Toward determining amyloid fibril structures using experimental constraints from Raman spectroscopy

Area of Science:

• Biophysics
• Structural Biology
• Spectroscopy

Background:

• Amyloid fibrils are protein aggregates implicated in various diseases.
• Understanding the precise structure of amyloid polymorphs is crucial for disease mechanism studies.
• Existing techniques like solid-state NMR and cryo-EM provide high-resolution structures but can be limited in certain applications.

Purpose of the Study:

• To present novel structural models for amylin20-29 and amyloid-beta25-35 (Aβ25-35) fibril polymorphs.
• To establish Raman spectroscopy as a complementary method for amyloid fibril structure determination.
• To investigate the structural differences between amylin20-29 and Aβ25-35 fibril formations.

Main Methods:

• Utilized Raman spectroscopy to obtain structural constraints, specifically amide C=O bond and Ramachandran ψ-dihedral angle data.
• Employed molecular dynamics (MD) simulations guided by these spectroscopic constraints to build structural models.
• Prepared three distinct amyloid fibril polymorphs from amylin20-29 and Aβ25-35 peptides for analysis.

Main Results:

• The fundamental structural motif for both amylin20-29 and Aβ25-35 fibrils was identified as extended β-strands.
• Amylin20-29 fibrils were found to adopt both antiparallel and parallel β-sheet polymorphs.
• Aβ25-35 fibrils exclusively formed a parallel β-sheet fibril structure.

Conclusions:

• Raman spectroscopy, combined with MD simulations, offers a powerful approach for detailed amyloid fibril structural modeling.
• This method complements established techniques like solid-state NMR and cryo-EM.
• The findings provide insights into the structural diversity of amyloid fibrils formed by different peptide sequences.