Society is increasingly exposed to nanoparticles as they are ubiquitous in nature and introduced as man-made air pollutants and as functional ingredients in cosmetic products as well as in nanomedicine. Nanoparticles differ in size, shape and material properties. In addition to their intended function, the side effects on biochemical processes in organisms remain unclear. Nanoparticles can significantly influence the nucleation and aggregation process of peptides. The development of several neurodegenerative diseases, such as Alzheimer's disease, is related to the aggregation of peptides into amyloid fibrils. However, there is no comprehensive or universal mechanism to predict or explain apparent acceleration or inhibition of these aggregation processes. In this work, selected studies and possible mechanisms for amyloid peptide nucleation and aggregation, in the presence of nanoparticles, are highlighted. These studies are discussed in the context of recent data from our group on the role of gold nanoparticles in amyloid peptide aggregation using experimental methods and large-scale molecular dynamics simulations. A complex interplay of the surface properties of the nanoparticles, the properties of the peptides, as well as the resulting forces between both the nanoparticles and the peptides, appear to determine whether amyloid peptide aggregation is influenced, catalysed or inhibited by the presence of nanoparticles.
Many peptides aggregate into insoluble β-sheet rich amyloid fibrils. Some of these aggregation processes are linked to age-related diseases, such as Alzheimer’s disease and type 2 diabetes. Here, we show that the secondary structure of the peptide uperin 3.5 directs the kinetics and mechanism of amyloid fibrillar aggregation. Uperin 3.5 variants were investigated using thioflavin T fluorescence assays, circular dichroism spectroscopy, and structure prediction methods. Our results suggest that those peptide variants with a strong propensity to form an α-helical secondary structure under physiological conditions are more likely to aggregate into amyloid fibrils than peptides in an unstructured or “random coil” conformation. This conclusion is in good agreement with the hypothesis that an α-helical transition state is required for peptide aggregation into amyloid fibrils. Specifically, uperin 3.5 variants in which charged amino acids were replaced by alanine were richer in α-helical content, leading to enhanced aggregation compared to that of wild type uperin 3.5. However, the addition of 2,2,2-trifluoroethanol as a major co-solute or membrane-mimicking phospholipid environments locked uperin 3.5 to the α‑helical conformation preventing amyloid aggregation. Strategies for stabilizing peptides into their α-helical conformation could provide therapeutic approaches for overcoming peptide aggregation-related diseases. The impact of the physiological environment on peptide secondary structure could explain aggregation processes in a cellular environment.
Amyloid fibrils are highly ordered, β‐sheet rich forms of aggregated peptides and proteins that are associated with a variety of pathological human disorders, including Alzheimer's and Parkinson's diseases. Amyloid fibril‐forming peptides may be functionally related to antimicrobial peptides, despite differing significantly in sequence and structure. Specifically, their interaction with lipid membranes has mechanistic similarities. The 17‐amino acid peptide uperin 3.5 (U3.5) from an Australian amphibian is antimicrobial and amyloidogenic. Using a quartz crystal microbalance, we investigated the interaction of U3.5 with artificial membranes and found that (i) the membrane interaction of U3.5 is independent of the peptide's aggregation state, (ii) the presence of cholesterol in the membrane dramatically alters peptide–membrane interaction leading to a transmembrane pore‐like arrangement of U3.5, and (iii) electrostatic interaction is important for the membrane activity of U3.5 whereby removal of the positive charge at position 7 of U3.5 enhanced its fibrillar aggregation and ablated its membrane interaction, i.e. there is an inverse relationship between the antimicrobial and amyloidogenic properties of U3.5.
Promotion of cell adhesion on biomaterials is crucial for the long-term success of a titanium implant. Herein a novel concept is highlighted combining very stable and affine titanium surface adhesive properties with specific cell binding moieties in one molecule. A peptide containing L-3,4-dihydroxyphenylalanine was synthesized and affinity to titanium was investigated. Modification with a cyclic RGD peptide and a heparin binding peptide (HBP) was realized by an efficient on-resin combination of Diels-Alder reaction with inverse electron demand and Cu(I) catalyzed azide-alkyne cycloaddition. The peptide was fluorescently labeled by thiol Michael addition. Conjugating the cyclic RGD and HBP in one peptide gave improved spreading, proliferation, viability, and the formation of well-developed actin cytoskeleton and focal contacts of osteoblast-like cells.
Wireframe DNA origami assemblies can now be programmed automatically from the top-down using simple wireframe target geometries, or meshes, in 2D and 3D, using either rigid, six-helix bundle (6HB) or more compliant, two-helix bundle (DX) edges. While these assemblies have numerous applications in nanoscale materials fabrication due to their nanoscale spatial addressability and high degree of customization, no easy-to-use graphical user interface software yet exists to deploy these algorithmic approaches within a single, standalone interface. Further, top-down sequence design of 3D DX-based objects previously enabled by DAEDALUS was limited to discrete edge lengths and uniform vertex angles, limiting the scope of objects that can be designed. Here, we introduce the open-source software package ATHENA with a graphical user interface that automatically renders single-stranded DNA scaffold routing and staple strand sequences for any target wireframe DNA origami using DX or 6HB edges, including irregular, asymmetric DX-based polyhedra with variable edge lengths and vertices demonstrated experimentally, which significantly expands the set of possible 3D DNA-based assemblies that can be designed. ATHENA also enables external editing of sequences using caDNAno, demonstrated using asymmetric nanoscale positioning of gold nanoparticles, as well as providing atomic-level models for molecular dynamics, coarse-grained dynamics with oxDNA, and other computational chemistry simulation approaches.
Surfaces are abundant in living systems, such as in the form of cellular membranes, and govern many biological processes. In this study, the adsorption of the amyloidogenic model peptides GNNQQNY, NNFGAIL, and VQIVYK as well as the amyloid-forming antimicrobial peptide uperin 3.5 (U3.5) were studied at low concentrations (100 μM) to different surfaces. The technique of a quartz crystal microbalance with dissipation monitoring (QCM-D) was applied as it enables the monitoring of mass binding to sensors at nanogram sensitivity. Gold-coated quartz sensors were used as unmodified gold surfaces or functionalized with self-assembled monolayers (SAMs) of alkanethiols (terminated as methyl, amino, carboxyl, and hydroxyl) resulting in different adsorption affinities of the peptides. Our objective was to evaluate the underlying role of the nature and feature of interfaces in biological systems which could concentrate peptides and impact or trigger peptide aggregation processes. In overall, the largely hydrophobic peptides adsorbed with preference to hydrophobic or countercharged surfaces. Further, the glycoprotein lubricin (LUB) was tested as an antiadhesive coating. Despite its hydrophilicity, the adsorption of peptides to LUB coated sensors was similar to the adsorption to unmodified gold surfaces, which indicates that some peptides diffused through the LUB layer to reach the underlying gold sensor surface. The LUB protein-antiadhesive is thus more effective as a biomaterial coating against larger biomolecules than small peptides under the conditions used here. This study provides directions toward a better understanding of amyloid peptide adsorption to biologically relevant interfaces, such as cellular membranes.
Biological membranes are natural barriers to the transport of molecules and drugs within human bodies. Many antibacterial agents need to cross these membranes to reach their target and elicit specific effects. Kanamycin A belongs to the family of aminoglycoside antibiotics that target cellular RNA to inhibit bacterial and viral replication. Previous studies have shown that aminoglycosides bind to mammalian but disrupt bacterial membranes. In this study, molecular dynamics (MD) simulations and infrared (IR) spectroscopy were applied to investigate the initial, first key interactions of kanamycin A, as a representative aminoglycoside, with both bacterial and mammalian lipid bilayers at the molecular level. Computational studies revealed strong hydrogen bonding interactions between the hydroxyl and amino groups of the aminoglycoside with the ester carbonyl and phosphate groups of the lipids. IR spectroscopy provided experimental verification of the important role of the lipid's ester carbonyl, phosphate and hydroxyl groups for aminoglycoside binding. The bacterial membrane became disordered upon aminoglycoside addition, whereas the mammalian membrane became stiffer and more ordered. This indicates the bacterial membrane disruption observed by previous studies.
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