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Membrane partitioning of anionic, ligand-coated nanoparticles is accompanied by ligand snorkeling, local disordering, and cholesterol depletion.

Gkeka P, Angelikopoulos P, Sarkisov L, Cournia Z - PLoS Comput. Biol. (2014)

Bottom Line: This picture is supported by the free energy analysis, revealing a considerable free energy barrier for NP translocation across the lipid bilayer. 5-µs unbiased MD simulations with the NP inserted in the bilayer core reveal that the hydrophobic and hydrophilic ligands of the NP surface rearrange to form optimal contacts with the lipid bilayer, leading to the so-called snorkeling effect.Inside cholesterol-containing bilayers, the NP induces rearrangement of the structure of the lipid bilayer in its vicinity from the liquid-ordered to the liquid phase spanning a distance almost twice its core radius (8-10 nm).Based on the physical insights obtained in this study, we propose a mechanism of cellular anionic NP partitioning, which requires structural rearrangements of both the NP and the bilayer, and conclude that the translocation of anionic NPs through cholesterol-rich membranes must be accompanied by formation of cholesterol-lean regions in the proximity of NPs.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Research Foundation, Academy of Athens, Athens, Greece.

ABSTRACT
Intracellular uptake of nanoparticles (NPs) may induce phase transitions, restructuring, stretching, or even complete disruption of the cell membrane. Therefore, NP cytotoxicity assessment requires a thorough understanding of the mechanisms by which these engineered nanostructures interact with the cell membrane. In this study, extensive Coarse-Grained Molecular Dynamics (MD) simulations are performed to investigate the partitioning of an anionic, ligand-decorated NP in model membranes containing dipalmitoylphosphatidylcholine (DPPC) phospholipids and different concentrations of cholesterol. Spontaneous fusion and translocation of the anionic NP is not observed in any of the 10-µs unbiased MD simulations, indicating that longer timescales may be required for such phenomena to occur. This picture is supported by the free energy analysis, revealing a considerable free energy barrier for NP translocation across the lipid bilayer. 5-µs unbiased MD simulations with the NP inserted in the bilayer core reveal that the hydrophobic and hydrophilic ligands of the NP surface rearrange to form optimal contacts with the lipid bilayer, leading to the so-called snorkeling effect. Inside cholesterol-containing bilayers, the NP induces rearrangement of the structure of the lipid bilayer in its vicinity from the liquid-ordered to the liquid phase spanning a distance almost twice its core radius (8-10 nm). Based on the physical insights obtained in this study, we propose a mechanism of cellular anionic NP partitioning, which requires structural rearrangements of both the NP and the bilayer, and conclude that the translocation of anionic NPs through cholesterol-rich membranes must be accompanied by formation of cholesterol-lean regions in the proximity of NPs.

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Spatially averaged lipid order parameters for bilayer systems with different cholesterol concentrations.The characteristic values P2 order parameter for various bilayer phases are demarcated in the color bar on the right [35]. The different box sizes are due to the gradual condensing effect of cholesterol on the bilayer.
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pcbi-1003917-g004: Spatially averaged lipid order parameters for bilayer systems with different cholesterol concentrations.The characteristic values P2 order parameter for various bilayer phases are demarcated in the color bar on the right [35]. The different box sizes are due to the gradual condensing effect of cholesterol on the bilayer.

Mentions: To describe the structure of the lipid bilayer in the vicinity of the NP, we calculated the spatially averaged second-rank lipid order parameter, , which is a metric of the order of the lipid hydrocarbon chains and characterizes the alignment of lipid molecules with the bilayer normal (Figure 4). The square brackets denote an ensemble average and α is the angle between the bond formed by two CG beads and the bilayer normal. A value of corresponds to perfect alignment with the bilayer normal, to perfect anti-alignment, and to a random orientation of molecules with respect to the bilayer normal. The Ld phase is characterized by order parameters ranging between 0.2–0.5 and the Lo phase order parameters are in the range 0.7–1 [35] (see also the color bar scale of Figure 4). In Figure 4 it is shown that the presence of the NP induces a local increase in the disorder of lipids in all systems. Remarkably, for the systems with high cholesterol concentration (more than 30% mol.), we find that in a spherical segment area of approximately 2–3 nm (depending on cholesterol concentration) radius around the NP, the bilayer is in the liquid-disordered (Ld) phase for all the systems as indicated by the average lipid tail order parameter of ∼0.4.


Membrane partitioning of anionic, ligand-coated nanoparticles is accompanied by ligand snorkeling, local disordering, and cholesterol depletion.

Gkeka P, Angelikopoulos P, Sarkisov L, Cournia Z - PLoS Comput. Biol. (2014)

Spatially averaged lipid order parameters for bilayer systems with different cholesterol concentrations.The characteristic values P2 order parameter for various bilayer phases are demarcated in the color bar on the right [35]. The different box sizes are due to the gradual condensing effect of cholesterol on the bilayer.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4256007&req=5

pcbi-1003917-g004: Spatially averaged lipid order parameters for bilayer systems with different cholesterol concentrations.The characteristic values P2 order parameter for various bilayer phases are demarcated in the color bar on the right [35]. The different box sizes are due to the gradual condensing effect of cholesterol on the bilayer.
Mentions: To describe the structure of the lipid bilayer in the vicinity of the NP, we calculated the spatially averaged second-rank lipid order parameter, , which is a metric of the order of the lipid hydrocarbon chains and characterizes the alignment of lipid molecules with the bilayer normal (Figure 4). The square brackets denote an ensemble average and α is the angle between the bond formed by two CG beads and the bilayer normal. A value of corresponds to perfect alignment with the bilayer normal, to perfect anti-alignment, and to a random orientation of molecules with respect to the bilayer normal. The Ld phase is characterized by order parameters ranging between 0.2–0.5 and the Lo phase order parameters are in the range 0.7–1 [35] (see also the color bar scale of Figure 4). In Figure 4 it is shown that the presence of the NP induces a local increase in the disorder of lipids in all systems. Remarkably, for the systems with high cholesterol concentration (more than 30% mol.), we find that in a spherical segment area of approximately 2–3 nm (depending on cholesterol concentration) radius around the NP, the bilayer is in the liquid-disordered (Ld) phase for all the systems as indicated by the average lipid tail order parameter of ∼0.4.

Bottom Line: This picture is supported by the free energy analysis, revealing a considerable free energy barrier for NP translocation across the lipid bilayer. 5-µs unbiased MD simulations with the NP inserted in the bilayer core reveal that the hydrophobic and hydrophilic ligands of the NP surface rearrange to form optimal contacts with the lipid bilayer, leading to the so-called snorkeling effect.Inside cholesterol-containing bilayers, the NP induces rearrangement of the structure of the lipid bilayer in its vicinity from the liquid-ordered to the liquid phase spanning a distance almost twice its core radius (8-10 nm).Based on the physical insights obtained in this study, we propose a mechanism of cellular anionic NP partitioning, which requires structural rearrangements of both the NP and the bilayer, and conclude that the translocation of anionic NPs through cholesterol-rich membranes must be accompanied by formation of cholesterol-lean regions in the proximity of NPs.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Research Foundation, Academy of Athens, Athens, Greece.

ABSTRACT
Intracellular uptake of nanoparticles (NPs) may induce phase transitions, restructuring, stretching, or even complete disruption of the cell membrane. Therefore, NP cytotoxicity assessment requires a thorough understanding of the mechanisms by which these engineered nanostructures interact with the cell membrane. In this study, extensive Coarse-Grained Molecular Dynamics (MD) simulations are performed to investigate the partitioning of an anionic, ligand-decorated NP in model membranes containing dipalmitoylphosphatidylcholine (DPPC) phospholipids and different concentrations of cholesterol. Spontaneous fusion and translocation of the anionic NP is not observed in any of the 10-µs unbiased MD simulations, indicating that longer timescales may be required for such phenomena to occur. This picture is supported by the free energy analysis, revealing a considerable free energy barrier for NP translocation across the lipid bilayer. 5-µs unbiased MD simulations with the NP inserted in the bilayer core reveal that the hydrophobic and hydrophilic ligands of the NP surface rearrange to form optimal contacts with the lipid bilayer, leading to the so-called snorkeling effect. Inside cholesterol-containing bilayers, the NP induces rearrangement of the structure of the lipid bilayer in its vicinity from the liquid-ordered to the liquid phase spanning a distance almost twice its core radius (8-10 nm). Based on the physical insights obtained in this study, we propose a mechanism of cellular anionic NP partitioning, which requires structural rearrangements of both the NP and the bilayer, and conclude that the translocation of anionic NPs through cholesterol-rich membranes must be accompanied by formation of cholesterol-lean regions in the proximity of NPs.

Show MeSH