The Role of Structural Polymorphism in Driving the Mechanical Performance of the Alzheimer's Beta Amyloid Fibrils

Abstract

Alzheimer's Disease (AD) is related with the abnormal aggregation of amyloid β-peptides Aβ_1-40 and Aβ_1-42, 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 Aβ_1-42 species as a target of election in computational screen/design/optimization of effective aggregation modulators.

Keywords: Alzheimer's Disease; Young Modulus; amyloid fibrils; biomechanics; molecular dynamics simulations; structural polymorphism.

Figure 1

Representation of the deformation protocols applied to the fibril model in case of (A) U-shaped and (B) S-shaped. Each deformation is defined by a pulling direction, highlighted by the blue arrow. For each deformation, the constrained pulled group and the restrained reference group (both composed only by C-alpha atoms) are evidenced in yellow and orange, respectively. All the other atoms of the peptides are free to move. Molecular systems inside their simulation box throughout stretch and shear SMD simulations are shown in (C).

Figure 2

Representative snapshots of U- and S-models evolving in time when the three deformation protocols are applied. On the right side the corresponding force-time profile is plotted.

Figure 3

Average values with related standard error of the Peak Forces (A) and Stiffness Constants (B) recorded for U- and S-models during each type of SMD protocol.

Figure 4

Interchain H-bonds (between chain B and chain C) as function of the interchain chain displacement in (A) X-, (B) Y-, and (C) Z-direction along the SMD simulations at pulling rate v = 0.01 Å/ps. Plots show the probability of H-bonds presence as function of interchain displacement in case of U- (top) and S-shaped (bottom) arrangements. For each residue in one chain (e.g., chain B) the presence of H-bonds with the adjacent chain (e.g., chain C) is quantified as a probability calculated over 5 SMD replicas. Black color indicates a probability of 1, whereas the white code represents a probability of 0, as reported in the legend.