Issue 48, 2020

An α-helix mimetic oligopyridylamide, ADH-31, modulates Aβ42 monomer aggregation and destabilizes protofibril structures: insights from molecular dynamics simulations

Abstract

Alzheimer's disease (AD), an epidemic growing worldwide due to no effective medical aid available in the market, is a neurological disorder. AD is known to be directly associated with the toxicity of amyloid-β (Aβ) aggregates. In search of potent inhibitors of Aβ aggregation, Hamilton and co-workers reported an α-helix mimetic, ADH-31, which acts as a powerful antagonist of Aβ42 aggregation. To identify the key interactions between protein–ligand complexes and to gain insights into the inhibitory mechanism of ADH-31 against Aβ42 aggregation, molecular dynamics (MD) simulations were performed in the present study. The MD simulations highlighted that ADH-31 showed distinct binding capabilities with residues spanning from the N-terminal to the central hydrophobic core (CHC) region of Aβ42 and restricted the conformational transition of the helix-rich structure of Aβ42 into another form of secondary structures (coil/turn/β-sheet). Hydrophobic contacts, hydrogen bonding and π–π interaction contribute to the strong binding between ADH-31 and Aβ42 monomer. The Dictionary of Secondary Structure of Proteins (DSSP) analysis highlighted that the probability of helical content increases from 38.5% to 50.2% and the turn content reduces from 14.7% to 6.2% with almost complete loss of the β-sheet structure (4.5% to 0%) in the Aβ42 monomer + ADH-31 complex. The per-residue binding free energy analysis demonstrated that Arg5, Tyr10, His14, Gln15, Lys16, Val18, Phe19 and Lys28 residues of Aβ42 are responsible for the favourable binding free energy in Aβ42 monomer + ADH-31 complex, which is consistent with the 2D HSQC NMR of the Aβ42 monomer that depicted a change in the chemical shift of residues spanning from Glu11 to Phe20 in the presence of ADH-31. The MD simulations highlighted the prevention of sampling of amyloidogenic β-strand conformations in Aβ42 trimer in the presence of ADH-31 as well as the ability of ADH-31 to destabilize Aβ42 trimer and protofibril structures. The lower binding affinity between Aβ42 trimer chains in the presence of ADH-31 highlights the destabilization of the Aβ42 trimer structure. Overall, MD results highlighted that ADH-31 inhibited Aβ42 aggregation by constraining Aβ peptides into helical conformation and destabilized Aβ42 trimer as well as protofibril structures. The present study provides a theoretical insight into the atomic level details of the inhibitory mechanism of ADH-31 against Aβ42 aggregation as well as protofibril destabilization and could be implemented in the structure-based drug design of potent therapeutic agents for AD.

Graphical abstract: An α-helix mimetic oligopyridylamide, ADH-31, modulates Aβ42 monomer aggregation and destabilizes protofibril structures: insights from molecular dynamics simulations

Supplementary files

Article information

Article type
Paper
Submitted
04 Sep 2020
Accepted
05 Nov 2020
First published
10 Nov 2020

Phys. Chem. Chem. Phys., 2020,22, 28055-28073

An α-helix mimetic oligopyridylamide, ADH-31, modulates Aβ42 monomer aggregation and destabilizes protofibril structures: insights from molecular dynamics simulations

A. Kaur, D. Goyal and B. Goyal, Phys. Chem. Chem. Phys., 2020, 22, 28055 DOI: 10.1039/D0CP04672H

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