jcc.540130812 · DOI · Paper page
  47. D Shoup, 1982, Role of diffusion in ligand binding to macromolecules and cell-bound receptors., Biophys J, 40, 33, 10.1016/S0006-3495(82)84455-X · DOI

Cited by

Sorted by citations

See all 198

Metadata

Authors
López, C. A., de Vries, A. H., & Marrink, S. J.
Venue
PLoS Computational Biology
Publisher
Public Library of Science (PLoS)
Published
2011-03-24
Volume
7
Issue
3
Pages
e1002020
ISSN
1553-7358
DOI
10.1371/journal.pcbi.1002020
PMC
PMC3063748
Cited by
198
References
0
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (unspecified)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: Molecular Mechanism of Cyclodextrin Mediated Cholesterol Extraction. https://app.cochat.ai/papers/10.1371/journal.pcbi.1002020
The paper
López, C. A., de Vries, A. H., & Marrink, S. J. (2011). Molecular Mechanism of Cyclodextrin Mediated Cholesterol Extraction. PLoS Computational Biology. https://doi.org/10.1371/journal.pcbi.1002020