scholarly journals Membrane-wrapped nanoparticles probe divergent roles of GM3 and phosphatidylserine in lipid-mediated viral entry pathways

2018 ◽  
Vol 115 (39) ◽  
pp. E9041-E9050 ◽  
Author(s):  
Fangda Xu ◽  
Asanga Bandara ◽  
Hisashi Akiyama ◽  
Behnaz Eshaghi ◽  
David Stelter ◽  
...  
Keyword(s):  
Viral Entry ◽  
Lipid Membrane ◽  
Membrane Composition ◽  
Binding Studies ◽  
Antagonistic Action ◽  
Intracellular Targeting ◽  
Biological Surface ◽  
Artificial Virus ◽  
Optical Cross Section ◽  
Dynamics Simulations

Gold nanoparticles (NPs) wrapped in a membrane can be utilized as artificial virus nanoparticles (AVNs) that combine the large nonblinking or bleaching optical cross-section of the NP core with the biological surface properties and functionalities provided by a self-assembled lipid membrane. We used these hybrid nanomaterials to test the roles of monosialodihexosylganglioside (GM3) and phosphatidylserine (PS) for a lipid-mediated targeting of virus-containing compartments (VCCs) in macrophages. GM3-presenting AVNs bind to CD169 (Siglec-1)–expressing macrophages, but inclusion of PS in the GM3-containing AVN membrane decreases binding. Molecular dynamics simulations of the AVN membrane and experimental binding studies of CD169 to GM3-presenting AVNs reveal Na+-mediated interactions between GM3 and PS as a potential cause of the antagonistic action on binding by the two negatively charged lipids. GM3-functionalized AVNs with no or low PS content localize to tetherin+, CD9+ VCC in a membrane composition-depending fashion, but increasing amounts of PS in the AVN membrane redirect the NP to lysosomal compartments. Interestingly, this compartmentalization is highly GM3 specific. Even AVNs presenting the related monosialotetrahexosylganglioside (GM1) fail to achieve an accumulation in VCC. AVN localization to VCC was observed for AVN with gold NP core but not for liposomes, suggesting that NP sequestration into VCC has additional requirements beyond ligand (GM3)–receptor (CD169) recognition that are related to the physical properties of the NP core. Our results confirm AVN as a scalable platform for elucidating the mechanisms of lipid-mediated viral entry pathways and for selective intracellular targeting.

scholarly journals Unsaturated fatty acids augment protein transport via the SecA:SecYEG translocon

2021 ◽  
Author(s):  
Michael Kamel ◽  
Maryna Löwe ◽  
Stephan Schott-Verdugo ◽  
Holger Gohlke ◽  
Alexej Kedrov
Keyword(s):  
Fatty Acids ◽  
Protein Transport ◽  
Unsaturated Fatty Acids ◽  
Lipid Membrane ◽  
Cell Envelope ◽  
Membrane Surface ◽  
Bacterial Cells ◽  
Hydrophobic Core ◽  
Membrane Composition ◽  
Dynamics Simulations

AbstractThe translocon SecYEG forms the primary protein-conducting channel in the cytoplasmic membrane of bacteria, and the associated ATPase SecA provides the energy for the transport of secretory and cell envelope protein precursors. The translocation requires negative charge at the lipid membrane surface, but its dependence on the properties of the membrane hydrophobic core is not known. Here, we demonstrate that SecA:SecYEG-mediated protein transport is immensely stimulated by unsaturated fatty acids (UFAs). Furthermore, UFA-rich tetraoleoyl-cardiolipin, but not bis(palmitoyloleoyl)-cardiolipin, facilitate the translocation via the monomeric translocon. Biophysical analysis and molecular dynamics simulations show that UFAs determine the loosely packed membrane interface, where the N-terminal amphipathic helix of SecA docks. While UFAs do not affect the translocon folding, they promote SecA binding to the membrane, and the effect is enhanced manifold at elevated ionic strength. Tight SecA:lipid interactions convert into the augmented translocation. As bacterial cells actively change their membrane composition in response to their habitat, the modulation of SecA:SecYEG activity via the fatty acids may be crucial for protein secretion over a broad range of environmental conditions.

scholarly journals Menaquinone-mediated regulation of membrane fluidity is relevant for fitness of Listeria monocytogenes

2021 ◽  
Author(s):  
Alexander Flegler ◽  
Vanessa Kombeitz ◽  
André Lipski
Keyword(s):  
Fatty Acid ◽  
Listeria Monocytogenes ◽  
Membrane Fluidity ◽  
Low Temperatures ◽  
Lipid Membrane ◽  
Feedback Inhibition ◽  
Aromatic Amino Acids ◽  
Adaptation Effect ◽  
Membrane Composition ◽  
Lower Growth

AbstractListeria monocytogenes is a food-borne pathogen with the ability to grow at low temperatures down to − 0.4 °C. Maintaining cytoplasmic membrane fluidity by changing the lipid membrane composition is important during growth at low temperatures. In Listeria monocytogenes, the dominant adaptation effect is the fluidization of the membrane by shortening of fatty acid chain length. In some strains, however, an additional response is the increase in menaquinone content during growth at low temperatures. The increase of this neutral lipid leads to fluidization of the membrane and thus represents a mechanism that is complementary to the fatty acid-mediated modification of membrane fluidity. This study demonstrated that the reduction of menaquinone content for Listeria monocytogenes strains resulted in significantly lower resistance to temperature stress and lower growth rates compared to unaffected control cultures after growth at 6 °C. Menaquinone content was reduced by supplementation with aromatic amino acids, which led to a feedback inhibition of the menaquinone synthesis. Menaquinone-reduced Listeria monocytogenes strains showed reduced bacterial cell fitness. This confirmed the adaptive function of menaquinones for growth at low temperatures of this pathogen.

scholarly journals Structure and Interdigitation of Chain-Asymmetric Phosphatidylcholines and Milk Sphingomyelin in the Fluid Phase

Symmetry ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1441
Author(s):  
Moritz P. K. Frewein ◽  
Milka Doktorova ◽  
Frederick A. Heberle ◽  
Haden L. Scott ◽  
Enrico F. Semeraro ◽  
...  
Keyword(s):  
Chain Length ◽  
Hydration Shell ◽  
Fluid Phase ◽  
Hydrocarbon Chain ◽  
Specific Model ◽  
Glycerol Backbone ◽  
Membrane Composition ◽  
Membrane Structures ◽  
Hydrocarbon Chain Length ◽  
Dynamics Simulations

We addressed the frequent occurrence of mixed-chain lipids in biological membranes and their impact on membrane structure by studying several chain-asymmetric phosphatidylcholines and the highly asymmetric milk sphingomyelin. Specifically, we report trans-membrane structures of the corresponding fluid lamellar phases using small-angle X-ray and neutron scattering, which were jointly analyzed in terms of a membrane composition-specific model, including a headgroup hydration shell. Focusing on terminal methyl groups at the bilayer center, we found a linear relation between hydrocarbon chain length mismatch and the methyl-overlap for phosphatidylcholines, and a non-negligible impact of the glycerol backbone-tilting, letting the sn1-chain penetrate deeper into the opposing leaflet by half a CH2 group. That is, penetration-depth differences due to the ester-linked hydrocarbons at the glycerol backbone, previously reported for gel phase structures, also extend to the more relevant physiological fluid phase, but are significantly reduced. Moreover, milk sphingomyelin was found to follow the same linear relationship suggesting a similar tilt of the sphingosine backbone. Complementarily performed molecular dynamics simulations revealed that there is always a part of the lipid tails bending back, even if there is a high interdigitation with the opposing chains. The extent of this back-bending was similar to that in chain symmetric bilayers. For both cases of adaptation to chain length mismatch, chain-asymmetry has a large impact on hydrocarbon chain ordering, inducing disorder in the longer of the two hydrocarbons.

scholarly journals A de novo substitution in BCL11B leads to loss of interaction with transcriptional complexes and craniosynostosis

2019 ◽  
Vol 28 (15) ◽  
pp. 2501-2513 ◽  
Author(s):  
Jacqueline A C Goos ◽  
Walter K Vogel ◽  
Hana Mlcochova ◽  
Christopher J Millard ◽  
Elahe Esfandiari ◽  
...  
Keyword(s):  
De Novo ◽  
Cranial Sutures ◽  
Coronal Suture ◽  
Nurd Complex ◽  
Binding Studies ◽  
Amino Terminal ◽  
Skull Vault ◽  
Order Of Magnitude ◽  
Transcriptional Complexes ◽  
Dynamics Simulations

Abstract Craniosynostosis, the premature ossification of cranial sutures, is a developmental disorder of the skull vault, occurring in approximately 1 in 2250 births. The causes are heterogeneous, with a monogenic basis identified in ~25% of patients. Using whole-genome sequencing, we identified a novel, de novo variant in BCL11B, c.7C>A, encoding an R3S substitution (p.R3S), in a male patient with coronal suture synostosis. BCL11B is a transcription factor that interacts directly with the nucleosome remodelling and deacetylation complex (NuRD) and polycomb-related complex 2 (PRC2) through the invariant proteins RBBP4 and RBBP7. The p.R3S substitution occurs within a conserved amino-terminal motif (RRKQxxP) of BCL11B and reduces interaction with both transcriptional complexes. Equilibrium binding studies and molecular dynamics simulations show that the p.R3S substitution disrupts ionic coordination between BCL11B and the RBBP4–MTA1 complex, a subassembly of the NuRD complex, and increases the conformational flexibility of Arg-4, Lys-5 and Gln-6 of BCL11B. These alterations collectively reduce the affinity of BCL11B p.R3S for the RBBP4–MTA1 complex by nearly an order of magnitude. We generated a mouse model of the BCL11B p.R3S substitution using a CRISPR-Cas9-based approach, and we report herein that these mice exhibit craniosynostosis of the coronal suture, as well as other cranial sutures. This finding provides strong evidence that the BCL11B p.R3S substitution is causally associated with craniosynostosis and confirms an important role for BCL11B in the maintenance of cranial suture patency.

Abstract P404: Membrane Composition Of Cardiac-derived Extracellular Vesicles Changes With Vesicle Origin And Determines Uptake

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Sruti Bheri ◽  
Jessica R Hoffman ◽  
Hyun-Ji Park ◽  
Michael E Davis
Keyword(s):  
Extracellular Vesicles ◽  
Lipid Membrane ◽  
Recipient Cell ◽  
Donor Cell ◽  
Membrane Lipid ◽  
Least Squares Regression ◽  
Membrane Composition ◽  
Cell Type ◽  
Uptake Mechanism ◽  
Donor Cell Type

Introduction: Myocardial infarction (MI) is a leading cause of mortality worldwide. The potency of cell-based therapies for MI is increasingly attributed to the release of extracellular vesicles (EVs) which consist of a lipid/protein membrane and encapsulate RNA cargo. Specifically, EVs from ckit+ progenitor cells (CPCs) and mesenchymal stromal cells (MSCs) are shown to be pro-reparative, with clinical trials ongoing. Despite copious research into EV cargo, the role of donor cell type on EV membrane composition and its effects on EV uptake mechanism by recipient cells remain unclear. This is crucial for designing EV-based therapeutics as uptake mechanism dictates the functionality of the cargo. Thus, we hypothesized that (1) EV membrane composition varies by donor cell type and (2) this variation covaries with the mechanism of uptake. Methods: EVs were isolated using differential ultracentrifugation from four cardiac cell types: CPCs, MSCs, cardiac endothelial cells (CECs) and rat cardiac fibroblasts (RCFs) grown in normoxia (18% O 2 ) or hypoxia (1% O 2 ) to mimic ischemic conditions. EVs were characterized for size and concentration. EV lipid membrane profile was assessed through LC/MS/MS. Donor cell’s role on EV uptake mechanism was determined by inhibiting known uptake pathways (clathrin, dynamin, macropinocytosis and caveolae/lipid raft) with small molecules and quantifying CEC/RCF endocytosis of EVs with flow cytometry. Finally, partial least squares regression was used to determine the most important lipids involved in EV uptake mechanism. Results: EVs were successfully isolated and characterized. The EV membrane lipid profiles clustered by donor cell type. Uptake mechanism of EVs varied based on both donor and recipient cell type with dynamin mediated endocytosis being the most common. Further, the uptake mechanism was independent of normoxic/hypoxic conditioning. Finally, supervised learning methods revealed specific lipid classes (sphingolipids and glycerophospholipids) covaried with EV uptake mechanism. Conclusion: This work highlights the importance of the understudied EV membrane and its role in delivering therapeutic cargo. Active donor cell selection for efficient EV uptake will allow for more potent EV-based MI therapies.

scholarly journals Computational Study of the Interaction of a PEGylated Hyperbranched Polymer/Doxorubicin Complex with a Bilipid Membrane

Fluids ◽  
2019 ◽  
Vol 4 (1) ◽  
pp. 17 ◽  
Author(s):  
Prodromos Arsenidis ◽  
Kostas Karatasos
Keyword(s):  
Hyperbranched Polymer ◽  
Lipid Membrane ◽  
Hydrophobic Interactions ◽  
Computational Study ◽  
Translational Motion ◽  
Spatial Arrangement ◽  
Aqueous Environment ◽  
Drug Molecules ◽  
Dynamics Simulations ◽  
A Charge

Fully atomistic molecular dynamics simulations are employed to study in detail the interactions between a complex comprised by a PEGylated hyperbranched polyester (HBP) and doxorubicin molecules, with a model dipalmitoylphosphatidylglycerol membrane in an aqueous environment. The effects of the presence of the lipid membrane in the drug molecules’ spatial arrangement were examined in detail and the nature of their interaction with the latter were discussed and quantified where possible. It was found that a partial migration of the drug molecules towards the membrane’s surface takes place, driven either by hydrogen-bonding (for the protonated drugs) or by hydrophobic interactions (for the neutral drug molecules). The clustering behavior of the drug molecules appeared to be enhanced in the presence of the membrane, while the development of a charge excess close to the surface of the hyperbranched polymer and of the lipid membrane was observed. The uneven charge distribution created an effective overcharging of the HBP/drug complex and the membrane/drug surface. The translational motion of the drug molecules was found to be strongly affected by the presence of the membrane. The extent of the observed changes depended on the charge of the drug molecule. The build-up of the observed charge excesses close to the surface of the polymeric host and the membrane, together with the changes in the diffusional behavior of the drug molecules are of particular interest. Both phenomena could be important at the latest stages of the liposomal disruption and the release of the drug cargo in formulations based on relevant liposomal carriers.

scholarly journals Complexity in Lipid Membrane Composition Induces Resilience to Aβ42 Aggregation

2020 ◽  
Vol 11 (9) ◽  
pp. 1347-1352 ◽  
Author(s):  
Michele Sanguanini ◽  
Kevin N. Baumann ◽  
Swapan Preet ◽  
Sean Chia ◽  
Johnny Habchi ◽  
...  
Keyword(s):  
Lipid Membrane ◽  
Membrane Composition

A Finite Element-Based Coarse-Grained Model for Cell–Nanomaterial Interactions by Combining Absolute Nodal Coordinate Formula and Brownian Dynamics

2020 ◽  
Vol 88 (4) ◽  
Author(s):  
Teng Ma ◽  
Yuanpeng Liu ◽  
Guochang Lin ◽  
Changguo Wang ◽  
Huifeng Tan
Keyword(s):  
Finite Element ◽  
Brownian Dynamics ◽  
Lipid Membrane ◽  
Contact Region ◽  
Detection Algorithm ◽  
Polymer Chains ◽  
Coarse Grained ◽  
Absolute Nodal Coordinate ◽  
Coarse Grained Model ◽  
Dynamics Simulations

Abstract A fundamental understanding of the interactions between one-dimensional nanomaterials and the cell membrane is of great importance for assessing the hazardous effects of viruses and improving the performance of drug delivery. Here, we propose a finite element-based coarse-grained model to describe the cell entry of nanomaterials based on an absolute nodal coordinate formula and Brownian dynamics. The interactions between nanoparticles and lipid membrane are described by the Lennard–Jones potential, and a contact detection algorithm is used to determine the contact region. Compared with the theoretical and published experimental results, the correctness of the model has been verified. We take two examples to test the robustness of the model: the endocytosis of nanorods grafted with polymer chains and simultaneous entry of multiple nanorods into a lipid membrane. It shows that the model can not only capture the effect of ligand–receptor binding on the penetration but also accurately characterize the cooperative or separate entry of multiple nanorods. This coarse-grained model is computationally highly efficient and will be powerful in combination with molecular dynamics simulations to provide an understanding of cell–nanomaterial interactions.

scholarly journals Structure and Dynamics of Glycosphingolipids in Lipid Bilayers: Insights from Molecular Dynamics Simulations

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Ronak Y. Patel ◽  
Petety V. Balaji
Keyword(s):  
Molecular Dynamics ◽  
Lipid Bilayers ◽  
Membrane Structure ◽  
Lipid Membrane ◽  
Biological Membranes ◽  
Md Simulations ◽  
Atomic Level ◽  
Structure And Dynamics ◽  
Hydrogen Bonding Interactions ◽  
Dynamics Simulations

Glycolipids are important constituents of biological membranes, and understanding their structure and dynamics in lipid bilayers provides insights into their physiological and pathological roles. Experimental techniques have provided details into their behavior at model and biological membranes; however, computer simulations are needed to gain atomic level insights. This paper summarizes the insights obtained from MD simulations into the conformational and orientational dynamics of glycosphingolipids and their exposure, hydration, and hydrogen-bonding interactions in membrane environment. The organization of glycosphingolipids in raft-like membranes and their modulation of lipid membrane structure are also reviewed.

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