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Atomic Scale Structural Studies of Macromolecular Assemblies by Solid-state Nuclear Magnetic Resonance Spectroscopy
Published on: September 17, 2017
All-atom computer simulations of amyloid fibrils disaggregation
Jun Wang1, Chunhu Tan, Hai-Feng Chen
1Department of Molecular Biology and Biochemistry, University of California at Irvine, Irvine, California, USA.
Biophysical Journal
|September 2, 2008
Summary
Molecular dynamics simulations reveal amyloid fibril aggregation pathways. Tetramers act as a transition state, with initial aggregation nuclei forming at eight peptides, suggesting a smooth progression once the nucleus forms.
Area of Science:
- Biophysics
- Computational Biology
- Biochemistry
Background:
- Amyloid-like fibrils are implicated in various fatal diseases like Alzheimer's.
- Protein misfolding and aggregation into fibrils are central to these pathologies.
- Understanding the kinetics of fibril aggregation is crucial but remains challenging.
Purpose of the Study:
- To investigate the disaggregation mechanism of GNNQQNY fibrils.
- To elucidate the likely aggregation pathways of amyloid-like fibrils.
- To provide insights into the early stages of fibril formation.
Main Methods:
- Utilized GNNQQNY crystal structure for computational analysis.
- Employed high-temperature molecular dynamics simulations in explicit solvent.
- Simulated hexamer and 12-mer models at various temperatures for cumulative microsecond timescales.
Main Results:
- Tetramers identified as the probable transition state in both hexamer and 12-mer simulations.
- Initial aggregation nucleus determined to be eight peptides in 12-mer simulations.
- Aggregation landscape shows minimal barriers from 8-mers to 12-mers, indicating a smooth process.
Conclusions:
- The likely aggregation pathway involves monomers forming an 8-peptide nucleus with tetramers as the transition state.
- Dominant transition state conformations include tetramers in 3-1 and 2-2 arrangements.
- Parallel beta-sheets form before dry side-chain contacts during aggregation, offering insights into early fibril formation.
Related Concept Videos
03:03Amyloid Fibrils
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...
03:03Amyloid Fibrils
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...