Local Structure and Dynamics of Hydration Water in Amyloid-β Aggregation and Caffeine-Mediated Inhibition

The self-assembly of amyloid-β (Aβ) peptides into amyloid fibrils is a hallmark of Alzheimer's disease (AD). This study explores the hydration structure of the amyloid dimer both with and without the inhibitor caffeine via all-atom, explicit-solvent molecular dynamics simulations combined with the umbrella sampling method. This study highlights the relatively unexplored role of protein–water interactions in both aggregation and caffeine-mediated inhibition of Aβ. The effect of caffeine on the hydration environment of the Aβ dimer is evaluated through the solvent-accessible surface area, tetrahedral order parameter, hydrogen bonding analysis, and the survival probability of water molecules within the hydration shell. The results demonstrate that the Aβ dimer in the absence of the inhibitor is more prone to aggregation and is less exposed to water compared to the dimer in the presence of caffeine. Water molecules are found to be more ordered around the dimer with the inhibitor than the one without it. The dynamics of hydration water molecules is found to be slower around the dimer without the inhibitor than the dimer with the inhibitor. These findings provide novel insights into the role of hydration water in Aβ aggregation and its caffeine-mediated inhibition.