Roughness of a transmembrane peptide reduces lipid membrane dynamics

Transmembrane domains integrate proteins into cellular membranes and support their function. The capacity of these prevalently a-helical structures in mammals to influence membrane properties is poorly understood. Combining experiments with molecular dynamics simulations, we provide evidence that helical transmembrane peptides with their rough surface reduce lateral mobility of membrane constituents. The molecular mechanism involves trapping of lipid acyl chains on the rough surface and segregation of cholesterol from the vicinity of peptides. The observations are supported by our toy model indicating strong effect of rough objects on membrane dynamics. Herein described effect has implications for the organization and function of biological membranes, especially the plasma membrane with high cholesterol content.

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Characterization of Lipid Membrane Properties for Tunable Electroporation

ASME 2012 Third International Conference on Micro/Nanoscale Heat and Mass Transfer ◽

10.1115/mnhmt2012-75321 ◽

2012 ◽

Author(s):

H. Jeremy Cho ◽

Shalabh C. Maroo ◽

Evelyn N. Wang

Keyword(s):

Lipid Bilayers ◽

Lipid Membrane ◽

Contact Angle Measurement ◽

Angle Measurement ◽

Membrane Properties ◽

Force Microscopy ◽

Packing Structure ◽

Atomic Force ◽

Dynamics Simulations

Lipid bilayers form nanopores on the application of an electric field. This process of electroporation can be utilized in different applications ranging from targeted drug delivery in cells to nano-gating membrane for engineering applications. However, the ease of electroporation is dependent on the surface energy of the lipid layers and thus directly related to the packing structure of the lipid molecules. 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid monolayers were deposited on a mica substrate using the Langmuir-Blodgett (LB) technique at different packing densities and analyzed using atomic force microscopy (AFM). The wetting behavior of these monolayers was investigated by contact angle measurement and molecular dynamics simulations. It was found that an equilibrium packing density of liquid-condensed (LC) phase DPPC likely exists and that water molecules can penetrate the monolayer displacing the lipid molecules. The surface tension of the monolayer in air and water was obtained along with its breakthrough force.

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Escherichia coli response to subinhibitory concentration of Colistin: Insights from study of membrane dynamics and morphology.

10.1101/2022.01.16.476501 ◽

2022 ◽

Author(s):

Ilanila Ilangumaran Ponmalar ◽

Jitendriya Swain ◽

Jaydeep Kumar Basu

Keyword(s):

Bacterial Infections ◽

Molecular Mechanisms ◽

Lipid Membrane ◽

Membrane Dynamics ◽

Correlation Spectroscopy ◽

Membrane Properties ◽

Bacterial Response ◽

Lipid Dynamics ◽

The Impact ◽

Altered Lipid

Prevalence of wide spread bacterial infections bring forth a critical need in understanding the molecular mechanisms of the antibiotics as well as the bacterial response to those antibiotics. Improper usage of antibiotics, which can be in sub-lethal concentrations is one among the multiple reasons for acquiring antibiotic resistance which makes it vital to understand the bacterial response towards sub-lethal concentrations of antibiotics. In this work, we have used colistin, a well-known membrane active antibiotic used to treat severe bacterial infections and explored the impact of its subminimum inhibitory concentration (MIC) on the lipid membrane dynamics and morphological changes of E. coli. Upon investigation of live cell membrane properties such as lipid dynamics using fluorescence correlation spectroscopy, we observed that colistin disrupts the lipid membrane at sub-MIC by altering the lipid diffusivity. Interestingly, filamentationlike cell elongation was observed upon colistin treatment which led to further exploration of surface morphology with the help of atomic force spectroscopy. The changes in the surface roughness upon colistin treatment provides additional insight on the colistin-membrane interaction corroborating with the altered lipid diffusion. Although altered lipid dynamics could be attributed to an outcome of lipid rearrangement due to direct disruption by antibiotic molecules on the membrane or an indirect consequence of disruptions in lipid biosynthetic pathways, we were able to ascertain that altered bacterial membrane dynamics is due to direct disruptions. Our results provide a broad overview on the consequence of the cyclic polypeptide, colistin on membrane specific lipid dynamics and morphology of a live Gram-negative bacterial cell.

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Entropic effects enable life at extreme temperatures

Science Advances ◽

10.1126/sciadv.aaw4783 ◽

2019 ◽

Vol 5 (5) ◽

pp. eaaw4783 ◽

Cited By ~ 1

Author(s):

Young Hun Kim ◽

Geoffray Leriche ◽

Karthik Diraviyam ◽

Takaoki Koyanagi ◽

Kaifu Gao ◽

...

Keyword(s):

Lipid Membranes ◽

Elevated Temperatures ◽

Membrane Integrity ◽

Membrane Dynamics ◽

Extreme Temperatures ◽

Molecular Interpretation ◽

Dynamics And Function ◽

Membrane Spanning ◽

Dynamics Simulations ◽

And Function

Maintaining membrane integrity is a challenge at extreme temperatures. Biochemical synthesis of membrane-spanning lipids is one adaptation that organisms such as thermophilic archaea have evolved to meet this challenge and preserve vital cellular function at high temperatures. The molecular-level details of how these tethered lipids affect membrane dynamics and function, however, remain unclear. Using synthetic monolayer-forming lipids with transmembrane tethers, here, we reveal that lipid tethering makes membrane permeation an entropically controlled process that helps to limit membrane leakage at elevated temperatures relative to bilayer-forming lipid membranes. All-atom molecular dynamics simulations support a view that permeation through membranes made of tethered lipids reduces the torsional entropy of the lipids and leads to tighter lipid packing, providing a molecular interpretation for the increased transition-state entropy of leakage.

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Polyunsaturated phospholipids facilitate membrane deformation and fission by endocytic proteins

Science ◽

10.1126/science.1255288 ◽

2014 ◽

Vol 345 (6197) ◽

pp. 693-697 ◽

Cited By ~ 165

Author(s):

Mathieu Pinot ◽

Stefano Vanni ◽

Sophie Pagnotta ◽

Sandra Lacas-Gervais ◽

Laurie-Anne Payet ◽

...

Keyword(s):

Membrane Curvature ◽

Membrane Properties ◽

Energetic Cost ◽

Synthetic Membranes ◽

Acyl Chains ◽

Biochemical Measurements ◽

Membrane Bending ◽

Pulling Force ◽

Dynamics Simulations ◽

Cellular Organelles

Phospholipids (PLs) with polyunsaturated acyl chains are extremely abundant in a few specialized cellular organelles such as synaptic vesicles and photoreceptor discs, but their effect on membrane properties is poorly understood. Here, we found that polyunsaturated PLs increased the ability of dynamin and endophilin to deform and vesiculate synthetic membranes. When cells incorporated polyunsaturated fatty acids into PLs, the plasma membrane became more amenable to deformation by a pulling force and the rate of endocytosis was accelerated, in particular, under conditions in which cholesterol was limiting. Molecular dynamics simulations and biochemical measurements indicated that polyunsaturated PLs adapted their conformation to membrane curvature. Thus, by reducing the energetic cost of membrane bending and fission, polyunsaturated PLs may help to support rapid endocytosis.

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Lipid Membrane Mimetics in Functional and Structural Studies of Integral Membrane Proteins

Membranes ◽

10.3390/membranes11090685 ◽

2021 ◽

Vol 11 (9) ◽

pp. 685

Author(s):

Saman Majeed ◽

Akram Bani Ahmad ◽

Ujala Sehar ◽

Elka R. Georgieva

Keyword(s):

Membrane Proteins ◽

Lipid Membrane ◽

Physiological State ◽

Integral Membrane Proteins ◽

Membrane Properties ◽

Protein Activity ◽

Functional Studies ◽

Dynamics And Function ◽

And Function

Integral membrane proteins (IMPs) fulfill important physiological functions by providing cell–environment, cell–cell and virus–host communication; nutrients intake; export of toxic compounds out of cells; and more. However, some IMPs have obliterated functions due to polypeptide mutations, modifications in membrane properties and/or other environmental factors—resulting in damaged binding to ligands and the adoption of non-physiological conformations that prevent the protein from returning to its physiological state. Thus, elucidating IMPs’ mechanisms of function and malfunction at the molecular level is important for enhancing our understanding of cell and organism physiology. This understanding also helps pharmaceutical developments for restoring or inhibiting protein activity. To this end, in vitro studies provide invaluable information about IMPs’ structure and the relation between structural dynamics and function. Typically, these studies are conducted on transferred from native membranes to membrane-mimicking nano-platforms (membrane mimetics) purified IMPs. Here, we review the most widely used membrane mimetics in structural and functional studies of IMPs. These membrane mimetics are detergents, liposomes, bicelles, nanodiscs/Lipodisqs, amphipols, and lipidic cubic phases. We also discuss the protocols for IMPs reconstitution in membrane mimetics as well as the applicability of these membrane mimetic-IMP complexes in studies via a variety of biochemical, biophysical, and structural biology techniques.

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Orientation of Fluorescent Lipid Analogue BODIPY-PC to Probe Lipid Membrane Properties: Insights from Molecular Dynamics Simulations

The Journal of Physical Chemistry B ◽

10.1021/jp109629v ◽

2011 ◽

Vol 115 (19) ◽

pp. 6157-6165 ◽

Cited By ~ 23

Author(s):

Kevin C. Song ◽

Philip W. Livanec ◽

Jeffery B. Klauda ◽

Krzysztof Kuczera ◽

Robert C. Dunn ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Lipid Membrane ◽

Membrane Properties ◽

Dynamics Simulations ◽

Fluorescent Lipid

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The Effect of Oxidized Cholesterol on the Aorta of Rabbits- Scanning Electron Microscopic Observations

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100054327 ◽

1982 ◽

Vol 40 ◽

pp. 340-341

Author(s):

S. K. Pena ◽

C. B. Taylor ◽

J. Hill ◽

J. Safarik

Keyword(s):

Cholesterol Biosynthesis ◽

Cholesterol Content ◽

Arterial Injury ◽

Electron Microscopic ◽

Aortic Smooth Muscle ◽

Oxidized Cholesterol ◽

Initial Event ◽

Membrane Structure And Function ◽

Scanning Electron Microscopic ◽

And Function

Introduction: Oxidized cholesterol derivatives have been demonstrated in various cell cultures to be very potent inhibitors of 3-hvdroxy-3- methylglutaryl Coenzyme A reductase which is a principle regulator of cholesterol biosynthesis in the cell. The cholesterol content in the cells exposed to oxidized cholesterol was found to be markedly decreased. In aortic smooth muscle cells, the potency of this effect was closely related to the cytotoxicity of each derivative. Furthermore, due to the similarity of their molecular structure to that of cholesterol, these oxidized cholesterol derivatives might insert themselves into the cell membrane, alter membrane structure and function and eventually cause cell death. Arterial injury has been shown to be the initial event of atherosclerosis.

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Interactions of Linear Analogues of Battacin with Negatively Charged Lipid Membranes

Membranes ◽

10.3390/membranes11030192 ◽

2021 ◽

Vol 11 (3) ◽

pp. 192

Author(s):

Kinga Burdach ◽

Dagmara Tymecka ◽

Aneta Urban ◽

Robert Lasek ◽

Dariusz Bartosik ◽

...

Keyword(s):

Lipid Membranes ◽

Liquid Crystalline ◽

Lipid Membrane ◽

Attenuated Total Reflection ◽

Gram Positive ◽

Insertion Depth ◽

Force Microscopy ◽

Acyl Chains ◽

Hydrophobic Portion ◽

Membrane Fluidization

The increasing resistance of bacteria to available antibiotics has stimulated the search for new antimicrobial compounds with less specific mechanisms of action. These include the ability to disrupt the structure of the cell membrane, which in turn leads to its damage. In this context, amphiphilic lipopeptides belong to the class of the compounds which may fulfill this requirement. In this paper, we describe two linear analogues of battacin with modified acyl chains to tune the balance between the hydrophilic and hydrophobic portion of lipopeptides. We demonstrate that both compounds display antimicrobial activity with the lowest values of minimum inhibitory concentrations found for Gram-positive pathogens. Therefore, their mechanism of action was evaluated on a molecular level using model lipid films mimicking the membrane of Gram-positive bacteria. The surface pressure measurements revealed that both lipopeptides show ability to bind and incorporate into the lipid monolayers, resulting in decreased ordering of lipids and membrane fluidization. Atomic force microscopy (AFM) imaging demonstrated that the exposure of the model bilayers to lipopeptides leads to a transition from the ordered gel phase to disordered liquid crystalline phase. This observation was confirmed by attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR) results, which revealed that lipopeptide action causes a substantial increase in the average tilt angle of lipid acyl chains with respect to the surface normal to compensate for lipopeptide insertion into the membrane. Moreover, the peptide moieties in both molecules do not adopt any well-defined secondary structure upon binding with the lipid membrane. It was also observed that a small difference in the structure of a lipophilic chain, altering the balance between hydrophobic and hydrophilic portion of the molecules, results in different insertion depth of the active compounds.

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New insights into structure and function of bis-phosphinic acid derivatives and implications for CFTR modulation

Scientific Reports ◽

10.1038/s41598-021-83240-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sara Bitam ◽

Ahmad Elbahnsi ◽

Geordie Creste ◽

Iwona Pranke ◽

Benoit Chevalier ◽

...

Keyword(s):

Phosphinic Acid ◽

Site Directed Mutagenesis ◽

Side Chain ◽

Transmembrane Conductance Regulator ◽

Intracellular Loop ◽

Respiratory Cells ◽

Cftr Protein ◽

Dynamics Simulations ◽

And Function ◽

Molecular Mode

AbstractC407 is a compound that corrects the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein carrying the p.Phe508del (F508del) mutation. We investigated the corrector effect of c407 and its derivatives on F508del-CFTR protein. Molecular docking and dynamics simulations combined with site-directed mutagenesis suggested that c407 stabilizes the F508del-Nucleotide Binding Domain 1 (NBD1) during the co-translational folding process by occupying the position of the p.Phe1068 side chain located at the fourth intracellular loop (ICL4). After CFTR domains assembly, c407 occupies the position of the missing p.Phe508 side chain. C407 alone or in combination with the F508del-CFTR corrector VX-809, increased CFTR activity in cell lines but not in primary respiratory cells carrying the F508del mutation. A structure-based approach resulted in the synthesis of an extended c407 analog G1, designed to improve the interaction with ICL4. G1 significantly increased CFTR activity and response to VX-809 in primary nasal cells of F508del homozygous patients. Our data demonstrate that in-silico optimized c407 derivative G1 acts by a mechanism different from the reference VX-809 corrector and provide insights into its possible molecular mode of action. These results pave the way for novel strategies aiming to optimize the flawed ICL4–NBD1 interface.

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Modeled 3D-Structures of Proteobacterial Transglycosylases from Glycoside Hydrolase Family 17 Give Insight in Ligand Interactions Explaining Differences in Transglycosylation Products

Applied Sciences ◽

10.3390/app11094048 ◽

2021 ◽

Vol 11 (9) ◽

pp. 4048

Author(s):

Javier A. Linares-Pastén ◽

Lilja Björk Jonsdottir ◽

Gudmundur O. Hreggvidsson ◽

Olafur H. Fridjonsson ◽

Hildegard Watzlawick ◽

...

Keyword(s):

Glycoside Hydrolase ◽

Ligand Docking ◽

Glycoside Hydrolase Family ◽

Ligand Interactions ◽

Tim Barrel ◽

Branching Point ◽

The Difference ◽

Dynamics Simulations ◽

And Function ◽

Hydrolase Family

The structures of glycoside hydrolase family 17 (GH17) catalytic modules from modular proteins in the ndvB loci in Pseudomonas aeruginosa (Glt1), P. putida (Glt3) and Bradyrhizobium diazoefficiens (previously B. japonicum) (Glt20) were modeled to shed light on reported differences between these homologous transglycosylases concerning substrate size, preferred cleavage site (from reducing end (Glt20: DP2 product) or non-reducing end (Glt1, Glt3: DP4 products)), branching (Glt20) and linkage formed (1,3-linkage in Glt1, Glt3 and 1,6-linkage in Glt20). Hybrid models were built and stability of the resulting TIM-barrel structures was supported by molecular dynamics simulations. Catalytic amino acids were identified by superimposition of GH17 structures, and function was verified by mutagenesis using Glt20 as template (i.e., E120 and E209). Ligand docking revealed six putative subsites (−4, −3, −2, −1, +1 and +2), and the conserved interacting residues suggest substrate binding in the same orientation in all three transglycosylases, despite release of the donor oligosaccharide product from either the reducing (Glt20) or non-reducing end (Glt1, Gl3). Subsites +1 and +2 are most conserved and the difference in release is likely due to changes in loop structures, leading to loss of hydrogen bonds in Glt20. Substrate docking in Glt20 indicate that presence of covalently bound donor in glycone subsites −4 to −1 creates space to accommodate acceptor oligosaccharide in alternative subsites in the catalytic cleft, promoting a branching point and formation of a 1,6-linkage. The minimum donor size of DP5, can be explained assuming preferred binding of DP4 substrates in subsite −4 to −1, preventing catalysis.

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