Stabilizing Off-pathway Oligomers by Polyphenol Nanoassemblies for IAPP Aggregation Inhibition

Experimental studies have shown that many naturally occurring polyphenols have inhibitory effect on the aggregation of several proteins. Here, we use discrete molecular dynamics (DMD) simulations and high-throughput dynamic light scattering (DLS) experiments to study the anti-aggregation effects of...

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Bibliographic Details
Published in:Scientific reports 2016-01, Vol.6 (1), p.19463-19463, Article 19463
Main Authors: Nedumpully-Govindan, Praveen, Kakinen, Aleksandr, Pilkington, Emily H, Davis, Thomas P, Chun Ke, Pu, Ding, Feng
Format: Article
Language:English
Subjects:
Amylin
Amyloid
Aspirin - chemistry
Aspirin - pharmacology
Computer applications
Curcumin
Curcumin - chemistry
Curcumin - pharmacology
Hydrogen bonding
Hydrophobic and Hydrophilic Interactions
Hydrophobicity
Islet Amyloid Polypeptide - chemistry
Islet Amyloid Polypeptide - metabolism
Light scattering
Models, Molecular
Molecular Conformation
Molecular weight
Nanostructures - chemistry
Polyphenols
Polyphenols - chemistry
Polyphenols - pharmacology
Protein Aggregates - drug effects
Protein Aggregation, Pathological - drug therapy
Protein Aggregation, Pathological - metabolism
Protein Binding
Resveratrol
Stilbenes - chemistry
Stilbenes - pharmacology
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Summary:Experimental studies have shown that many naturally occurring polyphenols have inhibitory effect on the aggregation of several proteins. Here, we use discrete molecular dynamics (DMD) simulations and high-throughput dynamic light scattering (DLS) experiments to study the anti-aggregation effects of two polyphenols, curcumin and resveratrol, on the aggregation of islet amyloid polypeptide (IAPP or amylin). Our DMD simulations suggest that the aggregation inhibition is caused by stabilization of small molecular weight IAPP off-pathway oligomers by the polyphenols. Our analysis indicates that IAPP-polyphenol hydrogen bonds and π-π stacking combined with hydrophobic interactions are responsible for the stabilization of oligomers. The presence of small oligomers is confirmed with DLS measurements in which nanometer-sized oligomers are found to be stable for up to 7.5 hours, the time frame within which IAPP aggregates in the absence of polyphenols. Our study offers a general anti-aggregation mechanism for polyphenols, and further provides a computational framework for the future design of anti-amyloid aggregation therapeutics.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep19463