(597g) Dynamics in Alzheimer's Disease: The Role of Peptide Flexibility On Amyloid Beta Aggregation

Aggregates of the amyloid beta peptide (Aβ) are thought to trigger brain cell death in Alzheimer's patients. Two different types of Aβ aggregates have been identified: soluble, and insoluble. Soluble aggregates are formed in early stages of peptide association, whereas insoluble aggregates are the final state of aggregation. Interestingly, it is the soluble aggregates, not the insoluble ones, which correlate with disease progression. Despite the relevance of soluble aggregates as a target for Alzheimer's disease, their mechanism of formation is unknown. The role of local flexibility in protein function has recently received attention: in this study we ask if local flexibility plays a similar role in the formation of soluble aggregates. To answer this question, we perform all-atom molecular dynamics simulations of wild-type Aβ, and two mutated forms that vary in their ability to form soluble aggregates. We find that increased soluble aggregate formation is associated with increased flexibility, and propose that this drives soluble aggregate formation by allowing the peptide to more easily access those conformations most favorable to association.

1-2009-->