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Characterizing Individual Protein Aggregates by Infrared Nanospectroscopy and Atomic Force Microscopy
Published on: September 12, 2019
Nanoscale insights into the local structural rearrangements of amyloid-β induced by bexarotene
Kamila Sofińska1, Piotr Batys2, Adrian Cernescu3
1Jagiellonian University, Faculty of Physics, Astronomy and Applied Computer Science, M. Smoluchowski Institute of Physics, Łojasiewicza 11, 30-348 Krakow, Poland. ewelina.lipiec@uj.edu.pl.
Abstract:
A better understanding of the abnormal protein aggregation and the effect of anti-aggregation agents on the fibrillation pathways and the secondary structure of aggregates can determine strategies for the early treatment of dementia. Herein, we present a combination of experimental and theoretical studies providing new insights into the influence of the anti-aggregation drug bexarotene on the secondary structure of individual amyloid-β aggregates and its primary aggregation. The molecular rearrangements and the spatial distribution of β-sheets within individual aggregates were monitored at the nanoscale with infrared nanospectroscopy. We observed that bexarotene limits the parallel β-sheets formation, known to be highly abundant in fibrils at later phases of the amyloid-β aggregation composed of in-register cross-β structure. Moreover, we applied molecular dynamics to provide molecular-level insights into the investigated system. Both theoretical and experimental results revealed that bexarotene slows down the protein aggregation process via steric effects, largely prohibiting the antiparallel to parallel β-sheet rearrangement. We also found that bexarotene interacts not only via the single hydrogen bond formation with the peptide backbone but also with the amino acid side residue via a hydrophobic effect. The studied model of the drug-amyloid-β interaction contributes to a better understanding of the inhibition mechanism of the amyloid-β aggregation by the small molecule drugs. However, our nanoscale findings need to meet in vivo research requiring different analytical approaches.
Insights
Bexarotene, an anti-aggregation drug, inhibits amyloid-β protein clumping by limiting parallel beta-sheet formation. This drug interaction offers insights into early dementia treatment strategies.
Area of Science:
- Biochemistry
- Neuroscience
- Drug Discovery
Background:
- Abnormal protein aggregation, particularly amyloid-β (Aβ) peptides, is central to dementia pathogenesis.
- Understanding anti-aggregation agents' effects on fibrillation pathways is crucial for developing early dementia treatments.
Purpose of the Study:
- To investigate the influence of the anti-aggregation drug bexarotene on amyloid-β aggregate secondary structure and primary aggregation.
- To provide new insights into the molecular mechanisms of bexarotene's interaction with amyloid-β.
Main Methods:
- Utilized infrared nanospectroscopy to monitor molecular rearrangements and β-sheet distribution in individual amyloid-β aggregates at the nanoscale.
- Employed molecular dynamics simulations to gain molecular-level insights into the drug-peptide interactions.
Main Results:
- Bexarotene was observed to limit the formation of parallel β-sheets, which are characteristic of later-stage amyloid-β fibrils.
- Both experimental and theoretical findings indicated that bexarotene slows protein aggregation via steric effects, hindering antiparallel to parallel β-sheet rearrangement.
- Bexarotene interacts with amyloid-β through hydrogen bonds with the peptide backbone and hydrophobic interactions with amino acid side residues.
Conclusions:
- The study provides a nanoscale understanding of bexarotene's mechanism in inhibiting amyloid-β aggregation.
- This model of drug-amyloid-β interaction contributes to understanding small molecule drug inhibition of protein aggregation.
- Further in vivo research using different analytical approaches is needed to validate these nanoscale findings.
