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.