Molecular insight into amyloid oligomer destabilizing mechanism of flavonoid derivative 2-(4′ benzyloxyphenyl)-3-hydroxy-chromen-4-one through docking and molecular dynamics simulations

Abstract

Aggregation of amyloid peptide (Aβ) has been shown to be directly related to progression of Alzheimer's disease (AD). Aβ is neurotoxic and its deposition and aggregation ultimately lead to cell death. In our previous work, we reported flavonoid derivative (compound 1) showing promising result in transgenic AD model of Drosophila. Compound 1 showed prevention of Aβ-induced neurotoxicity and neuroprotective efficacy in Drosophila system. However, mechanism of action of compound 1 and its effect on the amyloid is not known. We therefore performed molecular docking and atomistic, explicit-solvent molecular dynamics simulations to investigate the process of Aβ interaction, inhibition, and destabilizing mechanism. Results showed different preferred binding sites of compound 1 and good affinity toward the target. Through the course of 35 ns molecular dynamics simulation, conformations_5 of compound 1 intercalates into the hydrophobic core near the salt bridge and showed major structural changes as compared to other conformations. Compound 1 showed interference with the salt bridge and thus reducing the inter strand hydrogen bound network. This minimizes the side chain interaction between the chains A-B leading to disorder in oligomer. Contact map analysis of amino acid residues between chains A and B also showed lesser interaction with adjacent amino acids in the presence of compound 1 (conformations_5). The study provides an insight into how compound 1 interferes and disorders the Aβ peptide. These findings will further help to design better inhibitors for aggregation of the amyloid oligomer.

Nonequilibrium all-atom molecular dynamics simulation of the bubble cavitation and application to dissociate amyloid fibrils

“…Several MD simulations have shown that this fibril is very stable under ambient equilibrium conditions, 20,28,45 and can only be dissociated under external forces such as ultrasound, 12 laser excitation, 28 or binding with molecular compounds. 46 The result displayed in Fig. 2(d) shows that when the bubbles reach the maximum size the highest pressure exerted on (A β 17−42 ) 5 is about 3000 bars.…”

Molecular insights into Aβ42 protofibril destabilization with a fluorinated compound D744: A molecular dynamics simulation study

“…The MD simulations were performed using GROMACS (version 5.0.5) with GROMOS96 43a1 force field . GROMOS force field has been widely used to study the structural dynamics of peptides in a number of recent studies 10b,23f,30 . Using GROMOS96, Kumar et al investigated the destabilizing mechanism of flavonoid derivative 2‐(4'benzyloxyphenyl)‐3‐hydroxy‐chromen‐4‐one on the amyloid oligomer structure, 2BEG, using MD simulations of length 35 ns 30a .…”

“…GROMOS force field has been widely used to study the structural dynamics of peptides in a number of recent studies 10b,23f,30 . Using GROMOS96, Kumar et al investigated the destabilizing mechanism of flavonoid derivative 2‐(4'benzyloxyphenyl)‐3‐hydroxy‐chromen‐4‐one on the amyloid oligomer structure, 2BEG, using MD simulations of length 35 ns 30a . Autiero et al explored the mechanism of interaction between trehalose‐conjugated beta‐sheet breaker (BSB) peptides and Aβ(1–42) fibrils, 2BEG, by MD simulations of 100 ns using GROMOS96 force field 23f .…”

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

“…The cross-β strands are defined the strands of a β-sheet run vertically to the axis of fibril forming mature fibrils [ 20 ]. As schematically shown in Fig 1 , there are two main strategies to destabilize and/or dissipate the amyloid mature fibrils including; a) changing cross-β strands [ 17 , 21 – 23 ] mainly based on alteration of Aβ peptides’ quaternary structure ( Fig 1 , pathways 1 and 1' ), and b) focusing on the dissociated β strands from fibrils and converting β-sheet conformations to other secondary structures (changing tertiary and predominantly secondary structures of peptides, pathway 2 ). The disruption of mature fibrils is an effective procedure to decrease the toxicity of amyloid’s plaques at therapeutic mediation in the late phase of AD.…”

“…Both experimental and theoretical literatures currently suggest that flavonoids-related compounds inhibit early stage of Aβ aggregation which also disrupt the late stages of the of Alzheimer’s cross-β fibrils, providing the motivation for the present study. The structural feature of oligomeric protofilament state of Aβ17–42 peptides and destabilizing cross oligomeric-β by the interaction with flavonoids (pathways 1 and 1' ) have been extensively studied using MD simulation methods [ 17 , 21 , 23 , 29 ]. Besides, despite of wide studies on Aβ peptides’ fibrillogenesis, the conformational stability and affinity of the fibril Aβ17–42 peptide in the case of interaction with excipients remains unclear.…”