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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
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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

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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)

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