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Results for “Membrane Lipid Composition”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 37 records · Page 2
All sourcesNASA NTRSDOE OSTI
DOE OSTI2023

Mitocans induce lipid flip-flop and permeabilize the membrane to signal apoptosis

Pancratistatin (PST) and narciclasine (NRC) are natural therapeutic agents that exhibit specificity toward the mitochondria of cancerous cells and initiate apoptosis. Unlike traditional cancer therapeutic agents, PST and NRC are effective, targeted, and have limited adverse effects on neighboring healthy, noncancerous cells. Currently, the mechanistic pathway of action for PST and NRC remains elusive, which in part inhibits PST and NRC from becoming efficacious therapeutic alternatives. Herein, we use neutron and x-ray scattering in combination with calcein leakage assays to characterize the effects of PST, NRC, and tamoxifen (TAM) on a biomimetic model membrane. We report an increase in lipid flip-flop half-times (t 1/2 ) (≈12.0%, ≈35.1%, and a decrease of ≈45.7%) with 2 mol percent PST, NRC, and TAM respectively. An increase in bilayer thickness (≈6.3%, ≈7.8%, and ≈7.8%) with 2 mol percent PST, NRC, and TAM, respectively, was also observed. Lastly, increases in membrane leakage (≈31.7%, ≈37.0%, and ≈34.4%) with 2 mol percent PST, NRC, and TAM, respectively, were seen. Considering the maintenance of an asymmetric lipid composition across the outer mitochondrial membrane (OMM) is crucial to eukaryotic cellular homeostasis and survival, our results suggest PST and NRC may play a role in disrupting the native distribution of lipids within the OMM. A possible mechanism of action for PST- and NRC-induced mitochondrial apoptosis is proposed via the redistribution of the native OMM lipid organization and through OMM permeabilization.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Electrostatic gating of ion transport in carbon nanotube porins: A modeling study

Carbon nanotube porins (CNTPs) are biomimetic membrane channels that demonstrate excellent biocompatibility and unique water and ion transport properties. Gating transport in CNTPs with external voltage could increase control over ion flow and selectivity. Herein, we used continuum modeling to probe the parameters that enable and further affect CNTP gating efficiency, including the size and composition of the supporting lipid membrane, slip flow in the carbon nanotube, and the intrinsic electronic properties of the nanotube. Our results show that the optimal gated CNTP device consists of a semiconducting CNTP inserted into a small membrane patch containing an internally conductive layer. Moreover, we demonstrate that the ionic transport modulated by gate voltages is controlled by the charge distribution along the CNTP under the external gate electric potential. The theoretical understanding developed in this study offers valuable guidance for the design of gated CNTP devices for nanofluidic studies, novel biomimetic membranes, and cellular interfaces in the future.

36 MATERIALS SCIENCE↗
DOE OSTI2026

Protocol for Engineered Compositional Asymmetry Within Nanodiscs

Membrane proteins remain the most challenging targets for structural characterization, yet their elucidation provides valuable insights into protein function, disease mechanisms, and drug specificity. Structural biology platforms have advanced rapidly in recent years, notably through the development and implementation of nanodiscs—discoidal lipid–protein complexes that encapsulate and solubilize membrane proteins within a controlled, native-like environment. While nanodiscs have become powerful tools for studying membrane proteins, faithfully reconstituting the compositional asymmetry intrinsic to nearly all biological membranes has not yet been achieved. Proper membrane leaflet lipid distribution is critical for accurate protein folding, stability, and insertion. Here, we share a protocol for reconstituting tailored compositional asymmetry within nanodiscs through membrane extraction from giant unilamellar vesicles (GUVs) treated with a leaflet-specific methyl-β-cyclodextrin (mβCD) lipid exchange. Nanodisc asymmetry is verified through a geometric approach: biotin-DPPE-preloaded mβCD engages in lipid exchange with the outer leaflet of POPC GUVs solubilized by the lipid-free membrane scaffold protein (MSP) Δ49ApoA-I to form nanodisc structures. Once isolated, nanodiscs are introduced to the biotin-binding bacterial protein streptavidin. High-speed atomic force microscopy imaging depicts nanodisc–dimer complexes, indicating that biotin-DPPE was successfully reconstituted into a single leaflet of the nanodiscs. This finding outlines the first step toward engineering tailored nanodisc asymmetry and mimicking the native environment of integral proteins—a potentially powerful tool for accurately reconstituting and structurally analyzing integral membrane proteins whose functions are modulated by lipid asymmetry.

Biological and medical sciences↗
DOE OSTI2025

Highly tail-asymmetric lipids interdigitate and cause bidirectional ordering

Phospholipids form structurally and compositionally diverse membranes. A less studied type of compositional diversity involves phospholipid tail variety. Some phospholipids contain two acyl tails which differ in length. These tail-asymmetric lipids are shown to contribute to temperature sensitivity, oxygen adaptability, and membrane fluidity. Membranes of a highly virulent intracellular bacterium, Francisella tularensis, contain highly tail-asymmetric 1-lignoceroyl-2-decanoyl-sn-glycero-3-phosphatidylethanolamine (XJPE) lipids which were previously shown to inhibit inflammatory responses in host cells. XJPE tails have unusually high asymmetry, and how they contribute to membrane properties on a molecular level is unknown. Here, we use small angle X-ray scattering and molecular dynamics simulations to investigate how varying XJPE ratios alters properties of simple membranes. Our results demonstrate that at high concentration they promote liquid-to-gel transition in otherwise liquid membranes, while at low concentration they are tolerated well, minimally altering membrane properties. In liquid membranes, XJPE lipids dynamically adopt two main conformations; with the long tail extended into the opposing leaflet or bent-back residing in its own leaflet. When added to both leaflets XJPE primarily adopts an extended confirmation, while asymmetric addition results in more bent-back orientations. The former increases tail ordering and the latter decreases it. XJPE tails adopt different conformations that induce composition- and leaflet-dependent bidirectional effect on membrane fluidity and this suggests that Francisella tularensis could use tail asymmetry to facilitate vesicle fusion and destabilize host cells. The effect of tail-asymmetric lipids on complex membranes should be further investigated to reveal the regulatory roles of high tail asymmetry.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Phosphatidylinositol phosphates modulate interactions between the StarD4 sterol trafficking protein and lipid membranes

There is substantial evidence for extensive nonvesicular sterol transport in cells. For example, lipid transfer by the steroidogenic acute regulator-related proteins (StarD) containing a StarT domain has been shown to involve several pathways of nonvesicular trafficking. Among the soluble StarT domain–containing proteins, StarD4 is expressed in most tissues and has been shown to be an effective sterol transfer protein. However, it was unclear whether the lipid composition of donor or acceptor membranes played a role in modulating StarD4-mediated transport. Here, we used fluorescence-based assays to demonstrate a phosphatidylinositol phosphate (PIP)-selective mechanism by which StarD4 can preferentially extract sterol from liposome membranes containing certain PIPs (especially, PI(4,5)P 2 and to a lesser degree PI(3,5)P2). Monophosphorylated PIPs and other anionic lipids had a smaller effect on sterol transport. This enhancement of transport was less effective when the same PIPs were present in the acceptor membranes. Furthermore, using molecular dynamics (MD) simulations, we mapped the key interaction sites of StarD4 with PIP-containing membranes and identified residues that are important for this interaction and for accelerated sterol transport activity. We show that StarD4 recognizes membrane-specific PIPs through specific interaction with the geometry of the PIP headgroup as well as the surrounding membrane environment. Finally, we also observed that StarD4 can deform membranes upon longer incubations. Taken together, these results suggest a mechanism by which PIPs modulate cholesterol transfer activity via StarD4.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

Impact of Fatty-Acid Labeling of Bacillus subtilis Membranes on the Cellular Lipidome and Proteome

Developing cultivation methods that yield chemically and isotopically defined fatty acid (FA) compositions within bacterial cytoplasmic membranes establishes an in vivo experimental platform to study membrane biophysics and cell membrane regulation using novel approaches. Yet before fully realizing the potential of this method, it is prudent to understand the systemic changes in cells induced by the labeling procedure itself. In this work, analysis of cellular membrane compositions was paired with proteomics to assess how the proteome changes in response to the directed incorporation of exogenous FAs into the membrane of Bacillus subtilis. Key findings from this analysis include an alteration in lipid headgroup distribution, with an increase in phosphatidylglycerol lipids and decrease in phosphatidylethanolamine lipids, possibly providing a fluidizing effect on the cell membrane in response to the induced change in membrane composition. Changes in the abundance of enzymes involved in FA biosynthesis and degradation are observed; along with changes in abundance of cell wall enzymes and isoprenoid lipid production. The observed changes may influence membrane organization, and indeed the well-known lipid raft-associated protein flotillin was found to be substantially down-regulated in the labeled cells – as was the actin-like protein MreB. Taken as a whole, this study provides a greater depth of understanding for this important cell membrane experimental platform and presents a number of new connections to be explored in regard to modulating cell membrane FA composition and its effects on lipid headgroup and raft/cytoskeletal associated proteins.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Investigation of the Impact of Lipid Acyl Chain Saturation on Fusion Peptide Interactions with Lipid Bilayers

The interaction of many peptides with lipid bilayer membranes strongly depends on the lipid composition. Here, a study of the impact of unsaturated lipid acyl chains on the interaction of a derivative of the HIV-1 fusion peptide with lipid bilayer vesicles is presented. Lipid bilayer vesicles composed of mixtures of lipids with two saturated acyl chains and lipids and one saturated and one unsaturated acyl chain, but identical head groups, were studied. The dependence of the peptide conformation on the unsaturated lipid content was probed by circular dichroism spectroscopy, while the impact of the peptide on the bilayer structure was determined by small-angle neutron scattering. The impact of the peptide on the lipid bilayer vesicle dynamics was investigated using neutron spin echo spectroscopy. Molecular dynamics simulations were used to characterize the behavior of the systems studied to determine if there were clear differences in their physical properties. The results reveal that the peptide–bilayer interaction is not a simple function of the unsaturated lipid acyl chain content of the bilayer. Instead, the peptide behavior is more consistent with that seen for the bilayer containing only unsaturated lipids, which is supported by lipid-specific interactions revealed by the simulations.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Nanoscale simulation of the thylakoid membrane response to extreme temperatures

Abstract The thylakoid membrane is in a temperature‐sensitive equilibrium that shifts repeatedly during the life cycle in response to ambient temperature or solar irradiance. Plants respond to seasonal temperature variation by changing their thylakoid lipid composition, while a more rapid mechanism for short‐term heat exposure is required. The emission of the small organic molecule isoprene has been postulated as one such possible rapid mechanism. The protective mechanism of isoprene is unknown, but some plants emit isoprene at high temperature. We investigate the dynamics and structure for lipids within a thylakoid membrane across temperatures and varied isoprene content using classical molecular dynamics simulations. The results are compared with experimental findings for temperature‐dependent changes in the lipid composition and shape of thylakoids. The surface area, volume, and flexibility of the membrane, as well as the lipid diffusion, increase with temperature, while the membrane thickness decreases. Saturated thylakoid 34:3 glycolipids derived from eukaryotic synthesis pathways exhibit altered dynamics relative to lipids from prokaryotic synthesis paths, which could explain the upregulation of specific lipid synthesis pathways at different temperatures. Increasing isoprene concentration was not observed to have a significant thermoprotective effect on the thylakoid membranes, and that isoprene readily permeated the membrane models tested.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Membrane hydrophobicity determines the activation free energy of passive lipid transport

The collective behavior of lipids with diverse chemical and physical features determines a membrane's thermodynamic properties. Yet, the influence of lipid physicochemical properties on lipid dynamics, in particular interbilayer transport, remains underexplored. Here, we systematically investigate how the activation free energy of passive lipid transport depends on lipid chemistry and membrane phase. Through all-atom molecular dynamics simulations of 11 chemically distinct glycerophospholipids, we determine how lipid acyl chain length, unsaturation, and headgroup influence the free energy barriers for two elementary steps of lipid transport: lipid desorption, which is rate limiting, and lipid insertion into a membrane. Consistent with previous experimental measurements, we find that lipids with longer, saturated acyl chains have increased activation free energies compared to lipids with shorter, unsaturated chains. Lipids with different headgroups exhibit a range of activation free energies; however, no clear trend based solely on chemical structure can be identified, mirroring difficulties in the interpretation of previous experimental results. Compared to liquid-crystalline phase membranes, gel phase membranes exhibit substantially increased free energy barriers. Overall, we find that the activation free energy depends on a lipid's local hydrophobic environment in a membrane and that the free energy barrier for lipid insertion depends on a membrane's interfacial hydrophobicity. Both of these properties can be altered through changes in lipid acyl chain length, lipid headgroup, and membrane phase. Thus, the rate of lipid transport can be tuned through subtle changes in local membrane composition and order, suggesting an unappreciated role for nanoscale membrane domains in regulating cellular lipid dynamics.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Membrane Profiling by Free Flow Electrophoresis and SWATH-MS to Characterize Subcellular Compartment Proteomes in Mesembryanthemum crystallinum

The study of subcellular membrane structure and function facilitates investigations into how biological processes are divided within the cell. However, work in this area has been hampered by the limited techniques available to fractionate the different membranes. Free Flow Electrophoresis (FFE) allows for the fractionation of membranes based on their different surface charges, a property made up primarily of their varied lipid and protein compositions. In this study, high-resolution plant membrane fractionation by FFE, combined with mass spectrometry-based proteomics, allowed the simultaneous profiling of multiple cellular membranes from the leaf tissue of the plant Mesembryanthemum crystallinum. Comparisons of the fractionated membranes’ protein profile to that of known markers for specific cellular compartments sheds light on the functions of proteins, as well as provides new evidence for multiple subcellular localization of several proteins, including those involved in lipid metabolism.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2025

Dynamics and lipid membrane coupling of the RAS-RAF complex revealed via multiscale simulations

To gain molecular and mechanistic insights into initiation of the RAS-RAF signaling cascade, we developed and used a combination of multiscale simulation and experimental approaches. The influence and impact of the membrane on RAS and RAF proteins is a factor we are just beginning to understand and appreciate in more detail. Molecular simulation is an ideal methodology to further study this complicated relationship between the membrane and associated proteins. Our previous work using Multiscale Machine-learned Modeling Infrastructure investigated different lipid compositions solely around the KRAS4b protein and the interplay between protein behavior and these membrane environments. Multiscale Machine-learned Modeling Infrastructure uses machine learning to couple adjacent simulation scales and has been efficiently scaled across some of the world’s largest high-performance computers. Recently, we have expanded this multiresolution framework to include the all-atom simulation scale and to incorporate the RAF RBDCRD domains. Here, we present the overall analysis results from this new simulation campaign comprising a mixture of RAS and RAF RBDCRD proteins. Approximately 35,000 coarse-grained and 10,000 all-atom molecular dynamics simulations were completed, sampled from a variety of protein/lipid composition configurations that were generated from a micron-scale continuum simulation containing hundreds of copies of the proteins. Our studies suggest that orientations of the RAS-RBDCRD complex on the membrane occupy distinct configurational states, and the spatial patterns of lipid arrangements around these different protein states are unique to each state. The extent and size of lipid “fingerprints” imposed on the membrane by the RAS-RBDCRD protein complex are significantly larger than observed for just the RAS protein on its own. These protein complexes strongly associate, but we do not observe statistically significant preferred protein-protein orientations. These observations indicate that spatial colocalization of RAS-RBDCRD proteins in the same vicinity may be assisted by specific membrane environments, acting to increase the probability of signaling complex formation.

Carpenter, Timothy S. [Lawrence Livermore National↗
DOE OSTI2023

Brominated lipid probes expose structural asymmetries in constricted membranes

Lipids in biological membranes are thought to be functionally organized, but few experimental tools can probe nanoscale membrane structure. Using brominated lipids as contrast probes for cryo-EM and a model ESCRT-III membrane-remodeling system composed of human CHMP1B and IST1, we observed leaflet-level and protein-localized structural lipid patterns within highly constricted and thinned membrane nanotubes. These nanotubes differed markedly from protein-free, flat bilayers in leaflet thickness, lipid diffusion rates and lipid compositional and conformational asymmetries. Simulations and cryo-EM imaging of brominated stearoyl-docosahexanenoyl-phosphocholine showed how a pair of phenylalanine residues scored the outer leaflet with a helical hydrophobic defect where polyunsaturated docosahexaenoyl tails accumulated at the bilayer surface. Combining cryo-EM of halogenated lipids with molecular dynamics thus enables new characterizations of the composition and structure of membranes on molecular length scales.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

MOMP telonanoparticles, and related compositions, methods and systems

A telodendrimer-nanolipoprotein particle (t-NLP), comprising one or more membrane forming lipids, one or more telodendrimers, and a scaffold protein and a Chlamydia major outer membrane protein (MOMP) comprising a MOMP hydrophobic region, and related compositions methods and systems.

Coleman, Matthew A.↗
DOE OSTI2020

Functional lipid pairs as building blocks of phase-separated membranes

Biological membranes exhibit a great deal of compositional and phase heterogeneity due to hundreds of chemically distinct components. As a result, phase separation processes in cell membranes are extremely difficult to study, especially at the molecular level. It is currently believed that the lateral membrane heterogeneity and the formation of domains, or rafts, are driven by lipid–lipid and lipid–protein interactions. Nevertheless, the underlying mechanisms regulating membrane heterogeneity remain poorly understood. In the present work, we combine inelastic X-ray scattering with molecular dynamics simulations to provide direct evidence for the existence of strongly coupled transient lipid pairs. These lipid pairs manifest themselves experimentally through optical vibrational (a.k.a. phononic) modes observed in binary (1,2-dipalmitoyl- sn -glycero-3-phosphocholine [DPPC]–cholesterol) and ternary (DPPC–1,2-dioleoyl- sn -glycero-3-phosphocholine/1-palmitoyl-2-oleoyl-glycero-3-phosphocholine [DOPC/POPC]–cholesterol) systems. The existence of a phononic gap in these vibrational modes is a direct result of the finite size of patches formed by these lipid pairs. The observation of lipid pairs provides a spatial (subnanometer) and temporal (subnanosecond) window into the lipid–lipid interactions in complex mixtures of saturated/unsaturated lipids and cholesterol. Our findings represent a step toward understanding the lateral organization and dynamics of membrane domains using a well-validated probe with a high spatial and temporal resolution.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Amantadine interactions with phase separated lipid membranes

Amantadine, a small amphilphic organic compound that consists of an adamantane backbone and an amino group, was first recognized as an antiviral in 1963 and received approval for prophylaxis against the type A influenza virus in 1976. Since then, it has also been used to treat Parkinson’s disease-related dyskinesia and is being considered as a treatment for corona viruses. Since amantadine usually targets membrane-bound proteins, its interactions with the membrane are also thought to be important. Biological membranes are now widely understood to be laterally heterogeneous and certain proteins are known to preferentially co-localize within specific lipid domains. Does amantadine, therefore, preferentially localize in certain lipid composition domains? To address this question, here, we studied amantadine’s interactions with phase separating membranes composed of cholesterol, DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), POPC (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine), and DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), as well as single-phase DPhPC (1,2-diphytanoyl-sn-glycero-3-phos-phocholine) membranes. From Langmuir trough and differential scanning calorimetry (DSC) measurements, we determined, respectively, that amantadine preferentially binds to disordered lipids, such as POPC, and lowers the phase transition temperature of POPC/DSPC/cholesterol mixtures, implying that amantadine increases membrane disorder. Further, using droplet interface bilayers (DIBs), we observed that amantadine disrupts DPhPC membranes, consistent with its disordering properties. Finally, we carried out molecular dynamics (MD) simulations on POPC/DSPC/cholesterol membranes with varying amounts of amantadine. Consistent with experiment, MD simulations showed that amantadine prefers to associate with disordered POPC-rich domains, domain boundaries, and lipid glycerol backbones. Since different proteins co-localize with different lipid domains, our results have possible implications as to which classes of proteins may be better targets for amantadine.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2025

Cholesterol modulates membrane elasticity via unified biophysical laws

Cholesterol and lipid unsaturation underlie a balance of opposing forces that features prominently in adaptive cell responses to diet and environmental cues. These competing factors have resulted in contradictory observations of membrane elasticity across different measurement scales, requiring chemical specificity to explain incompatible structural and elastic effects. Here, we demonstrate that – unlike macroscopic observations – lipid membranes exhibit a unified elastic behavior in the mesoscopic regime between molecular and macroscopic dimensions. Using nuclear spin techniques and computational analysis, we find that mesoscopic bending moduli follow a universal dependence on the lipid packing density regardless of cholesterol content, lipid unsaturation, or temperature. Our observations reveal that compositional complexity can be explained by simple biophysical laws that directly map membrane elasticity to molecular packing associated with biological function, curvature transformations, and protein interactions. The obtained scaling laws closely align with theoretical predictions based on conformational chain entropy and elastic stress fields. These findings provide unique insights into the membrane design rules optimized by nature and unlock predictive capabilities for guiding the functional performance of lipid-based materials in synthetic biology and real-world applications.

Kumarage, Teshani [Virginia Polytechnic Inst. and ↗
DOE OSTI2022

Using molecular simulation to understand the skin barrier

Skin's effectiveness as a barrier to permeation of water and other chemicals rests almost entirely in the outermost layer of the epidermis, the stratum corneum (SC), which consists of layers of corneocytes surrounded by highly organized lipid lamellae. As the only continuous path through the SC, transdermal permeation necessarily involves diffusion through these lipid layers. The role of the SC as a protective barrier is supported by its exceptional lipid composition consisting of ceramides (CERs), cholesterol (CHOL), and free fatty acids (FFAs) and the complete absence of phospholipids, which are present in most biological membranes. Molecular simulation, which provides molecular level detail of lipid configurations that can be connected with barrier function, has become a popular tool for studying SC lipid systems. We review this ever-increasing body of literature with the goals of (1) enabling the experimental skin community to understand, interpret and use the information generated from the simulations, (2) providing simulation experts with a solid background in the chemistry of SC lipids including the composition, structure and organization, and barrier function, and (3) presenting a state of the art picture of the field of SC lipid simulations, highlighting the difficulties and best practices for studying these systems, to encourage the generation of robust reproducible studies in the future. This review describes molecular simulation methodology and then critically examines results derived from simulations using atomistic and then coarse-grained models.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

From sensing to acclimation: The role of membrane lipid remodeling in plant responses to low temperatures

Abstract Low temperatures pose a dramatic challenge to plant viability. Chilling and freezing disrupt cellular processes, forcing metabolic adaptations reflected in alterations to membrane compositions. Understanding the mechanisms of plant cold tolerance is increasingly important due to anticipated increases in the frequency, severity, and duration of cold events. This review synthesizes current knowledge on the adaptive changes of membrane glycerolipids, sphingolipids, and phytosterols in response to cold stress. We delve into key mechanisms of low-temperature membrane remodeling, including acyl editing and headgroup exchange, lipase activity, and phytosterol abundance changes, focusing on their impact at the subcellular level. Furthermore, we tabulate and analyze current gycerolipidomic data from cold treatments of Arabidopsis, maize, and sorghum. This analysis highlights congruencies of lipid abundance changes in response to varying degrees of cold stress. Ultimately, this review aids in rationalizing observed lipid fluctuations and pinpoints key gaps in our current capacity to fully understand how plants orchestrate these membrane responses to cold stress.

Plant Sciences↗