Racemic Peptides from Amyloid β and Amylin Form Rippled β-Sheets Rather Than Pleated β-Sheets

Abstract

The rippled β-sheet was theorized by Pauling and Corey in 1953 as a structural motif in which mirror image peptide strands assemble into hydrogen-bonded periodic arrays with strictly alternating chirality. Structural characterization of the rippled β-sheet was limited to biophysical methods until 2022 when atomic resolution structures of the motif were first obtained. The crystal structural foundation is restricted to four model tripeptides composed exclusively of aromatic residues. Here, we report five new rippled sheet crystal structures derived from amyloid β and amylin, the aggregating toxic peptides of Alzheimer's disease and type II diabetes, respectively. Despite the variation in peptide sequence composition, all five structures form antiparallel rippled β-sheets that extend, like a fibril, along the entire length of the crystalline needle. The long-range packing of the crystals, however, varies. In three of the crystals, the sheets pack face-to-face and exclude water, giving rise to cross-β architectures grossly resembling the steric zipper motif of amyloid fibrils but differing in fundamental details. In the other two crystals, the solvent is encapsulated between the sheets, yielding fibril architectures capable of host−guest chemistry. Our study demonstrates that the formation of rippled β-sheets from aggregating racemic peptide mixtures in three-dimensional (3D) assemblies is a general phenomenon and provides a structural basis for targeting intrinsically disordered proteins.

Amyloid engineering – how terminal capping modifies morphology and secondary structure of supramolecular peptide aggregates

“…Additionally, it has been reported that aromatic residues Phe, Tyr, and Trp favor the formation of rippled sheets. 62–64 In our case, the investigated TTR(105–115) peptides possess in their sequence 2 Tyr residues and AFM images strongly support the co-assembly of quasi-racemic fibrils. Accordingly, we observed totally different morphologies in enantiopure l - and d -peptide samples (Fig.…”

“…57 Such predictions were confirmed by other groups as well. 58–61 Very recent study performed by A. Hazari et al 62 demonstrates that racemic mixtures of amyloid-like peptide assemblies possess rippled sheets and it is their generic property. Additionally, it has been reported that aromatic residues Phe, Tyr, and Trp favor the formation of rippled sheets.…”

Two-Dimensional Molecular Architectonics through Controlled Noncovalent Interactions: Structure, Functional Properties, and Applications

“…Overall, these observations in principle could provide evidence for both spontaneous deracemization and enhanced mechanisms for achieving biological homochirality. In another study, the formation of rippled β-sheets from assembling racemic peptide mixtures is demonstrated . The X-ray crystallography study revealed that peptide sequences ( 26 – 29 ) derived from amyloid β and amylin exhibited the formation of antiparallel rippled β-sheets (Figure n–q) from assembling racemic peptide mixtures.…”

“…Copyright 2011 and 2013, respectively, Wiley-VCH. Panels (e, f), (m), and (n–q) were adapted from ref , ref , and ref , respectively. Copyright 2016, 2011, and 2023, respectively, American Chemical Society.…”