Trp residues near peptide termini enhance the membranolytic activity of cationic amphipathic α-helices.

KIA peptides were designed as a series of cationic antimicrobial agents of different lengths, based on the repetitive motif [KIAGKIA]. As amphiphilic helices, they tend to bind initially to the surface of lipid membranes. Depending on the conditions, they are proposed to flip, insert and form toroidal pores, such that the peptides are aligned in a transmembrane orientation.

Length matters: Functional flip of the short TatA transmembrane helix.

The twin arginine translocase (Tat) exports folded proteins across bacterial membranes. The putative pore-forming or membrane-weakening component (TatA in B. subtilis) is anchored to the lipid bilayer via an unusually short transmembrane α-helix (TMH), with less than 16 residues.

Twisting of Porphyrin by Assembly in a Metal-Organic Framework yielding Chiral Photoconducting Films for Circularly-Polarized-Light Detection.

While materials based on organic molecules usually have either superior optoelectronic or superior chiral properties, the combination of both is scarce. Here, a crystalline chiroptical film based on porphyrin with homochiral side groups is presented. While the dissolved molecule has a planar, thus, achiral porphyrin core, upon assembly in a metal-organic framework (MOF) film, the porphyrin core is twisted and chiral.

Temperature-Dependent Re-alignment of the Short Multifunctional Peptide BP100 in Membranes Revealed by Solid-State NMR Spectroscopy and Molecular Dynamics Simulations.

BP100 is a cationic undecamer peptide with antimicrobial and cell-penetrating activities. The orientation of this amphiphilic α-helix in lipid bilayers was examined under numerous conditions using solid-state F, N and H NMR. At high temperatures in saturated phosphatidylcholine lipids, BP100 lies flat on the membrane surface, as expected.

Membranolytic Mechanism of Amphiphilic Antimicrobial β-Stranded [KL] Peptides.

Amphipathic peptides can act as antibiotics due to membrane permeabilization. KL peptides with the repetitive sequence [Lys-Leu]-NH form amphipathic β-strands in the presence of lipid bilayers. As they are known to kill bacteria in a peculiar length-dependent manner, we suggest here several different functional models, all of which seem plausible, including a carpet mechanism, a β-barrel pore, a toroidal wormhole, and a β-helix.

Structural analysis of the peptides temporin-Ra and temporin-Rb and interactions with model membranes.

The skin of amphibians is widely exploited as rich sources of membrane active peptides that differ in chain size, polypeptide net charge, secondary structure, target selectivity and toxicity. In this study, two small antimicrobial peptides, temporin-Ra and temporin-Rb, originally isolated from the skin of the European marsh frog (Rana ridibunda), described as active against pathogen bacteria and presenting low toxicity to eukaryotic cells were synthesized and had their physicochemical properties and mechanism of action investigated. The temporin peptides were examined in aqueous solution and in the presence of membrane models (lipid monolayers, micelles, lipid bilayers and vesicles).

Remarkably high solvatochromism in the circular dichroism spectra of the polyproline-II conformation: limitations or new opportunities?

Circular dichroism is a conventional method for studying the secondary structures of peptides and proteins and their transitions. While certain circular dichroism features are characteristic of α-helices and β-strands, the third most abundant secondary structure, the polyproline-II helix, does not exhibit a strictly conserved spectroscopic appearance. Due to its extended nature, the polyproline-II helix is highly accessible to the surrounding solvent; thus, the environment has a critical influence on the lineshape of the circular dichroism spectra of this structure.

Membrane Interactions of Latarcins: Antimicrobial Peptides from Spider Venom.

A group of seven peptides from spider venom with diverse sequences constitute the latarcin family. They have been described as membrane-active antibiotics, but their lipid interactions have not yet been addressed. Using circular dichroism and solid-state N-NMR, we systematically characterized and compared the conformation and helix alignment of all seven peptides in their membrane-bound state.

Order and disorder-An integrative structure of the full-length human growth hormone receptor.

Because of its small size (70 kilodalton) and large content of structural disorder (>50%), the human growth hormone receptor (hGHR) falls between the cracks of conventional high-resolution structural biology methods. Here, we study the structure of the full-length hGHR in nanodiscs with small-angle x-ray scattering (SAXS) as the foundation. We develop an approach that combines SAXS, x-ray diffraction, and NMR spectroscopy data obtained on individual domains and integrate these through molecular dynamics simulations to interpret SAXS data on the full-length hGHR in nanodiscs.

Chiral Resolution of Spin-Crossover Active Iron(II) [2x2] Grid Complexes.

Chiral magnetic materials are proposed for applications in second-order non-linear optics, magneto-chiral dichroism, among others. Recently, we have reported a set of tetra-nuclear Fe(II) grid complex conformers with general formula C/S-[Fe L ] (L: 2,6-bis(6-(pyrazol-1-yl)pyridin-2-yl)-1,5-dihydrobenzo[1,2-d : 4,5-d']diimidazole). In the grid complexes, isomerism emerges from tautomerism and conformational isomerism of the ligand L, and the S-type grid complex is chiral, which originates from different non-centrosymmetric spatial organization of the trans type ligand around the Fe(II) center.

Chirality Remote Control in Nanoporous Materials by Circularly Polarized Light.

The ability to dynamically control chirality remains a grand challenge in chemistry. Although many molecules possess chiral isomers, lacking their isolation, for instance during photoisomerization, results in racemic mixtures with suppressed enantiospecific chiral properties. Here, we present a nanoporous solid in which chirality and enantioselective enrichment is induced by circularly polarized light (CPL).

Structural and functional characterization of the pore-forming domain of pinholin S68.

Pinholin S68 triggers the lytic cycle of bacteriophage φ21 in infected Activated transmembrane dimers oligomerize into small holes and uncouple the proton gradient. Transmembrane domain 1 (TMD1) regulates this activity, while TMD2 is postulated to form the actual "pinholes." Focusing on the TMD2 fragment, we used synchrotron radiation-based circular dichroism to confirm its α-helical conformation and transmembrane alignment.

Phosphate-dependent aggregation of [KL] peptides affects their membranolytic activity.

In this study, we investigate how the length of amphiphilic β-sheet forming peptides affects their interaction with membranes. Four polycationic model peptides with lengths from 6 to 18 amino acids were constructed from simple Lys-Leu repeats, giving [KL]. We found that (1) they exhibit a pronounced antimicrobial activity with an intriguing length dependent maximum for [KL] with 10 amino acids; (2) their hemolytic effect, on the other hand, increases steadily with peptide length.

Terminal charges modulate the pore forming activity of cationic amphipathic helices.

KIA peptides are a series of designer-made cationic amphipathic α-helical antimicrobial peptides of different lengths, based on the repetitive sequence [KIAGKIA]. They can form toroidal pores in membranes, wherein the helices are aligned in a transmembrane orientation. Solid-state N NMR is used here to differentiate between the surface-bound and transmembrane states.

Monofluoroalkene-Isostere as a F NMR Label for the Peptide Backbone: Synthesis and Evaluation in Membrane-Bound PGLa and (KIGAKI).

Solid-state F NMR is a powerful method to study the interactions of biologically active peptides with membranes. So far, in labelled peptides, the F-reporter group has always been installed on the side chain of an amino acid. Given the fact that monofluoroalkenes are non-hydrolyzable peptide bond mimics, we have synthesized a monofluoroalkene-based dipeptide isostere, Val-Ψ[(Z)-CF=CH]-Gly, and inserted it in the sequence of two well-studied antimicrobial peptides: PGLa and (KIGAKI) are representatives of an α-helix and a β-sheet.

Shape-Memory Effect by Sequential Coupling of Functions over Different Length Scales in an Architectured Hydrogel.

The integration of functions in materials in order to gain macroscopic effects in response to environmental changes is an ongoing challenge in material science. Here, functions on different hierarchical levels are sequentially linked to translate a pH-triggered conformational transition from the molecular to the macroscopic level to induce directed movements in hydrogels. When the pH is increased, lysine-rich peptide molecules change their conformation into a β-hairpin structure because of the reduced electrostatic repulsion among the deprotonated amino groups.

Switching the enantioselectivity of nanoporous host materials by light.

A chiral photoswitchable nanoporous material with remote-controllable enantioselective adsorption capacity is presented. This metal-organic framework possesses both homochiral d-camphoric acid and light-responsive azobenzene moieties. Although the structure at the chiral moieties is unaffected, the trans-cis-azobenzene-photoisomerization changes the pore environment and, thus, switches the enantioselective adsorption behavior of the homochiral MOF.

Tetrameric Charge-Zipper Assembly of the TisB Peptide in Membranes-Computer Simulation and Experiment.

TisB is a short amphiphilic α-helical peptide from Escherichia coli that induces a breakdown of the pH gradient across the inner membrane when the bacteria are under stress and require to form persister cells to turn into a biofilm. A computational-experimental approach combining all-atom and coarse-grained molecular dynamics simulation with circular dichroism spectroscopy and gel electrophoresis was used to reveal its structure and oligomeric assembly in a phospholipid bilayer. TisB is found to be inserted upright in the membrane as a tetrameric bundle with a left-handed sense of supercoiling, best described as an antiparallel dimer-of-dimers.

Molecular structure and function of myelin protein P0 in membrane stacking.

Compact myelin forms the basis of nerve insulation essential for higher vertebrates. Dozens of myelin membrane bilayers undergo tight stacking, and in the peripheral nervous system, this is partially enabled by myelin protein zero (P0). Consisting of an immunoglobulin (Ig)-like extracellular domain, a single transmembrane helix, and a cytoplasmic extension (P0ct), P0 harbours an important task in ensuring the integrity of compact myelin in the extracellular compartment, referred to as the intraperiod line.

Helix Fraying and Lipid-Dependent Structure of a Short Amphipathic Membrane-Bound Peptide Revealed by Solid-State NMR.

The amphipathic α-helical peptide KIA14 [(KIAGKIA)-NH] was studied in membranes using circular dichroism and solid-state NMR spectroscopy to obtain global as well as local structural information. By analyzing H NMR data from 10 analogues of KIA14 that were selectively labeled with Ala- d, those positions that are properly folded into a helix could be determined within the membrane-bound peptide. The N-terminus was found to be unraveled, whereas positions 4-14 formed an ideal helix all the way to the C-terminus.

Transmembrane Polyproline Helix.

The third most abundant polypeptide conformation in nature, the polyproline-II helix, is a polar, extended secondary structure with a local organization stabilized by intercarbonyl interactions within the peptide chain. Here we design a hydrophobic polyproline-II helical peptide based on an oligomeric octahydroindole-2-carboxylic acid scaffold and demonstrate its transmembrane alignment in model lipid bilayers by means of solid-state F NMR. As result, we provide a first example of a purely artificial transmembrane peptide with a structural organization that is not based on hydrogen-bonding.

Molecular mechanism of synergy between the antimicrobial peptides PGLa and magainin 2.

PGLa and magainin 2 (MAG2) are amphiphilic α-helical membranolytic peptides from frog skin with known synergistic antimicrobial activity. By systematically mutating residues in the two peptides it was possible to identify the ones crucial for the synergy, as monitored by biological assays, fluorescence vesicle leakage, and solid-state N-NMR. Electrostatic interactions between anionic groups in MAG2 and cationic residues in PGLa enhance synergy but are not necessary for the synergistic effect.

Lactam-Stapled Cell-Penetrating Peptides: Cell Uptake and Membrane Binding Properties.

Stapling of side chains to stabilize an α-helical structure has been generally associated with an increased uptake of CPPs. Here, we compare four amphiphilic stapled peptides with their linear counterparts in terms of their membrane binding and conformational features in order to correlate these with uptake efficiency and toxicological effects. The impact of lactam stapling was found to vary strongly with regard to the different aspects of peptide-membrane interactions.

Structure analysis of the membrane-bound dermcidin-derived peptide SSL-25 from human sweat.

SSL-25 (SSLLEKGLDGAKKAVGGLGKLGKDA) is one of the shortest peptides present in human sweat and is produced after the proteolytic processing of the parent peptide dermcidin. Both peptides are reported to have antimicrobial function. To determine the structure of SSL-25 in lipid bilayers, a series of F-labeled SSL-25 analogs were synthesized.

Membrane Association Landscape of Myelin Basic Protein Portrays Formation of the Myelin Major Dense Line.

Compact myelin comprises most of the dry weight of myelin, and its insulative nature is the basis for saltatory conduction of nerve impulses. The major dense line (MDL) is a 3-nm compartment between two cytoplasmic leaflets of stacked myelin membranes, mostly occupied by a myelin basic protein (MBP) phase. MBP is an abundant myelin protein involved in demyelinating diseases, such as multiple sclerosis.