Remodeling Cross‐β Nanotube Surfaces with Peptide/Lipid Chimeras

Abstract

Peptide/lipid chimeras, which are generally referred to as peptide amphiphiles, array specific peptides on the surface of ordered lipid assemblies. [1] These materials are being explored as tissue scaffolds, in drug delivery, as antimicrobrials, and for biomineralization applications. [2][3][4][5][6] However, the increasing realization that simple peptides with high cross-b fold propensity can achieve long-range ordered arrays comparable to lipid amphiphiles has now allowed for the creation of an entirely new architectural framework. This framework not only offers precisely controlled positioning of charges and hydrophobic patches along a robust nanotube surface, but also the systematic adjustment of that spacing in a manner that to this point has been unrealized in self-assembling materials.Peptide amphiphiles can achieve remarkable long-range order within a range of topological lipid phases. [2][3][4][5][6] For example, the elongated worm-like micelles have been modeled as having alkane interiors with peptide surfaces, [4] a morphology that reflects the same structural tension between head group and alkane that molds phospholipid assemblies. [5] This structure suggests that various self-assembling peptide elements might be able to extend the standard amphiphile tensions into new frameworks, and focused our attention on the strong self-organizing potential of the cross-b fold. [3,5,7,8] The nucleating core sequence of the amyloid forming Ab-peptide associated with Alzheimers disease, Ab(16-22), K 16 LVFFAE 22 -NH 2 , which organizes into diverse cross-b assemblies, [9][10][11][12][13] was acylated through conventional solid-phase Fmoc chemistry at the N-terminus with straightchain fatty acids ranging in length from two to sixteen carbon atoms. The products were purified by RP-HPLC, assembled under a range of conditions, and the resulting assemblies scored by electron microscopy (EM).Of the series assembled under acidic conditions, C 2 (Nacetyl) through C 4 (N-butyryl) assemblies were morpholog-ically indistinguishable (Supporting Information, Figure S1), and assigned as hollow tubes based on the previously characterized N-acetyl-Ab(16-22) assemblies. [10] Intermediate acyl chain lengths, C 5 to C 10 , assembled as ribbons, and longer lengths, C 14 and C 16 , formed fibers (Supporting Information, Figure S1). Most notably however, the C 11 (N-undecanoyl), C 12 (N-lauroyl), and C 13 (N-tridecanoyl) Ab(16-22) chimeras appeared as homogeneous tubes most similar to the N-acetyl assemblies, with the same distinct edges that arise from negative staining by uranyl acetate deposition inside and outside the tube cavity (Figure 1 b).High-resolution cryo-SEM further confirmed the Nlauroyl-Ab(16-22) assemblies as hollow nanotubes (Figure 1 b, inset) and the diameters of (56 AE 8) nm were also remarkably similar to the well-characterized N-acetyl-Ab(16-22) tubes. [10] Powder X-ray diffraction analyses [14] (Figure 2 a) gave sharp and distinct reflections for the H-bonded b-strand repeat at 4.7 for all acyl chain lengths, but ...

Peptide-Directed Assembly of Single-Helical Gold Nanoparticle Superstructures Exhibiting Intense Chiroptical Activity

“…We speculate that the aliphatic chains, which are relatively ordered ( vide supra ), aggregate with one another at the inner surface of the helical ribbon or possibly fold inward with one another in-between β-sheets and therefore make only a small contribution to the measured ribbon thickness. 71 In either case, the helical ribbon architecture segregates the relatively hydrophobic N-terminus from the aqueous buffer while exposing the hydrophilic C-terminus. 72 This is in contrast to a twisted ribbon structure where both sides of the tape would be equally exposed.…”

Context dependence of protein misfolding and structural strains in neurodegenerative diseases

“…To develop the necessary methods for characterizing any mixed molecular assemblies forming in the presence of brain lipids, a series of simple peptide/lipid chimeras were prepared with Aβ(16–22) N ‐acylated with fatty acid chains containing from 2 ( N ‐acetyl) to 16 ( N ‐palmitoyl) carbon atoms . Remarkably, all of these chimeric peptides assembled and displayed the characteristic H‐bonded β‐sheet reflection at 4.7 Å by X‐ray diffraction (XRD) .…”

“…C 11 ( N ‐undecanoyl) to C 13 ( N ‐tridecanoyl) assembled as tubes morphologically identical to those formed by the shorter chain (C 2 –C 4 ) chimeric peptides. This similarity between the morphology of the two distinctly different peptide amphiphiles ( N ‐acetyl (C 2 )‐ and N ‐lauroyl (C 12 )‐Aβ(16–22), Figures B and C) led us to investigate the structural differences between these assemblies, specifically the location of the acyl chain and the source of the altered laminate spacing of 9.8 Å for N ‐acetyl Aβ(16–22) to 11.5 Å for N ‐lauroyl Aβ(16–22) assembled peptides …”

Insights into protein misfolding and aggregation enabled by solid-state NMR spectroscopy

“…As with their naturally occurring counterparts, structural studies of these designer amyloids benefit from valuable insights enabled by ssNMR [23, 114–118]. In most cases, these amyloid- or cross-β-based materials are based on short amyloidogenic peptides that may be modified with acyl chains or by cross-linking [23, 115, 116]. Detailed structural (and dynamic) data on these synthetic assemblies enabled by ssNMR are likely to be critical for disentangling how these designer molecules self-assemble and to find ways to rationally modify their structures and properties.…”