Stabilizing off-pathway oligomers by polyphenol nanoassemblies for IAPP aggregation inhibition

Praveen Nedumpully-Govindan, Aleksandr Kakinen, Emily Helen Pilkington, Thomas Paul Davis, Pu Chun Ke, Feng Ding

Research output: Contribution to journalArticleResearchpeer-review

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 7.5hours, 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.
Original languageEnglish
Article number19463
Pages (from-to)1-12
Number of pages12
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 2016

Cite this

@article{adac9a908b47478f95248147ce14030e,
title = "Stabilizing off-pathway oligomers by polyphenol nanoassemblies for IAPP aggregation inhibition",
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 7.5hours, 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.",
author = "Praveen Nedumpully-Govindan and Aleksandr Kakinen and Pilkington, {Emily Helen} and Davis, {Thomas Paul} and Ke, {Pu Chun} and Feng Ding",
year = "2016",
doi = "10.1038/srep19463",
language = "English",
volume = "6",
pages = "1--12",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

Stabilizing off-pathway oligomers by polyphenol nanoassemblies for IAPP aggregation inhibition. / Nedumpully-Govindan, Praveen; Kakinen, Aleksandr; Pilkington, Emily Helen; Davis, Thomas Paul; Ke, Pu Chun; Ding, Feng.

In: Scientific Reports, Vol. 6, 19463, 2016, p. 1-12.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Stabilizing off-pathway oligomers by polyphenol nanoassemblies for IAPP aggregation inhibition

AU - Nedumpully-Govindan, Praveen

AU - Kakinen, Aleksandr

AU - Pilkington, Emily Helen

AU - Davis, Thomas Paul

AU - Ke, Pu Chun

AU - Ding, Feng

PY - 2016

Y1 - 2016

N2 - 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 7.5hours, 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.

AB - 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 7.5hours, 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.

UR - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4725907/pdf/srep19463.pdf

U2 - 10.1038/srep19463

DO - 10.1038/srep19463

M3 - Article

VL - 6

SP - 1

EP - 12

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 19463

ER -