The role of phenolic OH groups of flavonoid compounds with H-bond formation ability to suppress amyloid mature fibrils by destabilizing β-sheet conformation of monomeric Aβ17-42

Sahar Andarzi Gargari,Abolfazl Barzegar,Alireza Tarinejad,Anirban Bhunia

doi:10.1371/journal.pone.0199541

Sahar Andarzi Gargari, Abolfazl Barzegar + Show 2 more

Open Access

https://doi.org/10.1371/journal.pone.0199541

Copy DOI

Abstract

Alzheimer’s disease (AD) is a kind of brain disease that arises due to the aggregation and fibrillation of amyloid β-peptides (Aβ). The peptide Aβ17–42 forms U-shape protofilaments of amyloid mature fibrils by cross-β strands, detected in brain cells of individuals with AD. Targeting the structure of Aβ17–42 and destabilizing its β-strands by natural compounds could be effective in the treatment of AD patients. Therefore, the interaction features of monomeric U-shape Aβ17–42 with natural flavonoids including myricetin, morin and flavone at different mole ratios were comprehensively studied to recognize the mechanism of Aβ monomer instability using molecular dynamics (MD) simulations. We found that all flavonoids have tendency to interact and destabilize Aβ peptide structure with mole ratio-dependent effects. The interaction free energies of myricetin (with 6 OHs) and morin (with 5 OHs) were more negative compared to flavone, although the total binding energies of all flavonoids are favorable and negative. Myricetin, morin and flavone penetrated into the core of the Aβ17–42 and formed self-clusters of Aβ17-42-flavonoid complexes. Analysis of Aβ17-42-flavonoids interactions identified that the hydrophobic interactions related to SASA-dependent energy are weak in all complexes. However, the intermolecular H-bonds are a main binding factor for shifting U-shape rod-like state of Aβ17–42 to globular-like disordered state. Myricetin and morin polyphenols form H-bonds with both peptide’s carbonyl and amine groups whereas flavone makes H-bonds only with amine substitution. As a result, polyphenols are more efficient in destabilizing β-sheet structures of peptide. Accordingly, the natural polyphenolic flavonoids are useful in forming stable Aβ17-42-flavonoid clusters to inhibit Aβ17–42 aggregation and these compounds could be an effective candidate for therapeutically targeting U-shape protofilaments’ monomer in amyloid mature fibrils.

Highlights

Protein misfolding and aggregation is one of the most concerning problems in applied biophysics [1, 2] and molecular medicine [3]
The major component of brains plaques in Alzheimer’s disease (AD), are amino-terminal truncated Aβ17–42 peptide corresponded to the amyloid mature fibrils [10, 11]
We aimed to investigate the effectiveness of three different flavonoids including myricetin, morin and flavone in the interaction and destabilization effects on the conformation of monomeric cross-β element of Aβ17–42, using molecular dynamics (MD) simulations method

Summary

Introduction

Protein misfolding and aggregation is one of the most concerning problems in applied biophysics [1, 2] and molecular medicine [3]. Several human brain diseases occur due to the protein misfolding and aggregation considered as hallmark pathognomonic features of various neurodegenerative diseases, including Alzheimer, Parkinson, Huntington and Prion diseases [4, 5]. The underlying cause of AD is not completely clear, it is apparent that the major pathological features are because of the presence of macroscopic structures aggregation and deposition of β-amyloid peptides (Aβ). The aggregated peptides are derived from amyloid precursor protein by sequential cleaving of β- and γ –secretases [8]. The aggregation of Aβ42 peptides is necessary in the progression of AD associated with amyloid fibrils [2]. The major component of brains plaques in AD, are amino-terminal truncated Aβ17–42 peptide corresponded to the amyloid mature fibrils [10, 11]

Objectives

Methods

Results