Abstract
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.
Highlights
Aberrant aggregation of proteins into insoluble amyloid fibrils is implicated in a number of diseases including Alzheimer’s, Huntington’s and Parkinson’s diseases, and type-2 diabetes (T2D)[1]
An early experimental study reported that aspirin, a structural derivative of phenol, had an inhibitory effect on IAPP aggregation[33], no inhibition by aspirin was found in later studies by two different groups[20,34]
In our discrete molecular dynamics (DMD) simulations, we found that the nanoassemblies were consisted of a hydrophobic core of polyphenol molecules structurally reinforced by surrounding proteins
Summary
Aberrant aggregation of proteins into insoluble amyloid fibrils is implicated in a number of diseases including Alzheimer’s, Huntington’s and Parkinson’s diseases, and type-2 diabetes (T2D)[1]. Therapeutic strategies have been designed to target various species along the amyloid aggregation pathway Proteins such as transthyratin (TTR) and superoxide dismutase 1 (SOD1) form native homo-oligomers; stabilization of these functional oligomers by small molecule binding reduces the availability of protein monomers necessary for amyloid aggregation formation[6,7,8]. A recent computational study showed that resveratrol altered the structure of an hIAPP pentamer[31], which was modeled by the amyloid fibril structure derived from solid state NMR32 Despite multitudes of these studies, the molecular mechanism of inhibition remains largely unknown. We have employed DMD simulations to model the self-association and oligomer formation of IAPP and to study the effects of insulin and ions on hIAPP aggregation This new insight may prove highly beneficial to the rational design of alternative nanoassembly inhibitors
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