Abstract
Alzheimer's Disease (AD) is related with the abnormal aggregation of amyloid β-peptides Aβ1−40 and Aβ1−42, the latter having a polymorphic character which gives rise to U- or S-shaped fibrils. Elucidating the role played by the nanoscale-material architecture on the amyloid fibril stability is a crucial breakthrough to better understand the pathological nature of amyloid structures and to support the rational design of bio-inspired materials. The computational study here presented highlights the superior mechanical behavior of the S-architecture, characterized by a Young's modulus markedly higher than the U-shaped architecture. The S-architecture showed a higher mechanical resistance to the enforced deformation along the fibril axis, consequence of a better interchain hydrogen bonds' distribution. In conclusion, this study, focusing the attention on the pivotal multiscale relationship between molecular phenomena and material properties, suggests the S-shaped Aβ1−42 species as a target of election in computational screen/design/optimization of effective aggregation modulators.
Highlights
A number of neurodegenerative disorders, including Alzheimer’s disease (AD) are related with the abnormal aggregation of polypeptide chains (Chiti and Dobson, 2006)
steered molecular dynamics (SMD) simulations were carried out on the U-shaped model [Aβ17−42 pentamer extracted from 2BEG.pdb file (Luhrs et al, 2005)] and the S-shaped model [Aβ17−42 pentamer extracted from 2MXU.pdb file (Xiao et al, 2015)] surrounded by explicitly modeled water and ions
Analysis of SMD simulations highlighted that the structural anisotropy of amyloid fibrils is likely to manifest in a correspondent anisotropy of their mechanical properties as indicated by quantified stiffness (Figure 3B), i.e., the gradient of the force vs. displacement curves (Supporting Information S3) in the linear response regime
Summary
A number of neurodegenerative disorders, including Alzheimer’s disease (AD) are related with the abnormal aggregation of polypeptide chains (Chiti and Dobson, 2006). With the existence of several species of Aβ peptides, it was observed, that the most common peptides in the amyloid plaques are the Aβ1−40 and the Aβ1−42, the latter being the most toxic (Querfurth and LaFerla, 2010). For this main reason, previous experimental studies explored the existence of relationships between the molecular structure of amyloid fibrils and disease onset and severity, and on the brittleness of Amyloid Polymorfism Drives Fibril Mechanics fibrils assemblies (Guo and Akhremitchev, 2006; vandenAkker et al, 2011; Palhano et al, 2013; Schütz et al, 2015; Wang et al, 2017). Earlier models of Aβ1−42 fibrils, showed a Ushaped motif characterized by two β-strands V18-S26 and I31A42 and stabilized by the intra-chain salt bridge between residues D23-K28 (Luhrs et al, 2005)
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