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

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 Aβ 42 aggregation. To identify the key interactions between protein-ligand complexes and to gain insights into the inhibitory mechanism of ADH-31 against Aβ 42 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 Aβ 42 and restricted the conformational transition of the helix-rich structure of Aβ 42 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 Aβ 42 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 Aβ 42 monomer + ADH-31 complex. The per-residue binding free energy analysis demonstrated that Arg5, Tyr10, His14, Gln15, Lys16, Val18, Phe19 and Lys28 residues of Aβ 42 are responsible for the favourable binding free energy in Aβ 42 monomer + ADH-31 complex, which is consistent with the 2D HSQC NMR of the Aβ 42 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 Aβ 42 trimer in the presence of ADH-31 as well as the ability of ADH-31 to destabilize Aβ 42 trimer and protofibril structures. The lower binding affinity between Aβ 42 trimer chains in the presence of ADH-31 highlights the destabilization of the Aβ 42 trimer structure. Overall, MD results highlighted that ADH-31 inhibited Aβ 42 aggregation by constraining Aβ peptides into helical conformation and destabilized Aβ 42 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 Aβ 42 aggregation as well as protofibri