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.

The Impact of Natural Compounds on S-Shaped Aβ42 Fibril: From Molecular Docking to Biophysical Characterization

“…Moreover, this structure presents two different structural rearrangements, S-shaped and the U-shaped [54,55]. In the last years, several studies have investigated the different behaviour of these polymorphisms and the S-shaped form has demonstrated greater conformational and mechanical stability than the U-shaped form [11,12,56]. Therefore, the S-shaped structure represents the primary target for pharmacological treatments, aimed to reduce the amyloidogenic process and interfere with the amyloid aggregates' stability.…”

“…In particular, this work considers the S-shaped polymorphism as the ligand target. Previous computational works have mostly studied a different amyloid polymorphism, namely the U-shaped one [47,48,51], which might be less stable than the S-shaped one [11,12]. Moreover, this work also provides a comprehensive comparative investigation on a considerable number of natural inhibitors, investigating their binding and action mechanisms.…”

“…Among different lengths of Aβ peptides, senile aggregates are mostly made by the Aβ 40 fibrils, but the most toxic species are the Aβ 42 ones, due to their intrinsic tendency to self-assembly [5]. The stability of these structures is strongly linked with the progression and severity of the disease, and in the last years, many efforts have been made to characterize the molecular stability of amyloid aggregates [6][7][8][9][10][11][12][13][14].…”

“…However, the Aβ 42 may arrange also in other polymorphic structures, such as the S-shaped structural rearrangement [55]. Interestingly, recent works have indicated that the S-shaped structure is characterized by superior conformational and mechanical stability with respect to the U-shaped one, suggesting a correlation between structural stability and toxicity [11,12,56].…”

When Stiffness Matters: Mechanosensing in Heart Development and Disease

“…Among these theories, computational molecular modeling has gained great momentum in the past 20 years, as a theoretical set of methodologies able to predict conformational and thermodynamic properties of biological building blocks and macromolecular super-assemblies by means of models characterized by atomic or quasi-atomic resolution. In this context, molecular dynamics (MD) simulations have been widely used in the last decades to obtain new insights into biological functions of proteins by studying such molecular systems at the atomistic level ( Soncini et al, 2007 ; Lepre et al, 2017 ; Grasso et al, 2018 , 2019a , b ). After McCammon et al (1977) investigated the dynamic behavior of small proteins on the basis of MD simulations, the method was widely employed for helping experimental design and data rationalization, with the drawback of an accessible timescale in the order of several hundreds of nanoseconds up to a microsecond ( Abraham et al, 2015 ; Hollingsworth and Dror, 2018 ), in contrast with the generally much larger timescale encompassing protein function (nanoseconds up to seconds).…”