Caffeine destabilizes preformed Aβ protofilaments: insights from all atom molecular dynamics simulations

The aggregation and deposition of neurotoxic Aβ fibrils are key in the etiology of Alzheimer's disease (AD). It has been clinically recognized as a major form of dementia across the globe. Finding and testing various natural compounds to target Aβ fibrils to disrupt their stable structures seems to be a promising and attractive therapeutic strategy. The destabilization effects of caffeine on Aβ fibrils are investigated via in silico studies, where a series of molecular dynamics (MD) simulations, each of 100 ns, was conducted. The simulation outcomes obtained henceforth clearly indicated the drift of the terminal chains from the protofibrils, leading to disorganization of the characteristically organized cross-β structures of Aβ fibrils. The structural instability of Aβ17-42 protofibrils is explained through enhanced fluctuations in the RMSD, radius of gyration and RMSF values in the presence of caffeine. The key interactions providing stability, comprising D23-K28 salt bridges, intra- and inter-chain hydrogen bonding and hydrophobic interactions involving interchain A21-V36 and F19-G38 and intrachain L34-V36, were found to be disrupted due to increases in the distances between the participating components. The loss of β-sheet structure with the introduction of turns and α-helices in terminal chains may further inhibit the formation of higher order aggregates, which is necessary to stop the progression of the disease. The atomistic details obtained via MD studies relating to the mechanism behind the underlying destabilization of Aβ17-42 protofibrils by caffeine encourage further investigations exploring the potency of natural compounds to treat AD via disrupting preformed neurotoxic Aβ protofibrils.