High-resolution structure of coexisting nanoscopic and microscopic lipid domains

Belička, Michal; Weitzer, Anna; Pabst, Georg

doi:10.1039/c6sm02727j

Cited by 28 publications

(39 citation statements)

References 69 publications

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“…S1). After our previous SDP analysis of coexisting lipid domains (26,27), we combined the individual groups of POPE and POPG into one hybrid lipid structure using molecular averaging. In particular, we paired all hydrocarbon, CG, and PO 4 groups, assuming that they align at the same transbilayer position.…”

Section: Parsingmentioning

confidence: 99%

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

Pachler

Kabelka

Appavou

et al. 2019

Biophysical Journal

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We 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 smallangle x-ray and neutron scattering experiments on fully hydrated lipid vesicles in the presence of MG2a and L18W-PGLa to allatom and coarse-grained molecular dynamics simulations. In agreement with previous studies, both peptides, as well as their equimolar mixture, were found to remain upon adsorption in a surface-aligned topology 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 the formation of parallel heterodimers at concentrations below a synergistic increase of dye leakage from vesicles. 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 region 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.SIGNIFICANCE We 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 already provide, at low peptide concentrations, the nucleus for the peptides' well-known synergistic activity.

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Section: Parsingmentioning

confidence: 99%

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

Pachler

Kabelka

Appavou

et al. 2019

Biophysical Journal

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show abstract

“…S1). Following our previous SDP analysis of coexisting lipid domains (26,27), we combined the individual groups of POPE and POPG into one hybrid lipid structure, using molecular averaging. In particular, we paired all hydrocarbon, CG and PO 4 groups, assuming that they align at the same transbilayer position.…”

Section: Joint Saxs/sans Analysisunclassified

“…The individual volume distribution functions are detailed in the SI. The area per unit cell A U is a common scaling factor for all distribution functions and therefore was chosen as fit parameter (see also (27)). From the analysis we determined several structural parameters, such as, e.g., the Luzzati bilayer thickness (30)…”

Section: Joint Saxs/sans Analysisunclassified

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

Pachler

Kabelka

Appavou

et al. 2019

Preprint

Self Cite

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We 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.

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“…Critical fluctuations in domain mixing manifest at one or two points in ternary phase diagrams, depending on whether the immiscible region is open or closed. (27,30,(56)(57)(58)(59) Modern fluorescence, (34,60) x-ray, (39,61) and AFM experiments (41,42) Many theoretical works have considered the inter-leaflet coupling of lipids and domains, and arguments in favor of interleaflet registration or anti-registration of domains have been presented. Preference of domains for local curvature of the membrane surface as well as inter-leaflet interaction between domains can significantly impact the free energy of the membrane.…”

Section: Tous(2)mentioning

confidence: 99%

Regimes of Complex Lipid Bilayer Phases Induced by Cholesterol Concentration in MD Simulation

Pantelopulos

Straub

2018

Preprint

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Cholesterol is essential to the formation of phase separated lipid domains in membranes. Lipid domains can exist in different thermodynamic phases depending on the molecular composition, and play significant roles in determining structure and function of membrane proteins. We investigate the role of cholesterol in the structure and dynamics of ternary lipid mixtures displaying phase separation using Molecular Dynamics simulations, employing a physiologically-relevant span of cholesterol concentration. We find that cholesterol can induce formation of three regimes of phase behavior, I) miscible liquid disordered bulk, II) phase separated, domain registered coexistence of liquid disordered and liquid ordered and domains, and III) phase separated, domain-antiregistered coexistence of liquid-disordered and newly-identified nanoscopic gel domains composed of cholesterol threads we name "cholesterolic gel" domains. These findings are validated and discussed in the context of current experimental knowledge, models of cholesterol spatial distributions, and models of ternary lipid mixture phase separation.These collected observations substantially enhance our understanding of the role of Chol in complex phase behavior in ternary lipid mixtures and provide a framework for exploring structure and dynamics of domain formation in future computational, theoretical, and experimental investigations. ASSOCIATED CONTENT Supporting InformationSee supporting information for illustrative demonstrations of order parameters mix , ) , and f , explanation and illustraton of 50% miscibility mapping to mix , and visualizations of f and | f | in all systems. Additionally, order parameters measured for transleaflet clusters and illustrative demonstration of the clustering approach used is supplied.

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High-resolution structure of coexisting nanoscopic and microscopic lipid domains

Cited by 28 publications

References 69 publications

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

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

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

Regimes of Complex Lipid Bilayer Phases Induced by Cholesterol Concentration in MD Simulation

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