(201d) Simulation of Amyloid Beta in the Presence of Aggregation Inhibitors

In Alzheimer’s Disease (AD), the amyloid β (Abeta) peptide aggregates and forms oligomer and fibril structures, causing a decline in thought processes and memory, ultimately resulting in dementia and death. Compounds that inhibit the formation of these structures are being examined by both academic and industrial researchers.  Understanding the mechanisms of aggregation inhibition on a molecular level could provide insight into the characteristics that would be most effective for disrupting the aggregation process, further aiding drug design. To examine the effect of inhibitors on protein aggregation, discontinuous molecular dynamics simulations (DMD) combined with an intermediate resolution protein model developed in the Hall group, PRIME20, were applied to a peptide/inhibitor system. The system contained 48 Abeta(16-22) and a variable number of model inhibitors, represented here by simple  hydrophobic spheres. The effects of varying the number, size, and interaction strength of the spheres were examined.  Preliminary results indicate that aggregation is promoted when the number of hydrophobic spheres of fixed size is increased, leading to an increase in effective concentration.  When the size of the hydrophobic spheres at fixed inhibitor concentration is increased, aggregation is decreased because the increased mass and interaction range decreases peptide mobility.  The effect of increasing the interaction strength between the spheres and peptides depends on temperature. Peptide aggregation is promoted until a critical interaction strength above which aggregation is hindered.