scholarly journals Structure and Formation Mechanism of Antimicrobial Peptides Temporin B- and L-Induced Tubular Membrane Protrusion

2021 ◽  
Vol 22 (20) ◽  
pp. 11015
Author(s):  
Shan Zhang ◽  
Ming Ma ◽  
Zhuang Shao ◽  
Jincheng Zhang ◽  
Lei Fu ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Morphological Changes ◽  
Membrane Surface ◽  
Coarse Grained ◽  
Tubular Structures ◽  
Membrane Pore ◽  
Anionic Phospholipids ◽  
Bactericidal Activities ◽  
Highly Hydrophobic ◽  
Dynamics Simulations

Temporins are a family of antimicrobial peptides (AMPs) isolated from frog skin, which are very short, weakly charged, and highly hydrophobic. They execute bactericidal activities in different ways from many other AMPs. This work investigated morphological changes of planar bilayer membranes composed of mixed zwitterionic and anionic phospholipids induced by temporin B and L (TB and TL) using all-atom and coarse-grained molecular dynamics simulations. We found that TB and TL fold to α-helices at the membrane surface and penetrate shallowly into the bilayer. These short AMPs have low propensity to induce membrane pore formation but possess high ability to extract lipids out. At relatively high peptide concentrations, the strong hydrophobicity of TB and TL promotes them to aggregate into clusters on the membrane surface. These aggregates attract a large amount of lipids out of the membrane to release compression induced by other dispersed peptides binding to the membrane. The extruded lipids mix evenly with the peptides in the cluster and form tubule-like protrusions. Certain water molecules follow the movement of lipids, which not only fill the cavities of the protrusion but also assist in maintaining the tubular structures. In contrast, the peptide-free leaflet remains intact. The present results unravel distinctive antimicrobial mechanisms of temporins disturbing membranes.

Synergistic effects of magainin 2 and PGLa on their heterodimer formation, aggregation, and insertion into the bilayer

RSC Advances ◽  
2015 ◽  
Vol 5 (3) ◽  
pp. 2047-2055 ◽  
Author(s):  
Eol Han ◽  
Hwankyu Lee
Keyword(s):  
Molecular Dynamics ◽  
Antimicrobial Peptides ◽  
Molecular Dynamics Simulations ◽  
Lipid Bilayers ◽  
Synergistic Effects ◽  
Coarse Grained ◽  
Dynamics Simulations ◽  
Coarse Grained Molecular Dynamics

We performed coarse-grained molecular dynamics simulations of antimicrobial peptides PGLa and magainin 2 in lipid bilayers.

scholarly journals Reaction–diffusion basis of retroviral infectivity

2016 ◽  
Vol 374 (2080) ◽  
pp. 20160148 ◽  
Author(s):  
S. Kashif Sadiq
Keyword(s):  
Chemical Reactions ◽  
Membrane Surface ◽  
Reaction Diffusion ◽  
Coarse Graining ◽  
Coarse Grained ◽  
Multiscale Approach ◽  
The Matrix ◽  
Membrane Bound ◽  
Spatio Temporal ◽  
Dynamics Simulations

Retrovirus particle (virion) infectivity requires diffusion and clustering of multiple transmembrane envelope proteins (Env 3 ) on the virion exterior, yet is triggered by protease-dependent degradation of a partially occluding, membrane-bound Gag polyprotein lattice on the virion interior. The physical mechanism underlying such coupling is unclear and only indirectly accessible via experiment. Modelling stands to provide insight but the required spatio-temporal range far exceeds current accessibility by all-atom or even coarse-grained molecular dynamics simulations. Nor do such approaches account for chemical reactions, while conversely, reaction kinetics approaches handle neither diffusion nor clustering. Here, a recently developed multiscale approach is considered that applies an ultra-coarse-graining scheme to treat entire proteins at near-single particle resolution, but which also couples chemical reactions with diffusion and interactions. A model is developed of Env 3 molecules embedded in a truncated Gag lattice composed of membrane-bound matrix proteins linked to capsid subunits, with freely diffusing protease molecules. Simulations suggest that in the presence of Gag but in the absence of lateral lattice-forming interactions, Env 3 diffuses comparably to Gag-absent Env 3 . Initial immobility of Env 3 is conferred through lateral caging by matrix trimers vertically coupled to the underlying hexameric capsid layer. Gag cleavage by protease vertically decouples the matrix and capsid layers, induces both matrix and Env 3 diffusion, and permits Env 3 clustering. Spreading across the entire membrane surface reduces crowding, in turn, enhancing the effect and promoting infectivity. This article is part of the themed issue ‘Multiscale modelling at the physics–chemistry–biology interface’.

scholarly journals Quantification of in-plane flexoelectricity in lipid bilayers

2021 ◽  
Author(s):  
Nidhin Thomas ◽  
Ashutosh Agrawal
Keyword(s):  
Molecular Dynamics ◽  
Electric Field ◽  
Lipid Bilayers ◽  
Material Parameter ◽  
Membrane Surface ◽  
Dielectric Materials ◽  
Coarse Grained ◽  
Molecular Architecture ◽  
Dynamics Simulations ◽  
Continuum Theories

Lipid bilayers behave as 2D dielectric materials that undergo polarization and deformation in the presence of an electric field. This effect has been previously modeled by continuum theories which assume a polarization field oriented normal to the membrane surface. However, the molecular architecture of the lipids reveals that the heqadgroup dipoles are primarily oriented tangential to the membrane surface. Here, we perform atomistic and coarse-grained molecular dynamics simulations to quantify the in-plane polarization undergone by a flat bilayer and a spherical vesicle in the presence of an applied electric field. We use these predictions to compute an effective in-plane flexoelectric coefficient for four different lipid types. Our findings provide the first molecular proof of the in-plane polarization undergone by lipid bilayers and furnish the material parameter required to quantify membrane-electric field interactions.

scholarly journals Direct binding of phosphatidylglycerol at specific sites modulates desensitization of a ligand-gated ion channel

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Ailing Tong ◽  
John T Petroff ◽  
Fong-Fu Hsu ◽  
Philipp AM Schmidpeter ◽  
Crina M Nimigean ◽  
...  
Keyword(s):  
Ion Channel ◽  
Transmembrane Domain ◽  
Native Mass Spectrometry ◽  
Coarse Grained ◽  
Specific Lipids ◽  
Anionic Phospholipid ◽  
Anionic Phospholipids ◽  
Functional Assays ◽  
Direct Binding ◽  
Dynamics Simulations

Pentameric ligand-gated ion channels (pLGICs) are essential determinants of synaptic transmission, and are modulated by specific lipids including anionic phospholipids. The exact modulatory effect of anionic phospholipids in pLGICs and the mechanism of this effect are not well understood. Using native mass spectrometry, coarse-grained molecular dynamics simulations and functional assays, we show that the anionic phospholipid, 1-palmitoyl-2-oleoyl phosphatidylglycerol (POPG), preferentially binds to and stabilizes the pLGIC, Erwinia ligand-gated ion channel (ELIC), and decreases ELIC desensitization. Mutations of five arginines located in the interfacial regions of the transmembrane domain (TMD) reduce POPG binding, and a subset of these mutations increase ELIC desensitization. In contrast, a mutation that decreases ELIC desensitization, increases POPG binding. The results support a mechanism by which POPG stabilizes the open state of ELIC relative to the desensitized state by direct binding at specific sites.

scholarly journals Magainin 2 and PGLa in Bacterial Membrane Mimics I: Peptide-Peptide and Lipid-Peptide Interactions

2019 ◽  
Author(s):  
Michael Pachler ◽  
Ivo Kabelka ◽  
Marie-Sousai Appavou ◽  
Karl Lohner ◽  
Robert Vácha ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Lipid Vesicles ◽  
Coarse Grained ◽  
Joint Analysis ◽  
Synergistic Activity ◽  
Salt Bridges ◽  
Membrane Perturbation ◽  
High Concentrations ◽  
Dynamics Simulations ◽  
The Individual

ABSTRACTWe addressed the onset of synergistic activity of the two well-studied antimicrobial peptides magainin 2 (MG2a) and PGLa using lipid-only mimics of Gram-negative cytoplasmic membranes. Specifically, we coupled a joint analysis of small-angle X-ray and neutron scattering experiments on fully hydrated lipid vesicles in the presence of MG2a and L18W-PGLa to all-atom and coarse-grained molecular dynamics simulations. In agreement with previous studies both peptides, as well as their equimolar mixture, were found to remain in a surface-aligned topology upon membrane insertion and to induce significant membrane perturbation as evidenced by membrane thinning and hydrocarbon order parameter changes in the vicinity of the inserted peptide. These effects were particularly pronounced for the so called synergistic mixture of 1:1 (mol/mol) L18W-PGLa/MG2a and cannot be accounted for by a linear combination of the membrane perturbations of two peptides individually. Our data are consistent with parallel heterodimers forming at much lower concentrations than previously considered, but which do not induce a synergistic leakage of dyes. Our simulations further show that the heterodimers interact via salt bridges and hydrophobic forces, which apparently makes them more stable than putatively formed antiparallel L18W-PGLa and MG2a homodimers. Moreover, dimerization of L18W-PGLa and MG2a leads to a relocation of the peptides within the lipid headgroup regime as compared to the individual peptides. The early onset of dimerization of L18W-PGLa and MG2a at low peptide concentrations consequently appears to be key to their synergistic dye-releasing activity from lipid vesicles at high concentrations.STATEMENT OF SIGNIFICANCEWe demonstrate that specific interactions of the antimicrobial peptides MG2a and PGLa with each other in POPE/POPG bilayers lead to the formation of surface-aligned parallel dimers, which provide already at low peptide concentrations the nucleus for the peptides’ well-known synergistic activity.

scholarly journals A molecular view on the escape of lipoplexed DNA from the endosome

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Bart MH Bruininks ◽  
Paulo CT Souza ◽  
Helgi Ingolfsson ◽  
Siewert J Marrink
Keyword(s):  
Viral Vectors ◽  
Membrane Surface ◽  
Genetic Material ◽  
Cationic Liposome ◽  
Coarse Grained ◽  
Fusion Pore ◽  
Endosomal Membrane ◽  
Dynamics Simulations ◽  
The Cost

The use of non-viral vectors for in vivo gene therapy could drastically increase safety, whilst reducing the cost of preparing the vectors. A promising approach to non-viral vectors makes use of DNA/cationic liposome complexes (lipoplexes) to deliver the genetic material. Here we use coarse-grained molecular dynamics simulations to investigate the molecular mechanism underlying efficient DNA transfer from lipoplexes. Our computational fusion experiments of lipoplexes with endosomal membrane models show two distinct modes of transfection: parallel and perpendicular. In the parallel fusion pathway, DNA aligns with the membrane surface, showing very quick release of genetic material shortly after the initial fusion pore is formed. The perpendicular pathway also leads to transfection, but release is slower. We further show that the composition and size of the lipoplex, as well as the lipid composition of the endosomal membrane, have a significant impact on fusion efficiency in our models.

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 Direct Binding of Phosphatidylglycerol at Specific Sites Modulates Desensitization of a Pentameric Ligand-Gated Ion Channel

2019 ◽  
Author(s):  
Ailing Tong ◽  
John T. Petroff ◽  
Fong-Fu Hsu ◽  
Philipp A. M. Schmidpeter ◽  
Crina M. Nimigean ◽  
...  
Keyword(s):  
Ion Channel ◽  
Transmembrane Domain ◽  
Native Mass Spectrometry ◽  
Coarse Grained ◽  
Specific Lipids ◽  
Anionic Phospholipid ◽  
Anionic Phospholipids ◽  
Functional Assays ◽  
Direct Binding ◽  
Dynamics Simulations

AbstractPentameric ligand-gated ion channels (pLGICs) are essential determinants of synaptic transmission, and are modulated by specific lipids including anionic phospholipids. The exact modulatory effect of anionic phospholipids in pLGICs and the mechanism of this effect are not well understood. Using native mass spectrometry, coarse-grained molecular dynamics simulations and functional assays, we show that the anionic phospholipid, 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG), preferentially binds to and stabilizes the pLGIC, Erwinia ligand-gated ion channel (ELIC), and decreases ELIC desensitization. Mutations of five arginines located in the interfacial regions of the transmembrane domain (TMD) reduce POPG binding, and a subset of these mutations increase ELIC desensitization. In contrast, the L240A mutant known to decrease ELIC desensitization, increases POPG binding. The results support a mechanism by which POPG stabilizes the open state of ELIC relative to the desensitized state by direct binding at specific sites.

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