Understanding the Protective Role of Alphab Crystallin, a Molecular Chaperone, in Toxic Amyloid Beta Oligomer Formation at an Atomic Level

Abstract

The aggregation of 39-42 amino acid long amyloid-β (Aβ) peptides is thought to be critical to the pathogenesis of Alzheimer's disease, the most common cause of senile dementia. Interestingly, small heat-shock proteins, (sHsps) including alphaB crystallin, a ubiquitous class of molecular chaperones, are also found colocalized with Aβ peptides in extracellular plaques. Those shsps play a central role in the avoidance of protein misfolding and aggregation, however, the molecular mechanism is not well-understood. We characterize using unconstrained atomistic molecular dynamics simulations the interaction of alpha-crystallin domain (ACD) with Aβ peptides during their assembly. We focus our attention on small oligomers (n≤10) due to their importance in toxicity. Our simulations reveal how ACD influences Aβ aggregation, which is determined by the delicate interplay of surface hydrophobicitiy and electrostatics. These results provide a mechanistic understanding of the protective role of alphaB crystallin at an atomic level.