Atomistic Mechanism Of Polyphenol Amyloid Aggregation Inhibitors: Molecular Dynamics Study Of Curcumin, Exifone, And Myricetin Interaction With The Segment Of Tau Peptide Oligomer

Keywords

aggregation inhibitors; amyloid fibril; binding free energy; Curcumin; Exifone; hydrogen bond; polyphenols; MM-PBSA; molecular dynamic simulation; Myricetin

Abstract

Amyloid fibrils are highly ordered protein aggregates associated with many diseases affecting millions of people worldwide. Polyphenols such as Curcumin, Exifone, and Myricetin exhibit modest inhibition toward fibril formation of tau peptide which is associated with Alzheimers disease. However, the molecular mechanisms of this inhibition remain elusive. We investigated the binding of three polyphenol molecules to the protofibrils of an amyloidogenic fragment VQIVYK of tau peptide by molecular dynamics simulations in explicit solvent. We find that polyphenols induce conformational changes in the oligomer aggregate. These changes disrupt the amyloid H bonding, perturbing the aggregate. While the structural evolution of the control oligomer with no ligand is limited to the twisting of the β-sheets without their disassembly, the presence of polyphenol molecule pushes the β-sheets apart, and leads to a loosely packed structure where two of four β-sheets dissociate in each of the three cases considered here. The H-bonding capacity of polyphenols is responsible for the observed behavior. The calculated binding free energies and its individual components enabled better understanding of the binding. Results indicated that the contribution from Van der Waals interactions is more significant than electrostatic contribution to the binding. The findings from this study are expected to assist in the development of aggregation inhibitors. Significant binding between polyphenols and aggregate oligomer identified in our simulations confirms the previous experimental observations in which polyphenols refold the tau peptide without forming covalent bonds.

Publication Date

7-3-2015

Publication Title

Journal of Biomolecular Structure and Dynamics

Volume

33

Issue

7

Number of Pages

1399-1411

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1080/07391102.2014.951689

Socpus ID

84928602022 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/84928602022

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