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Biochemical Purification and Proteomic Characterization of Amyloid Fibril Cores from the Brain
Published on: April 28, 2022
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Energetics Underlying Twist Polymorphisms in Amyloid Fibrils.
Xavier Periole1, Thomas Huber2, Alessandra Bonito-Oliva2
1Groningen Biomolecular Sciences and Biotechnology Institute and Zernike Institute for Advanced Materials, University of Groningen , Groningen 9747 AG, The Netherlands.
The Journal of Physical Chemistry. B
|December 20, 2017
Summary
Amyloid fibril twist variability, linked to diseases like Alzheimer's, arises from molecular dynamics. Side chains, not the backbone, drive twisting, explaining polymorphism based on sequence and conditions.
Area of Science:
- Biophysics
- Structural Biology
- Neuroscience
Background:
- Amyloid fibrils are protein aggregates implicated in over 40 human diseases.
- Fibril polymorphism, including variations in twist, is influenced by growth conditions and affects mechanical properties.
- Amyloid β (Aβ) fibrils, associated with Alzheimer's disease, exhibit twist variability.
Purpose of the Study:
- To investigate the molecular basis of twist polymorphism in amyloid fibrils.
- To analyze the structural and thermodynamic factors governing fibril twisting.
- To understand how sequence, environment, and fibril assembly influence amyloid structure.
Main Methods:
- Transmission electron microscopy (TEM) of Aβ42 fibrils.
- Molecular dynamics (MD) simulations of GNNQQNY peptide protofilaments (a cross-β model).
- Structural and thermodynamic analysis, including potential of mean force (PMF) calculations.
Main Results:
- TEM revealed twist variability within single Aβ42 fibrils.
- MD simulations showed GNNQQNY protofilaments can twist from -11° to +8° under varying conditions without structural changes.
- PMF analysis indicated minimal energy (∼2kBT/peptide) to stabilize straight conformations, with side chains driving twisting, not the β-sheet backbone.
Conclusions:
- Twist polymorphism in amyloid fibrils is driven by side-chain interactions, not the core β-sheet structure.
- This provides a molecular rationale for how sequence, environmental factors, and protofilament number dictate fibril twist.
- Understanding twist variability is crucial for deciphering the mechanisms of amyloid-related diseases.
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