We previously reported that the synergistically enhanced antimicrobial activity of magainin 2 (MG2a) and PGLa is related to membrane adhesion and fusion. Here, we demonstrate that equimolar mixtures ...of MG2a and L18W-PGLa induce positive monolayer curvature stress and sense, at the same time, positive mean and Gaussian bilayer curvatures already at low amounts of bound peptide. The combination of both abilities—membrane curvature sensing and inducing—is most likely the base for the synergistically enhanced peptide activity. In addition, our coarse-grained simulations suggest that fusion stalks are promoted by decreasing the free-energy barrier for their formation rather than by stabilizing their shape. We also interrogated peptide partitioning as a function of lipid and peptide concentration using tryptophan fluorescence spectroscopy and peptide-induced leakage of dyes from lipid vesicles. In agreement with a previous report, we find increased membrane partitioning of L18W-PGLa in the presence of MG2a. However, this effect does not prevail to lipid concentrations higher than 1 mM, above which all peptides associate with the lipid bilayers. This implies that synergistic effects of MG2a and L18W-PGLa in previously reported experiments with lipid concentrations >1 mM are due to peptide-induced membrane remodeling and not their specific membrane partitioning.
Membrane-active molecules provide a promising strategy to target and kill pathogenic bacteria. Understanding how specific molecular features drive interactions with membrane components and ...subsequently cause disruption that leads to antimicrobial activity is a crucial step in designing next-generation treatments. Here, we test a library of lipid-like compounds (lipidoids) against Gram-negative bacteria Escherichia coli to garner in-depth structure–activity relationships using antimicrobial assays. Modular lipidoid molecules were synthesized in high-throughput, such that we could analyze 104 compounds with variable combinations of hydrophobic tails and cationic headgroups. Antibacterial activity was strongly correlated to specific structural features, including tail hydrophobicity and headgroup charge density, and also to the overall molecular shape and propensity for self-assembly into curved liquid crystalline phases. Dye permeabilization assays showed that E. coli membranes were permeabilized by lipidoids, confirming their membrane-active nature. The reduced permeabilization, as compared to Gram-positive Bacillus subtilis, alludes to the challenge of permeabilizing the additional outer membrane layer of E. coli. The effect of headgroup solubility in gemini-type lipidoids was also demonstrated, revealing that a headgroup with a more hydrophilic spacer between amine groups had enhanced activity against B. subtilis but not E. coli. This provides insight into features enabling outer membrane penetration and governing selectivity between bacterial species.
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Over the past decades, advances in lipid nanotechnology have shown that self-assembled lipid structures providing ease of preparation, chemical stability, and biocompatibility ...represent a landmark on the development of multidisciplinary technologies. Lipid nanotubes (LNTs) are a unique class of lipid self-assembled structures, bearing unique properties such as high-aspect ratio, tunable diameter size, and precise molecular recognition. They can be obtained either by the action of external factors to already formed vesicles or spontaneously, the latter depending strongly on subtle molecular features. Here, we report on the spontaneous formation of supported lipid nanotubes of a particular type of glycolipid, ohmline, whose hydrophobic core displays remarkable asymmetry. The combination of bulk and surface-sensitive techniques indicates that below its main transition, ohmline displays an interdigitated gel phase, likely driven by the unique asymmetry in its hydrophobic core. Enhanced order packing by interdigitation favors the formation of ohmline nanotubes in agreement with chiral-based models of nanotube formation. The findings presented in this work call for additional studies to link lipid molecular structure-assembly relationships, whose understanding is relevant for the controlled design of lipid nanotubes networks in particular and controlled design of soft-matter nanomaterials in general.
In order to understand the biological role of lipids in cell membranes, it is necessary to determine the mesoscopic structure of well-defined model membrane systems. Neutron and X-ray scattering are ...non-invasive, probe-free techniques that have been used extensively in such systems to probe length scales ranging from angstroms to microns, and dynamics occurring over picosecond to millisecond time scales. Recent developments in the area of phase separated lipid systems mimicking membrane rafts will be presented, and the underlying concepts of the different scattering techniques used to study them will be discussed in detail.
We have studied the contributions of stored elastic energies in liquid-ordered (Lo) and liquid-disordered (Ld) domains to transmembrane proteins using the lateral pressure concept. In particular we ...applied previously reported experimental data for the membrane thickness, intrinsic curvature and bending elasticities of coexisting Lo/Ld domains to calculate whether proteins of simple geometric shapes would preferentially diffuse into Lo or Ld domains and form oligomers of a certain size. For the studied lipid mixture we generally found that proteins with convex shapes prefer sorting to Ld phases and the formation of large clusters. Lo domains in turn would be enriched in monomers of concave shaped proteins. We further observed that proteins which are symmetric with respect to the bilayer center prefer symmetric Lo or Ld domains, while asymmetric proteins favor a location in domains with Lo/Ld asymmetry. In the latter case we additionally retrieved a strong dependence on protein directionality, thus providing a mechanism for transmembrane protein orientation.
We present the detailed structural analysis of polyunsaturated fatty acid-containing phospholipids namely, 1-palmitoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine (PDPC) and ...1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine (SDPC). A newly developed molecular dynamics (MD) simulation parsing scheme for lipids containing fatty acids with multiple double bonds was implemented into the scattering density profile (SDP) model to simultaneously refine differently contrasted neutron and X-ray scattering data. SDP analyses of scattering data at 30 °C yielded lipid areas of 71.1 Å2 and 70.4 Å2 for PDPC and SDPC bilayers, respectively, and a model free analysis of PDPC at 30 °C resulted in a lipid area of 72 Å2. In addition to bilayer structural parameters, using area-constrained MD simulations we determined the area compressibility modulus, KA, to be 246.4 mN/m, a value similar to other neutral phospholipids.
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