9,10-Anthraquinone hinders beta-aggregation: How does a small molecule interfere with Abeta-peptide amyloid fibrillation?

Title9,10-Anthraquinone hinders beta-aggregation: How does a small molecule interfere with Abeta-peptide amyloid fibrillation?
Publication TypeJournal Article
Year of Publication2009
AuthorsConvertino M., Pellarin R., Catto M., Carotti A., Caflisch A.
JournalProtein Science
Volume18
Issue4
Pagination792-800
Date Published2009 Apr
Type of ArticleResearch Article
ISSN1469-896X
KeywordsAmyloid, Amyloid beta-Peptides, Anthracenes, Anthraquinones, Computer Simulation, Humans, Models, Molecular, Protein Binding, Protein Conformation
Abstract

Amyloid aggregation is linked to a number of neurodegenerative syndromes, the most prevalent one being Alzheimer's disease. In this pathology, the β-amyloid peptides (Aβ) aggregate into oligomers, protofibrils, and fibrils and eventually into plaques, which constitute the characteristic hallmark of Alzheimer's disease. Several low-molecular-weight compounds able to impair the Aβ aggregation process have been recently discovered; yet, a detailed description of their interactions with oligomers and fibrils is hitherto missing. Here, molecular dynamics simulations are used to investigate the influence of two relatively similar tricyclic, planar compounds, that is, 9, 10-anthraquinone (AQ) and anthracene (AC), on the early phase of the aggregation of the Aβ heptapeptide segment H14QKLVFF20, the hydrophobic stretch that promotes the Aβ self-assembly. The simulations show that AQ interferes with β-sheet formation more than AC. In particular, AQ intercalates into the β-sheet because polar interactions between the compound and the peptide backbone destabilize the interstrand hydrogen bonds, thereby favoring disorder. The thioflavin T-binding assay indicates that AQ, but not AC, sensibly reduces the amount of aggregated Aβ1-40 peptide. Taken together, the in silico and in vitro results provide evidence that structural perturbations by AQ can remarkably affect ordered oligomerization. Moreover, the simulations shed light at the atomic level on the interactions between AQ and Aβ oligomers, providing useful insights for the design of small-molecule inhibitors of aggregation with therapeutic potential in Alzheimer's disease.

DOI10.1002/pro.87
pubindex

0111

Alternate JournalProtein Sci.
PubMed ID19309732
PubMed Central IDPMC2762591
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