Dataset Information

Few Ramachandran Angle Changes Provide Interaction Strength Increase in A?42 versus A?40 Amyloid Fibrils.

ABSTRACT: The pathology of Alzheimer's disease can ultimately be traced to the increased aggregation stability of A?42 peptides which possess two extra residues (Ile 41 &Ala 42) that the non-pathological strain (A?40) lacks. We have found A?42 fibrils to exhibit stronger energies in inter-chain interactions and we have also identified the cause for this increase to be the result of different Ramachandran angle values in certain residues of the A?42 strain compared to A?40. These unique angle configurations result in the peptide planes in the fibril structures to be more vertical along the fibril axis for A?42 which thus reduces the inter-atomic distance between interacting atoms on vicinal peptide chains thereby increasing the electrostatic interaction energies. We lastly postulate that these different Ramachandran angle values could possibly be traced to the unique conformational folding avenues sampled by the A?42 peptide owing to the presence of its two extra residues.

SUBMITTER: Bastidas OH

PROVIDER: S-EPMC5093553 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Publications

Few Ramachandran Angle Changes Provide Interaction Strength Increase in Aβ42 versus Aβ40 Amyloid Fibrils.

Bastidas Oscar H OH Green Benjamin B Sprague Mary M Peters Michael H MH

Scientific reports 20161103

The pathology of Alzheimer's disease can ultimately be traced to the increased aggregation stability of Aβ42 peptides which possess two extra residues (Ile 41 &Ala 42) that the non-pathological strain (Aβ40) lacks. We have found Aβ42 fibrils to exhibit stronger energies in inter-chain interactions and we have also identified the cause for this increase to be the result of different Ramachandran angle values in certain residues of the Aβ42 strain compared to Aβ40. These unique angle configuration ...[more]

PMID: 27808259

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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

Few Ramachandran Angle Changes Provide Interaction Strength Increase in A?42 versus A?40 Amyloid Fibrils.

Publications

Few Ramachandran Angle Changes Provide Interaction Strength Increase in Aβ42 versus Aβ40 Amyloid Fibrils.

Similar Datasets

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