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Resolving the Nanoscale Structure of β-Sheet Peptide Self-Assemblies Using Single-Molecule Orientation-Localization
Weiyan Zhou1, Conor L O'Neill2, Tianben Ding1
1Preston M. Green Department of Electrical and Systems Engineering, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, Missouri 63130, United States.
ACS Nano
|March 13, 2024
Summary
Single-molecule microscopy with Nile red reveals structural details of engineered and pathological amyloid fibrils. This technique distinguishes fibril structures and polymorphism, crucial for biomaterial development and understanding disease.
Area of Science:
- Biomaterials Science
- Biophysics
- Molecular Biology
Background:
- Synthetic peptides self-assemble into cross-β fibrils, useful for biomaterials but structurally similar to amyloid.
- Characterizing fibril polymorphs is challenging with traditional ensemble-averaging techniques.
Purpose of the Study:
- To develop and apply a high-resolution technique for characterizing engineered and pathological cross-β fibrils.
- To investigate the structural and morphological differences between designed peptides and amyloid-beta.
Main Methods:
- Utilized Nile red (NR), an amyloidophilic fluorogenic probe.
- Employed single-molecule orientation-localization microscopy (SMOLM) for high-resolution imaging.
- Applied NR SMOLM to KFE8 enantiomers and amyloid-beta peptide (Aβ42).
Main Results:
- NR SMOLM revealed the helical (bilayer) ribbon structure of both KFE8 and Aβ42 fibrils.
- Quantified the precise backbone tilt of fibrils without covalent labeling or mutations.
- Distinguished polymorphic morphologies (branched, curved) in KFE8 fibrils, showing greater heterogeneity than straight fibrils.
Conclusions:
- SMOLM is a powerful tool for interrogating structural differences and polymorphism in cross-β-rich fibrils.
- This technique aids in distinguishing engineered biomaterials from pathological amyloid species.
- Enables precise structural characterization relevant for biomaterial translation and disease research.
