Tips and Tricks in the Modeling of Supramolecular Peptide Assemblies.

Supramolecular peptide assemblies (SPAs) hold promise as materials for nanotechnology and biomedicine. Although their investigation often entails adapting experimental techniques from their protein counterparts, SPAs are fundamentally distinct from proteins, posing unique challenges for their study. Computational methods have emerged as indispensable tools for gaining deeper insights into SPA structures at the molecular level, surpassing the limitations of experimental techniques, and as screening tools to reduce the experimental search space.

Enhanced Hydrogen Bonding by Urea Functionalization Tunes the Stability and Biological Properties of Peptide Amphiphiles.

Self-assembled nanostructures such as those formed by peptide amphiphiles (PAs) are of great interest in biological and pharmacological applications. Herein, a simple and widely applicable chemical modification, a urea motif, was included in the PA's molecular structure to stabilize the nanostructures by virtue of intermolecular hydrogen bonds. Since the amino acid residue nearest to the lipid tail is the most relevant for stability, we decided to include the urea modification at that position.

Diverse crystalline protein scaffolds through metal-dependent polymorphism.

As protein crystals are increasingly finding diverse applications as scaffolds, controlled crystal polymorphism presents a facile strategy to form crystalline assemblies with controllable porosity with minimal to no protein engineering. Polymorphs of consensus tetratricopeptide repeat proteins with varying porosity were obtained through co-crystallization with metal salts, exploiting the innate metal ion geometric requirements. A single structurally exposed negative amino acid cluster was responsible for metal coordination, despite the abundance of negatively charged residues.

Assessment of the MARTINI 3 Performance for Short Peptide Self-Assembly.

The coarse-grained MARTINI force field, initially developed for membranes, has proven to be an exceptional tool for investigating supramolecular peptide assemblies. Over the years, the force field underwent refinements to enhance accuracy, enabling, for example, the reproduction of protein-ligand interactions and constant pH behavior. However, these protein-focused improvements seem to have compromised its ability to model short peptide self-assembly.

SERS analysis of cancer cell-secreted purines reveals a unique paracrine crosstalk in MTAP-deficient tumors.

The tumor microenvironment (TME) is a dynamic pseudoorgan that shapes the development and progression of cancers. It is a complex ecosystem shaped by interactions between tumor and stromal cells. Although the traditional focus has been on the paracrine communication mediated by protein messengers, recent attention has turned to the metabolic secretome in tumors.

CLIP-Seq analysis enables the design of protective ribosomal RNA bait oligonucleotides against ALS/FTD poly-GR pathophysiology.

Amyotrophic lateral sclerosis and frontotemporal dementia patients with a hexanucleotide repeat expansion in (C9-HRE) accumulate poly-GR and poly-PR aggregates. The pathogenicity of these arginine-rich dipeptide repeats (R-DPRs) is thought to be driven by their propensity to bind low-complexity domains of multivalent proteins. However, the ability of R-DPRs to bind native RNA and the significance of this interaction remain unclear.

Enhanced Neuron Growth and Electrical Activity by a Supramolecular Netrin-1 Mimetic Nanofiber.

Neurotrophic factors are essential not only for guiding the organization of the developing nervous system but also for supporting the survival and growth of neurons after traumatic injury. In the central nervous system (CNS), inhibitory factors and the formation of a glial scar after injury hinder the functional recovery of neurons, requiring exogenous therapies to promote regeneration. Netrin-1, a neurotrophic factor, can initiate axon guidance, outgrowth, and branching, as well as synaptogenesis, through activation of deleted in colorectal cancer (DCC) receptors.

Artificial extracellular matrix scaffolds of mobile molecules enhance maturation of human stem cell-derived neurons.

Human induced pluripotent stem cell (hiPSC) technologies offer a unique resource for modeling neurological diseases. However, iPSC models are fraught with technical limitations including abnormal aggregation and inefficient maturation of differentiated neurons. These problems are in part due to the absence of synergistic cues of the native extracellular matrix (ECM).

Key aspects of the past 30 years of protein design.

Proteins are the workhorse of life. They are the building infrastructure of living systems; they are the most efficient molecular machines known, and their enzymatic activity is still unmatched in versatility by any artificial system. Perhaps proteins' most remarkable feature is their modularity.

Supramolecular Copolymers of Peptides and Lipidated Peptides and Their Therapeutic Potential.

Supramolecular peptide chemistry offers a versatile strategy to create chemical systems useful as new biomaterials with potential to deliver nearly 1000 known candidate peptide therapeutics or integrate other types of bioactivity. We report here on the co-assembly of lipidated β-sheet-forming peptides with soluble short peptides, yielding with various degrees of internal order. At low peptide concentrations, the co-monomer is protected by lodging within internal aqueous compartments and stabilizing internal β-sheets formed by the lipidated peptides.

Modeling Interactions within and between Peptide Amphiphile Supramolecular Filaments.

Many peptides are able to self-assemble into one-dimensional (1D) nanostructures, such as cylindrical fibers or ribbons of variable widths, but the relationship between the morphology of 1D objects and their molecular structure is not well understood. Here, we use coarse-grained molecular dynamics (CG-MD) simulations to study the nanostructures formed by self-assembly of different peptide amphiphiles (PAs). The results show that ribbons are hierarchical superstructures formed by laterally assembled cylindrical fibers.

Engineered Repeat Protein Hybrids: The New Horizon for Biologic Medicines and Diagnostic Tools.

ConspectusThe last decades have witnessed unprecedented scientific breakthroughs in all the fields of knowledge, from basic sciences to translational research, resulting in the drastic improvement of the lifespan and overall quality of life. However, despite these great advances, the treatment and diagnosis of some diseases remain a challenge. Inspired by nature, scientists have been exploring biomolecules and their derivatives as novel therapeutic/diagnostic agents.

Hydrogen Bonding Stiffens Peptide Amphiphile Supramolecular Filaments by Aza-Glycine Residues.

Peptide amphiphiles (PAs) are a class of molecules comprised of short amino acid sequences conjugated to hydrophobic moieties that may exhibit self-assembly in water into supramolecular structures. We investigate here how mechanical properties of hydrogels formed by PA supramolecular nanofibers are affected by hydrogen bond densities within their internal structure by substituting glycine for aza-glycine (azaG) residues. We found that increasing the number of PA molecules that contain azaG up to 5 mol% in PA supramolecular nanofibers increases their persistence length fivefold and decreases their diffusion coefficients as measured by fluorescence recovery after photobleaching.

3D Printing of Supramolecular Polymer Hydrogels with Hierarchical Structure.

Liquid crystalline hydrogels are an attractive class of soft materials to direct charge transport, mechanical actuation, and cell migration. When such systems contain supramolecular polymers, it is possible in principle to easily shear align nanoscale structures and create bulk anisotropic properties. However, reproducibly fabricating and patterning aligned supramolecular domains in 3D hydrogels remains a challenge using conventional fabrication techniques.

Molecular dynamics simulations reveal disruptive self-assembly in dynamic peptide libraries.

There is significant interest in the use of unmodified self-assembling peptides as building blocks for functional, supramolecular biomaterials. Recently, dynamic peptide libraries (DPLs) have been proposed to select self-assembling materials from dynamically exchanging mixtures of dipeptide inputs in the presence of a nonspecific protease enzyme, where peptide sequences are selected and amplified based on their self-assembling tendencies. It was shown that the results of the DPL of mixed sequences (e.

Biocatalytic Self-Assembly Cascades.

The properties of supramolecular materials are dictated by both kinetic and thermodynamic aspects, providing opportunities to dynamically regulate morphology and function. Herein, we demonstrate time-dependent regulation of supramolecular self-assembly by connected, kinetically competing enzymatic reactions. Starting from Fmoc-tyrosine phosphate and phenylalanine amide in the presence of an amidase and phosphatase, four distinct self-assembling molecules may be formed which each give rise to distinct morphologies (spheres, fibers, tubes/tapes and sheets).

Metastable hydrogels from aromatic dipeptides.

We demonstrate that the well-known self-assembling dipeptide diphenylalanine (FF) and its amidated derivative (FF-NH) can form metastable hydrogels upon sonication of the dipeptide solutions. The hydrogels show instantaneous syneresis upon mechanical contact resulting in rapid expulsion of water and collapse into a semi-solid gel.

Dynamic peptide libraries for the discovery of supramolecular nanomaterials.

Sequence-specific polymers, such as oligonucleotides and peptides, can be used as building blocks for functional supramolecular nanomaterials. The design and selection of suitable self-assembling sequences is, however, challenging because of the vast combinatorial space available. Here we report a methodology that allows the peptide sequence space to be searched for self-assembling structures.

Using experimental and computational energy equilibration to understand hierarchical self-assembly of Fmoc-dipeptide amphiphiles.

Despite progress, a fundamental understanding of the relationships between the molecular structure and self-assembly configuration of Fmoc-dipeptides is still in its infancy. In this work, we provide a combined experimental and computational approach that makes use of free energy equilibration of a number of related Fmoc-dipeptides to arrive at an atomistic model of Fmoc-threonine-phenylalanine-amide (Fmoc-TF-NH) which forms twisted fibres. By using dynamic peptide libraries where closely related dipeptide sequences are dynamically exchanged to eventually favour the formation of the thermodynamically most stable configuration, the relative importance of C-terminus modifications (amide versus methyl ester) and contributions of aliphatic versus aromatic amino acids (phenylalanine F vs.

Elucidation of the bonding of a near infrared dye to hollow gold nanospheres - a chalcogen tripod.

Infrared surface enhanced Raman scattering (SERS) is an attractive technique for the detection of nanoprobes in biological samples due to the greater depth of penetration and reduced interference compared to SERS in the visible region. A key challenge is to understand the surface layer formed in suspension when a specific label is added to the SERS substrate in aqueous suspension. SERS taken at different wavelengths, theoretical calculations, and surface-selective sum frequency generation vibrational spectroscopy (SFG-VS) were used to define the surface orientation and manner of attachment of a new class of infrared SERS labels with a thiopyrylium core and four pendant 2-selenophenyl rings.

Enzymatically activated emulsions stabilised by interfacial nanofibre networks.

We report on-demand formation of emulsions stabilised by interfacial nanoscale networks. These are formed through biocatalytic dephosphorylation and self-assembly of Fmoc(9-fluorenylmethoxycarbonyl)dipeptide amphiphiles in aqueous/organic mixtures. This is achieved by using alkaline phosphatase which transforms surfactant-like phosphorylated precursors into self-assembling aromatic peptide amphiphiles (Fmoc-tyrosine-leucine, Fmoc-YL) that form nanofibrous networks.

Supramolecular Fibers in Gels Can Be at Thermodynamic Equilibrium: A Simple Packing Model Reveals Preferential Fibril Formation versus Crystallization.

Low molecular weight gelators are able to form nanostructures, typically fibers, which entangle to form gel-phase materials. These materials have wide-ranging applications in biomedicine and nanotechnology. While it is known that supramolecular gels often represent metastable structures due to the restricted molecular dynamics in the gel state, the thermodynamic nature of the nanofibrous structure is not well understood.

Biocatalytic Pathway Selection in Transient Tripeptide Nanostructures.

Structural adaption in living systems is achieved by competing catalytic pathways that drive assembly and disassembly of molecular components under the influence of chemical fuels. We report on a simple mimic of such a system that displays transient, sequence-dependent formation of supramolecular nanostructures based on biocatalytic formation and hydrolysis of self-assembling tripeptides. The systems are catalyzed by α-chymotrypsin and driven by hydrolysis of dipeptide aspartyl-phenylalanine-methyl ester (the sweetener aspartame, DF-OMe).