The two main branches of bionanotechnology involve the self-assembly of either peptides or DNA. Peptide scaffolds offer chemical versatility, architectural flexibility and structural complexity, but they lack the precise base pairing and molecular recognition available with nucleic acid assemblies. Here, inspired by the ability of aromatic dipeptides to form ordered nanostructures with unique physical properties, we explore the assembly of peptide nucleic acids (PNAs), which are short DNA mimics that have an amide backbone. All 16 combinations of the very short di-PNA building blocks were synthesized and assayed for their ability to self-associate. Only three guanine-containing di-PNAs-CG, GC and GG-could form ordered assemblies, as observed by electron microscopy, and these di-PNAs efficiently assembled into discrete architectures within a few minutes. The X-ray crystal structure of the GC di-PNA showed the occurrence of both stacking interactions and Watson-Crick base pairing. The assemblies were also found to exhibit optical properties including voltage-dependent electroluminescence and wide-range excitation-dependent fluorescence in the visible region.

Biocompatible hydrogels are of high interest as a class of biomaterials for tissue engineering, regenerative medicine, and controlled drug delivery. These materials offer three-dimensional scaffolds to support the growth of cells and development of hierarchical tissue structures. Fmoc-peptides were previously demonstrated as attractive building blocks for biocompatible hydrogels. Here, we further investigate the biophysical properties of Fmoc-peptide-based hydrogels for medical applications. We describe the structural and thermal properties of these Fmoc-peptides, as well as their self-assembly process. Additionally, we study the role of interactions between aromatic moieties in the self-assembly process and on the physical and structural properties of the hydrogels.

Neutron diffraction of tri(3,5-tert-butylphenyl)methane at 20 K reveals an intermolecular C-H···H-C distance of only 1.566(5) Å, which is the shortest reported to date. The compound crystallizes as a C-symmetric dimer in an unusual head-to-head fashion. Quantum chemical computations of the solid state at the HSE-3c level of theory reproduce the structure and the close contact well (1.555 Å at 0 K) and emphasize the significance of packing effects; the gas-phase dimer structure at the same level shows a 1.634 Å C-H···H-C distance. Intermolecular London dispersion interactions between contacting tert-butyl substituents surrounding the central contact deliver the decisive energetic contributions to enable this remarkable bonding situation.

The paired helical filaments (PHF) formed by the intrinsically disordered human protein tau are one of the pathological hallmarks of Alzheimer disease. PHF are fibers of amyloid nature that are composed of a rigid core and an unstructured fuzzy coat. The mechanisms of fiber formation, in particular the role that hydration water might play, remain poorly understood. We combined protein deuteration, neutron scattering, and all-atom molecular dynamics simulations to study the dynamics of hydration water at the surface of fibers formed by the full-length human protein htau40. In comparison with monomeric tau, hydration water on the surface of tau fibers is more mobile, as evidenced by an increased fraction of translationally diffusing water molecules, a higher diffusion coefficient, and increased mean-squared displacements in neutron scattering experiments. Fibers formed by the hexapeptide 306 VQIVYK 311 were taken as a model for the tau fiber core and studied by molecular dynamics simulations, revealing that hydration water dynamics around the core domain is significantly reduced after fiber formation. Thus, an increase in water dynamics around the fuzzy coat is proposed to be at the origin of the experimentally observed increase in hydration water dynamics around the entire tau fiber. The observed increase in hydration water dynamics is suggested to promote fiber formation through entropic effects. Detection of the enhanced hydration water mobility around tau fibers is conjectured to potentially contribute to the early diagnosis of Alzheimer patients by diffusion MRI.hydration water | tau protein | amyloid fibers | intrinsically disordered proteins | neutron scattering A myloid fibers are the most stable forms of ordered protein aggregates. They have attracted much attention because of their implication in so-called conformational diseases, which include a variety of neurodegenerative disorders (1). Consequently, means of hindering or reversing fiber formation are actively researched (2). Pathological fibers are often formed by intrinsically disordered proteins (IDPs) that lack a well-defined 3D structure in their native state and are best described by an ensemble of different conformations (3). The human protein tau is an IDP that normally regulates microtubule stability in neurons. When tau aggregates, it forms paired helical filaments (PHF) that are one of the two histological hallmarks of Alzheimer disease (AD) (4, 5). As yet, and despite considerable effort over the past 30 y, the understanding of tau fibrillation in AD and other taupathies remains largely incomplete (6). The longest human tau isoform, htau40, is composed of 441 amino acid residues and is organized into several domains (see Fig. 1), including the repeat domains R1−R4 (residues 244-369) that constitute, together with the P1 and P2 domains, the microtubule binding regions (7). Essential for the nucleation of tau fibers is the presence of hexapeptides ( 275 VQIINK 280 and 306 VQIVYK 311 ) in R2 and R3 (8) that have a high propensity t...

The ability to develop a rational basis for the binding of inorganic materials to specific binding sites within self-assembling biological scaffolds has important applications in nanobiotechnology. Amyloid-forming peptides are a class of such scaffolds and show enormous potential as templates for the fabrication of low resistance, conducting nanowires. Here we report the use of a self-assembling peptide building block as scaffold for the systematic introduction of metal-binding residues at specific locations within the structure. The octapeptide NSGAITIG (Asparagine-Serine-Glycine-Alanine-Isoleucine-Threonine-Isoleucine-Glycine) from the fiber protein of adenovirus has been identified in previous structural studies as an elementary fibril-forming building block. Using this building block as a scaffold, we have designed three new cysteine-containing octa-peptides to study their eventual fibril-forming ability and potential templating of metal nanoparticles. We find that the cysteine substitutions do not alter the fibril-forming potential of the peptides, and that the fibrils formed bind efficiently to silver, gold, and platinum nanoparticles; furthermore, we report unexpected behavior of serine in nucleating gold and platinum nanoparticles. We find that combination of cysteine and serine residues projecting from adjacent sites on a peptide scaffold represents a potentially useful strategy in nucleating inorganic materials. The ability to reliably produce metal-coated fibrils is a vital first step towards the exploitation of these fibrils as conducting nanowires with applications in nano-circuitry. Short, biologically inspired self-assembling peptide scaffolds derived from natural fibrous proteins with known three-dimensional structure may provide a viable approach towards the rational design of inorganic nanowires.

The title zwitterion (2S)-2-azaniumyl-1-hydroxy-3-phenylpropan-1-olate, C9H11NO2, also known as L-phenylalanine, was characterized using synchrotron X-rays. It crystallized in the monoclinic space group P21 with four molecules in the asymmetric unit. The 0.62 Å resolution structure is assumed to be closely related to the fibrillar form of phenylalanine, as observed by electron microscopy and electron diffraction. The structure exists in a zwitterionic form in which π-π stacking and hydrogen-bonding interactions are believed to form the basis of the self-assembling properties.

Self-assembled peptides gain increasing interest as biocompatible and biodegradable scaffolds for tissue engineering. Rationally designed self-assembling building blocks that carry cell adhesion motifs such as Arg-Gly−Asp (RGD) are especially attractive. We have used a combination of theoretical and experimental approaches toward such rational designs, especially focusing on modular designs that consist of a central ultrashort amphiphilic motif derived from the adenovirus fiber shaft. In this study, we rationally designed RGDSGAITIGC, a bifunctional self-assembling amyloid peptide which encompasses cell adhesion and potential cysteine-mediated functionalization properties through the incorporation of an RGD sequence motif and a cysteine residue at the N-and C-terminal end, respectively. We performed replica exchange MD simulations that suggested that the key factor determining cell adhesion is the total solvent accessibility of the RGD motif and also that the Cterminal cysteine is adequately exposed. The designer peptides self-assembled into fibers that are structurally characterized with Transmission Electron Microscopy, Scanning Electron Microscopy and X-ray fiber diffraction. Furthermore, they supported cell adhesion and proliferation of a model cell line. We consider that the current bifunctional properties of the RGDSGAITIGC fibrilforming peptide can be exploited to fabricate novel biomaterials with promising biomedical applications. Such short selfassembling peptides that are amenable to computational design offer open-ended possibilities toward multifunctional tissue engineering scaffolds of the future.

The GAIIG sequence, common to the amyloid beta peptide (residues 29-33) and to the HIV-1 gp120 (residues 24-28 in a typical V3 loop), self-assembles into amyloid fibrils, as suggested by theory and the experiments presented here. The longer YATGAIIGNII sequence from the V3 loop also self-assembles into amyloid fibrils, of which the first three and the last two residues are outside the amyloid GAIIG core. We postulate that this sequence, with suitably selected modifications at the flexible positions, can serve as a designable scaffold for novel amyloid-based materials. Moreover, we report the single crystal X-ray structure of the beta-breaker peptide GAIPIG at 1.05 Å resolution. The structural information provided in this study could serve as the basis for structure-based design of potential inhibitors of amyloid formation.