scholarly journals Cholesterol Oxidation Modulates the Formation of Liquid-Ordered Domains in Model Membranes

2021 ◽  
Author(s):  
Paul Smith ◽  
Peter G Petrov ◽  
Christian D Lorenz
Keyword(s):  
Lipid Membranes ◽  
Coarse Grained ◽  
Cholesterol Oxidation ◽  
Phosphatidylinositol 3 Kinase ◽  
Single Chemical ◽  
Liquid Ordered ◽  
Dynamics Simulations ◽  
Lateral Organization ◽  
Molecular Description ◽  
Liquid Liquid Phase Separation

7-ketocholesterol (KChol) is one of the most cytotoxic oxysterols found in the plasma membrane, and increased levels of KChol are associated with numerous pathologies. It is thought to induce apoptosis via inactivation of the phosphatidylinositol 3-kinase/Akt signaling pathway - a pathway that depends on lipid-rafts as signaling platforms. By means of coarse-grained molecular dynamics simulations, we demonstrate that KChol disrupts the liquid-liquid phase separation seen in an equimolar mixture of (dipalmitoylphosphatidylcholine) DPPC, (dioleoylphosphatidylcholine) DOPC, and Cholesterol (Chol). This disruption occurs via two mechanisms: i) KChol adopts a wider range of orientations with the membrane, which disrupts the packing of neighboring lipids and ii) KChol has no preference for DPPC over DOPC, which is the main driving force for lateral demixing in DPPC/DOPC/Chol membranes. This provides a molecular description of the means by which KChol induces apoptosis, and illustrates that a single chemical substitution to cholesterol can have a profound impact on the lateral organization of lipid membranes.

scholarly journals Membrane thickness, lipid phase and sterol type are determining factors in the permeability of membranes to small solutes

2021 ◽  
Author(s):  
Jacopo Frallicciardi ◽  
Josef Melcr ◽  
Pareskevi Siginou ◽  
Siewert Marrink ◽  
Bert Poolman
Keyword(s):  
Lipid Membranes ◽  
Lipid Phase ◽  
Membrane Thickness ◽  
Bacterial Cells ◽  
Concentration Gradients ◽  
Kinetic Measurements ◽  
Systematic Analysis ◽  
Liquid Ordered ◽  
Dynamics Simulations

Abstract Cell membranes provide a selective semi-permeable barrier to the passive transport of molecules. This property differs greatly between organisms. While the cytoplasmic membrane of bacterial cells is highly permeable for weak acids and glycerol, yeasts can maintain large concentration gradients. Here we show that such differences can arise from the physical state of the plasma membrane. By combining stopped-flow kinetic measurements with molecular dynamics simulations, we performed a systematic analysis of the permeability through synthetic lipid membranes to obtain detailed molecular insight into the permeation mechanisms. While membrane thickness is an important parameter for the permeability through fluid membranes, the largest differences occur when the membranes transit from the liquid-disordered to liquid-ordered and/or to gel state. By comparing our results with in vivo measurements from yeast, we conclude that the yeast membrane exists in a highly ordered and rigid state, which is comparable to synthetic saturated DPPC-sterol membranes.

scholarly journals Inverse design of cholesterol attracting transmembrane helices reveals a paradoxical role of hydrophobic length

2021 ◽  
Author(s):  
Jeroen Methorst ◽  
Niek van Hilten ◽  
Herre Jelger Risselada
Keyword(s):  
Molecular Dynamics ◽  
Lipid Membranes ◽  
Transmembrane Domain ◽  
Optimal Solution ◽  
Molecular Shape ◽  
Global Optimum ◽  
Coarse Grained ◽  
Hydrophobic Core ◽  
Recognition Motifs ◽  
Dynamics Simulations

The occurrence of linear cholesterol-recognition motifs in alpha-helical transmembrane domains has long been debated. Here, we demonstrate the ability of a genetic algorithm guided by coarse-grained molecular dynamics simulations---a method coined evolutionary molecular dynamics (evo-MD)---to directly resolve the sequence which maximally attracts/sorts cholesterol within a single-pass alpha-helical transmembrane domain (TMDs). We illustrate that the evolutionary landscape of cholesterol attraction in membrane proteins is characterized by a sharp, well-defined global optimum. Surprisingly, this optimal solution features an unusual short hydrophobic block, consisting of typically only eight short chain hydrophobic amino acids, surrounded by three successive lysines. Owing to the membrane thickening effect of cholesterol, cholesterol-enriched ordered phases favor TMDs characterized by a long rather than a short hydrophobic length. However, this short hydrophobic pattern evidently offers a pronounced net advantage for the binding of free cholesterol in both coarse-grained and atomistic simulations. Attraction is mediated by the unique ability of cholesterol to snorkel within the hydrophobic core of the membrane and thereby shield deeply located lysines from the unfavorable hydrophobic surrounding. Since this mechanism of attraction is of a thermodynamic nature and is not based on molecular shape specificity, a large diversity of sub-optimal cholesterol attracting sequences can exist. The puzzling sequence variability of proposed linear cholesterol-recognition motifs is thus consistent with sub-optimal, unspecific binding of cholesterol. Importantly, since evo-MD uniquely enables the targeted design of recognition motifs for distinct fluid lipid membranes, we foresee wide applications for evo-MD in the biological and biomedical fields.

scholarly journals Molecular dynamics simulations of membrane deformation induced by the amphiphilic helices of Epsin, Sar1p and Arf1

2017 ◽  
Author(s):  
Zhen-lu Li
Keyword(s):  
Lipid Membranes ◽  
Critical Role ◽  
Membrane Curvature ◽  
Coarse Grained ◽  
Insertion Depth ◽  
Membrane Deformation ◽  
Specific Distribution ◽  
Amphiphilic Helix ◽  
Coarse Grained Simulations ◽  
Dynamics Simulations

AbstractThe N-terminal amphiphilic helices of proteins Epsin, Sar1p and Arf1 play a critical role in initiating membrane deformation. We present here the study of the interactions of these amphiphilic helices with the lipid membranes by combining the all-atom and coarse-grained simulations. In the all-atom simulations, we find that the amphiphilic helices of Epsin and Sar1p have a shallower insertion depth into the membrane compared to the amphiphilic helix of Arf1, but remarkably, the amphiphilic helices of Epsin and Sar1p induce higher asymmetry in the lipid packing between the two monolayers of the membrane. The insertion depth of amphiphilic helix into the membrane is determined not only by the overall hydrophobicity but also by the specific distribution of polar and non-polar residues along the helix. To directly compare their ability of deforming the membrane, we further apply coarse-grained simulations to investigate the membranes deformation under the insertion of multiple helices. Importantly, it is found that the amphiphilic helices of Epsin and Sar1p generate a larger membrane curvature than that of Arf1, in accord with the experimental results qualitatively. These findings enhance our understanding of the molecular mechanism of the protein-driven membrane remodeling.

scholarly journals Membrane fusion and drug delivery with carbon nanotube porins

2021 ◽  
Vol 118 (19) ◽  
pp. e2016974118
Author(s):  
Nga T. Ho ◽  
Marc Siggel ◽  
Karen V. Camacho ◽  
Ramachandra M. Bhaskara ◽  
Jacqueline M. Hicks ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Carbon Nanotube ◽  
Treatment Efficacy ◽  
Lipid Membranes ◽  
Coarse Grained ◽  
Membrane Material ◽  
Cytoplasmic Delivery ◽  
Life Saving ◽  
Wide Range ◽  
Dynamics Simulations

Drug delivery mitigates toxic side effects and poor pharmacokinetics of life-saving therapeutics and enhances treatment efficacy. However, direct cytoplasmic delivery of drugs and vaccines into cells has remained out of reach. We find that liposomes studded with 0.8-nm-wide carbon nanotube porins (CNTPs) function as efficient vehicles for direct cytoplasmic drug delivery by facilitating fusion of lipid membranes and complete mixing of the membrane material and vesicle interior content. Fusion kinetics data and coarse-grained molecular dynamics simulations reveal an unusual mechanism where CNTP dimers tether the vesicles, pull the membranes into proximity, and then fuse their outer and inner leaflets. Liposomes containing CNTPs in their membranes and loaded with an anticancer drug, doxorubicin, were effective in delivering the drug to cancer cells, killing up to 90% of them. Our results open an avenue for designing efficient drug delivery carriers compatible with a wide range of therapeutics.

scholarly journals Curvature induction and sensing of the F-BAR protein Pacsin1 on lipid membranes via molecular dynamics simulations

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Md. Iqbal Mahmood ◽  
Hiroshi Noguchi ◽  
Kei-ichi Okazaki
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Lipid Membranes ◽  
Lipid Membrane ◽  
Complex Structure ◽  
Membrane Curvature ◽  
Coarse Grained ◽  
Lateral Interaction ◽  
Bar Domain ◽  
Dynamics Simulations

Abstract F-Bin/Amphiphysin/Rvs (F-BAR) domain proteins play essential roles in biological processes that involve membrane remodelling, such as endocytosis and exocytosis. It has been shown that such proteins transform the lipid membrane into tubes. Notably, Pacsin1 from the Pacsin/Syndapin subfamily has the ability to transform the membrane into various morphologies: striated tubes, featureless wide and thin tubes, and pearling vesicles. The molecular mechanism of this interesting ability remains elusive. In this study, we performed all-atom (AA) and coarse-grained (CG) molecular dynamics simulations to investigate the curvature induction and sensing mechanisms of Pacsin1 on a membrane. From AA simulations, we show that Pacsin1 has internal structural flexibility. In CG simulations with parameters tuned from the AA simulations, spontaneous assembly of two Pacsin1 dimers through lateral interaction is observed. Based on the complex structure, we show that the regularly assembled Pacsin1 dimers bend a tensionless membrane. We also show that a single Pacsin1 dimer senses the membrane curvature, binding to a buckled membrane with a preferred curvature. These results provide molecular insights into polymorphic membrane remodelling.

Stability of membrane-induced self-assemblies of spherical nanoparticles

Soft Matter ◽  
2018 ◽  
Vol 14 (24) ◽  
pp. 5019-5030 ◽  
Author(s):  
Eric J. Spangler ◽  
P. B. Sunil Kumar ◽  
Mohamed Laradji
Keyword(s):  
Molecular Dynamics ◽  
Self Assembly ◽  
Lipid Membranes ◽  
The Self ◽  
Coarse Grained ◽  
Implicit Solvent ◽  
Spherical Nanoparticles ◽  
Implicit Solvent Model ◽  
Solvent Model ◽  
Dynamics Simulations

The self-assembly of spherical nanoparticles, resulting from their adhesion on tensionless lipid membranes, is investigated through molecular dynamics simulations of a coarse-grained implicit-solvent model for self-assembled lipid membranes.

scholarly journals Membrane perforation by the pore-forming toxin pneumolysin

2019 ◽  
Vol 116 (27) ◽  
pp. 13352-13357 ◽  
Author(s):  
Martin Vögele ◽  
Ramachandra M. Bhaskara ◽  
Estefania Mulvihill ◽  
Katharina van Pee ◽  
Özkan Yildiz ◽  
...  
Keyword(s):  
Lipid Membranes ◽  
Pore Formation ◽  
Line Tension ◽  
Coarse Grained ◽  
Membrane Pore ◽  
Membrane Pores ◽  
Membrane Perforation ◽  
Membrane Spanning ◽  
Dynamics Simulations ◽  
Key Steps

Pneumolysin (PLY), a major virulence factor ofStreptococcus pneumoniae, perforates cholesterol-rich lipid membranes. PLY protomers oligomerize as rings on the membrane and then undergo a structural transition that triggers the formation of membrane pores. Structures of PLY rings in prepore and pore conformations define the beginning and end of this transition, but the detailed mechanism of pore formation remains unclear. With atomistic and coarse-grained molecular dynamics simulations, we resolve key steps during PLY pore formation. Our simulations confirm critical PLY membrane-binding sites identified previously by mutagenesis. The transmembrane β-hairpins of the PLY pore conformation are stable only for oligomers, forming a curtain-like membrane-spanning β-sheet. Its hydrophilic inner face draws water into the protein–lipid interface, forcing lipids to recede. For PLY rings, this zone of lipid clearance expands into a cylindrical membrane pore. The lipid plug caught inside the PLY ring can escape by lipid efflux via the lower leaflet. If this path is too slow or blocked, the pore opens by membrane buckling, driven by the line tension acting on the detached rim of the lipid plug. Interestingly, PLY rings are just wide enough for the plug to buckle spontaneously in mammalian membranes. In a survey of electron cryo-microscopy (cryo-EM) and atomic force microscopy images, we identify key intermediates along both the efflux and buckling pathways to pore formation, as seen in the simulations.

scholarly journals Membrane thickness, lipid phase and sterol type are determining factors in the permeability of membranes to small solutes

2021 ◽  
Author(s):  
Jacopo Frallicciardi ◽  
Joseph Melcr ◽  
Pareskevi Siginou ◽  
Siewert Jan Marrink ◽  
Bert Poolman
Keyword(s):  
Lipid Membranes ◽  
Lipid Phase ◽  
Membrane Thickness ◽  
Bacterial Cells ◽  
Concentration Gradients ◽  
Kinetic Measurements ◽  
Systematic Analysis ◽  
Liquid Ordered ◽  
Dynamics Simulations

Cell membranes provide a selective semi-permeable barrier to the passive transport of molecules. This property differs greatly between organisms. While the cytoplasmic membrane of bacterial cells is highly permeable for weak acids and glycerol, yeasts can maintain large concentration gradients. Here we show that such differences can arise from the physical state of the plasma membrane. By combining stopped-flow kinetic measurements with molecular dynamics simulations, we performed a systematic analysis of the permeability through synthetic lipid membranes to obtain detailed molecular insight into the permeation mechanisms. While membrane thickness is an important parameter for the permeability through fluid membranes, the largest differences occur when the membranes transit from the liquid-disordered to liquid-ordered and/or to gel state. By comparing our results with in vivo measurements from yeast, we conclude that the yeast membrane exists in a highly ordered and rigid state, which is comparable to synthetic saturated DPPC-sterol membranes.

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