Synthetic peptide and peptido-mimetic filaments and tubes represent a diverse class of nanomaterials with a broad range of potential applications, such as drug delivery, vaccine development, synthetic catalyst design, encapsulation, and energy transduction. The structures of these filaments comprise supramolecular polymers based on helical arrangements of subunits that can be derived from self-assembly of monomers based on diverse structural motifs. In recent years, structural analyses of these materials at near-atomic resolution (NAR) have yielded critical insights into the relationship between sequence, local conformation, and higher-order structure and morphology. This structural information offers the opportunity for development of new tools to facilitate the predictable and reproducible de novo design of synthetic helical filaments. However, these studies have also revealed several significant impediments to the latter process – most notably, the common occurrence of structural polymorphism due to the lability of helical symmetry in structural space. This article summarizes the current state of knowledge on the structures of designed peptide and peptido-mimetic filamentous assemblies, with a focus on structures that have been solved to NAR for which reliable atomic models are available.

The aggregation of the 11 residue long NACore peptide segment of α-synuclein (68-GAVVTGVTAVA-78) has been investigated using a combination of cryogenic transmission electron microscopy (cryo-TEM), small- and wide-angle X-ray scattering, and spectroscopy techniques. The aqueous peptide solubility is pH dependent, and aggregation was triggered by a pH quench from pH 11.3 to approximately pH 8 or 6, where the average peptide net charge is weakly negative (pH 8), or essentially zero (pH 6). Cryo-TEM shows the presence of long and stiff fibrillar aggregates at both pH, that are built up from β-sheets, as demonstrated by circular dichroism spectroscopy and thioflavin T fluorescence. The fibrils are crystalline, with a wide angle X-ray diffraction pattern that is consistent with a previously determined crystal structure of NACore. Of particular note is the cryo-TEM observation of small globular shaped aggregates, of the order of a few nanometers in size, adsorbed onto the surface of already formed fibrils at pH 6. The fibrillation kinetics is slow, and occurs on the time scale of days. Similarly slow kinetics is observed at both pH, but slightly slower at pH 6, even though the peptide solubility is here expected to be lower. The observation of the small globular shaped aggregates, together with the associated kinetics, could be highly relevant in relation to mechanisms of secondary nucleation and oligomer formation in amyloid systems.