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Structural polymorphism of Alzheimer Abeta and other amyloid fibrils.

ABSTRACT: Deposits of amyloid fibrils characterize a diverse group of human diseases that includes Alzheimer's disease, Creutzfeldt-Jakob disease and type II diabetes. Amyloid fibrils formed from different polypeptides contain a common cross-beta spine. Nevertheless, amyloid fibrils formed from the same polypeptide can occur in a range of structurally different morphologies. The heterogeneity of amyloid fibrils reflects different types of polymorphism: (i) variations in the protofilament number, (ii) variations in the protofilament arrangement and (iii) different polypeptide conformations. Amyloid fibril polymorphism implies that fibril formation can lead, for the same polypeptide sequence, to many different patterns of inter- or intra-residue interactions. This property differs significantly from native, monomeric protein folding reactions that produce, for one protein sequence, only one ordered conformation and only one set of inter-residue interactions.

SUBMITTER: Fandrich M

PROVIDER: S-EPMC2712605 | biostudies-literature | 2009 Apr-Jun

REPOSITORIES: biostudies-literature

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Structural polymorphism of Alzheimer Abeta and other amyloid fibrils.

Fändrich Marcus M Meinhardt Jessica J Grigorieff Nikolaus N

Prion 20090401 2

Deposits of amyloid fibrils characterize a diverse group of human diseases that includes Alzheimer's disease, Creutzfeldt-Jakob disease and type II diabetes. Amyloid fibrils formed from different polypeptides contain a common cross-beta spine. Nevertheless, amyloid fibrils formed from the same polypeptide can occur in a range of structurally different morphologies. The heterogeneity of amyloid fibrils reflects different types of polymorphism: (i) variations in the protofilament number, (ii) vari ...[more]

PMID: 19597329

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Project description:Amyloid fibrils are highly ordered protein aggregates that are associated with several pathological processes, including prion propagation and Alzheimer's disease. A key issue in amyloid science is the need to understand the mechanical properties of amyloid fibrils and fibers to quantify biomechanical interactions with surrounding tissues, and to identify mechanobiological mechanisms associated with changes of material properties as amyloid fibrils grow from nanoscale to microscale structures. Here we report a series of computational studies in which atomistic simulation, elastic network modeling, and finite element simulation are utilized to elucidate the mechanical properties of Alzheimer's Abeta(1-40) amyloid fibrils as a function of the length of the protein filament for both twofold and threefold symmetric amyloid fibrils. We calculate the elastic constants associated with torsional, bending, and tensile deformation as a function of the size of the amyloid fibril, covering fibril lengths ranging from nanometers to micrometers. The resulting Young's moduli are found to be consistent with available experimental measurements obtained from long amyloid fibrils, and predicted to be in the range of 20-31 GPa. Our results show that Abeta(1-40) amyloid fibrils feature a remarkable structural stability and mechanical rigidity for fibrils longer than approximately 100 nm. However, local instabilities that emerge at the ends of short fibrils (on the order of tens of nanometers) reduce their stability and contribute to their disassociation under extreme mechanical or chemical conditions, suggesting that longer amyloid fibrils are more stable. Moreover, we find that amyloids with lengths shorter than the periodicity of their helical pitch, typically between 90 and 130 nm, feature significant size effects of their bending stiffness due the anisotropy in the fibril's cross section. At even smaller lengths (50 nm), shear effects dominate lateral deformation of amyloid fibrils, suggesting that simple Euler-Bernoulli beam models fail to describe the mechanics of amyloid fibrils appropriately. Our studies reveal the importance of size effects in elucidating the mechanical properties of amyloid fibrils. This issue is of great importance for comparing experimental and simulation results, and gaining a general understanding of the biological mechanisms underlying the growth of ectopic amyloid materials.

Dataset Information

Structural polymorphism of Alzheimer Abeta and other amyloid fibrils.

Publications

Structural polymorphism of Alzheimer Abeta and other amyloid fibrils.

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