Interplay between Antimicrobial Peptides and Amyloid Proteins in Host Defense and Disease Modulation.

The biological properties of antimicrobial peptides (AMPs) and amyloid proteins and their cross-talks have gained increasing attention due to their potential implications in both host defense mechanisms and amyloid-related diseases. However, complex interactions, molecular mechanisms, and physiological applications are not fully understood. The interplay between antimicrobial peptides and amyloid proteins is crucial for uncovering new insights into immune defense and disease mechanisms, bridging critical gaps in understanding infectious and neurodegenerative diseases.

Lipid-Based Catalysis Demonstrated by Bilayer-Enabled Ester Hydrolysis.

Lipids have not traditionally been considered likely candidates for catalyzing reactions in biological systems. However, there is significant evidence that aggregates of amphiphilic compounds are capable of catalyzing reactions in synthetic organic chemistry. Here, we demonstrate the potential for the hydrophobic region of a lipid bilayer to provide an environment suitable for catalysis by means of a lipid aggregate capable of speeding up a chemical reaction.

Differential effects of ganglioside lipids on the conformation and aggregation of islet amyloid polypeptide.

Despite causing over 1 million deaths annually, Type 2 Diabetes (T2D) currently has no curative treatments. Aggregation of the islet amyloid polypeptide (hIAPP) into amyloid plaques plays an important role in the pathophysiology of T2D and thus presents a target for therapeutic intervention. The mechanism by which hIAPP aggregates contribute to the development of T2D is unclear, but it is proposed to involve disruption of cellular membranes.

Zinc and pH modulate the ability of insulin to inhibit aggregation of islet amyloid polypeptide.

Aggregation of the human islet amyloid polypeptide (hIAPP) contributes to the development and progression of Type 2 Diabetes (T2D). hIAPP aggregates within a few hours at few micromolar concentration in vitro but exists at millimolar concentrations in vivo. Natively occurring inhibitors of hIAPP aggregation might therefore provide a model for drug design against amyloid formation associated with T2D.

Polydopamine Adhesion: Catechol, Amine, Dihydroxyindole, and Aggregation Dynamics.

While polydopamine (PDA) possesses the surface-independent adhesion property of mussel-binding proteins, significant differences exist between them. Particularly, PDA's short and rigid backbone differs from the long and flexible protein sequence of mussel-binding proteins. Given that adhesion relies on achieving a conformal contact with large surface coverage, PDA has drawbacks as an adhesive.

Nanodisc Reconstitution and Characterization of Amyloid-β Precursor Protein C99.

Amyloid precursor protein (APP) plays a pivotal role in the pathology of Alzheimer's disease (AD). Since the fragmentation of the membrane-bound APP that results in the production of amyloid-β peptides is the starting point for amyloid toxicity in AD, it is important to investigate the structure and dynamics of APP in a near-native lipid-bilayer environment. However, the reconstitution of APP into a stable and suitable membrane-mimicking lipid environment is a challenging task.

Nanodisc reconstitution and characterization of amyloid-β precursor protein C99.

Amyloid precursor protein (APP) plays a pivotal role in the pathology of Alzheimer's disease. Since the fragmentation of the membrane-bound APP that results in the production of amyloid-beta peptides is the starting point for amyloid toxicity in AD, it is important to investigate the structure and dynamics of APP in a near-native lipid-bilayer environment. However, the reconstitution of APP into a stable/suitable membrane-mimicking lipid environment is a challenging task.

O Solid-State NMR Spectroscopy of Lipid Membranes.

Despite the limitations posed by poor sensitivity, studies have reported the unique advantages of O based NMR spectroscopy to study systems existing in liquid, solid, or semisolid states. O NMR studies have exploited the remarkable sensitivity of quadrupole coupling and chemical shift anisotropy tensors to the local environment in the characterization of a variety of intra- and intermolecular interactions and motion. Recent studies have considerably expanded the use of O NMR to study dynamic intermolecular interactions associated with some of the challenging biological systems under magic angle spinning (MAS) and aligned conditions.

LL-37: Structures, Antimicrobial Activity, and Influence on Amyloid-Related Diseases.

Antimicrobial peptides (AMPs), as well as host defense peptides (HDPs), constitute the first line of defense as part of the innate immune system. Humans are known to express antimicrobial precursor proteins, which are further processed to generate AMPs, including several types of α/β defensins, histatins, and cathelicidin-derived AMPs like LL37. The broad-spectrum activity of AMPs is crucial to defend against infections caused by pathogenic bacteria, viruses, fungi, and parasites.

Composition and Conformation of Hetero- versus Homo-Fluorinated Triazolamers Influence their Activity on Islet Amyloid Polypeptide Aggregation.

Novel fluorinated foldamers based on aminomethyl-1,4-triazolyl-difluoroacetic acid (1,4-Tz-CF) units were synthesized and their conformational behaviour was studied by NMR and molecular dynamics. Their activity on the aggregation of the human islet amyloid polypeptide (hIAPP) amyloid protein was evaluated by fluorescence spectroscopy and mass spectrometry. The fluorine labelling of these foldamers allowed the analysis of their interaction with the target protein.

Sulfonated polystyrenes: pH and Mg-insensitive amphiphilic copolymers for detergent-free membrane protein isolation.

Amphiphilic polymers are increasingly applied in the detergent-free isolation and functional studies of membrane proteins. However, the carboxylate group present in the structure of many popular variants, such as styrene-maleic acid (SMA) copolymers, brings limitations in terms of polymer sensitivity to precipitation at acidic pH or in the presence of divalent metal cations. Herein, we addressed this problem by replacing carboxylate with the more acidic sulfonate groups.

On-Pathway Oligomer of Human Islet Amyloid Polypeptide Induced and Stabilized by Mechanical Rotation during Magic Angle Spinning Nuclear Magnetic Resonance.

Intermediates along the fibrillation pathway are generally considered to be the toxic species responsible for the pathologies of amyloid diseases. However, structural studies of these species have been hampered by heterogeneity and poor stability under standard aqueous conditions. Here, we report a novel methodology for producing stable, on-pathway oligomers of the human type-2 diabetes-associated islet amyloid polypeptide (hIAPP or amylin) using the mechanical forces associated with magic angle spinning (MAS).

Direct interaction between the transmembrane helices stabilize cytochrome P450 2B4 and cytochrome b5 redox complex.

The catalytic activity of cytochrome P450 2B4 (CYP2B4) is moderated by its cognate redox partner cytochrome b5 (Cyt-b). The endoplasmic reticulum (ER) membrane and intermolecular transmembrane (TM) interaction between CYP2B4 and Cyt-b regulate the substrate catalysis and the reaction rate. This emphasizes the significance of elucidating the molecular basis of CYP2B4 and Cyt-b complexation in a membrane environment to better understand the enzymatic activity of CYP2B4.

Non-micellar ganglioside GM1 induces an instantaneous conformational change in Aβ leading to the modulation of the peptide amyloid-fibril pathway.

Alzheimer's disease is a progressive degenerative condition that mainly affects cognition and memory. Recently, distinct clinical and neuropathological phenotypes have been identified in AD. Studies revealed that structural variation in Aβ fibrillar aggregates correlates with distinct disease phenotypes.

On-Pathway Oligomer of Human Islet Amyloid Polypeptide Induced and Stabilized by Mechanical Rotation During MAS NMR.

Intermediates along the fibrillation pathway are generally considered to be the toxic species responsible for the pathologies of amyloid diseases. However, structural studies of these species have been hampered by heterogeneity and poor stability in standard aqueous conditions. Here, we report a novel methodology for producing stable, on-pathway oligomers of the human Type-2 Diabetes-associated islet amyloid polypeptide (hIAPP, or amylin) using the mechanical forces associated with magic angle spinning (MAS).

Ganglioside GM1 produces stable, short, and cytotoxic Aβ protofibrils.

Monosialoganglioside GM1-bound amyloid β-peptides have been found in patients' brains exhibiting early pathological changes of Alzheimer's disease. Herein, we report the ability of non-micellar GM1 to modulate Aβ aggregation resulting in the formation of stable, short, rod-like, and cytotoxic Aβ protofibrils with the ability to potentiate both Aβ and Aβ aggregation.

Conformation and Orientation of Antimicrobial Peptides MSI-594 and MSI-594A in a Lipid Membrane.

There is significant interest in the development of antimicrobial compounds to overcome the increasing bacterial resistance to conventional antibiotics. Studies have shown that naturally occurring and de novo-designed antimicrobial peptides could be promising candidates. MSI-594 is a synthetic linear, cationic peptide that has been reported to exhibit a broad spectrum of antimicrobial activities.

Enhancing the stability and homogeneity of non-ionic polymer nanodiscs by tuning electrostatic interactions.

The nanodisc technology is increasingly used for structural studies on membrane proteins and drug delivery. The development of synthetic polymer nanodiscs and the recent discovery of non-ionic inulin-based polymers have significantly broadened the scope of nanodiscs. While the lipid exchange and size flexibility properties of the self-assembled polymer-based nanodiscs are valuable for various applications, the non-ionic polymer nanodiscs are remarkably unique in that they enable the reconstitution of any protein, protein-protein complexes, or drugs irrespective of their charge.

Ultrafast Magic Angle Spinning Solid-State NMR Spectroscopy: Advances in Methodology and Applications.

Solid-state NMR spectroscopy is one of the most commonly used techniques to study the atomic-resolution structure and dynamics of various chemical, biological, material, and pharmaceutical systems spanning multiple forms, including crystalline, liquid crystalline, fibrous, and amorphous states. Despite the unique advantages of solid-state NMR spectroscopy, its poor spectral resolution and sensitivity have severely limited the scope of this technique. Fortunately, the recent developments in probe technology that mechanically rotate the sample fast (100 kHz and above) to obtain "solution-like" NMR spectra of solids with higher resolution and sensitivity have opened numerous avenues for the development of novel NMR techniques and their applications to study a plethora of solids including globular and membrane-associated proteins, self-assembled protein aggregates such as amyloid fibers, RNA, viral assemblies, polymorphic pharmaceuticals, metal-organic framework, bone materials, and inorganic materials.

Magnetically aligned nanodiscs enable direct measurement of O residual quadrupolar coupling for small molecules.

The use of O in NMR spectroscopy for structural studies has been limited due to its low natural abundance, low gyromagnetic ratio, and quadrupolar relaxation. Previous solution O work has primarily focused on studies of liquids where the O quadrupolar coupling is averaged to zero by isotropic molecular tumbling, and therefore has ignored the structural information contained in this parameter. Here, we use magnetically aligned polymer nanodiscs as an alignment medium to measure residual quadrupolar couplings (RQCs) for O-labelled benzoic acid in the aqueous phase.

Polymer-Nanodiscs as a Novel Alignment Medium for High-Resolution NMR-Based Structural Studies of Nucleic Acids.

Residual dipolar couplings (RDCs) are increasingly used for high-throughput NMR-based structural studies and to provide long-range angular constraints to validate and refine structures of various molecules determined by X-ray crystallography and NMR spectroscopy. RDCs of a given molecule can be measured in an anisotropic environment that aligns in an external magnetic field. Here, we demonstrate the first application of polymer-based nanodiscs for the measurement of RDCs from nucleic acids.