Nano-assembly of amyloid β peptide: role of the hairpin fold

Abstract

Structural investigations have revealed that β hairpin structures are common features in amyloid fibrils, suggesting that these motifs play an important role in amyloid assembly. To test this hypothesis, we characterized the effect of the hairpin fold on the aggregation process using a model β hairpin structure, consisting of two Aβ(14–23) monomers connected by a turn forming YNGK peptide. AFM studies of the assembled aggregates revealed that the hairpin forms spherical structures whereas linear Aβ(14–23) monomers form fibrils. Additionally, an equimolar mixture of the monomer and the hairpin assembles into non-fibrillar aggregates, demonstrating that the hairpin fold dramatically changes the morphology of assembled amyloid aggregates. To understand the molecular mechanism underlying the role of the hairpin fold on amyloid assembly, we performed single-molecule probing experiments to measure interactions between hairpin and monomer and two hairpin complexes. The studies reveal that the stability of hairpin-monomer complexes is much higher than hairpin-hairpin complexes. Molecular dynamics simulations revealed a novel intercalated complex for the hairpin and monomer and Monte Carlo modeling further demonstrated that such nano-assemblies have elevated stability compared with stability of the dimer formed by Aβ(14–23) hairpin. The role of such folding on the amyloid assembly is also discussed.

AFM Probing of Amyloid-Beta 42 Dimers and Trimers

“…These studies led to the conclusion that spontaneously assembled dimers are stable and have lifetimes in the range of seconds, which is orders of magnitude larger compared with the characteristic times for the intramolecular dynamics of the monomers (Lyubchenko et al, 2016). The measurements of the stability of amyloid dimers obtained with the AFM dynamics force spectroscopy were in line with direct measurements of dimers' lifetimes performed with the use of single molecule fluorescence studies (Lv et al, 2015;Maity et al, 2017a). The structures of dimers of Aβ40 and 42 proteins and their segments were revealed with the use of all-atom Molecular Dynamics (MD) simulations (Zhang and Lyubchenko, 2014;Zhang et al, 2016;Hashemi et al, 2019).…”

Single-molecule probing of amyloid nano-ensembles using the polymer nanoarray approach

“…The sandwich-type structure was identified in our recent studies of interactions between Aβ(14–23) hairpin and Aβ(14–23) monomer that produced complexes that ruptured at forces as large as ~180 pN. 37 …”

Self‐assembly of β‐turn motif‐connected tandem repeats of Aβ16‐22 and its aromatic analogs

“…This implies that the adjacent residues are out‐of‐register by two residues. Connecting two Aβ 14‐23 peptides with a tight turn would change the registry of β‐strands by two residues thereby diminishing their aggregation propensity as observed by Lyubchenko and coworkers . Polymorphism is another interesting aspect of amyloid fibrils.…”

“…Connecting two Aβ 14-23 peptides with a tight turn would change the registry of β-strands by two residues thereby diminishing their aggregation propensity as observed by Lyubchenko and coworkers. [49] Polymorphism is another interesting aspect of amyloid fibrils. It is now believed that amyloid fibrils are structurally polymorphic at the molecular level and such polymorphism could lead to variations in the disease development.…”