(388b) Effects of Macromolecular Crowding On Amyloid Beta (16-22) Aggregation Using Coarse-Grained Simulations
In Alzheimer’s Disease (AD), the amyloid β (Aβ) peptide aggregates in the human brain and forms oligomer and fibril structures, causing a decline in thought processes and memory, ultimately resulting in dementia and death. The intracellular and extracellular environments of the brain contain a variety of macromolecules and structures that can occupy anywhere from 7% to in excess of 40% of the total volume of their respective mediums with cellular cytoplasm typically falling within the 20% to 30% range. Typically studies of protein aggregation do not account for the fact that both intracellular and extracellular regions of the body are crowded and while the observations made in these experiments lead to a better understanding of protein aggregation, they do not accurately depict how the process occurs in vivo. Since the rate and extent of aggregation in a crowded environment such as the human brain could differ by orders of magnitude from that in dilute solution, an investigation of aggregation rates and mechanisms in the presence of crowding spheres using computer simulations could provide unique insight into what causes differences between in vitro and in vivo protein aggregation. To examine the effect of crowding on protein aggregation, discontinuous molecular dynamics (DMD) simulations combined with an intermediate resolution protein model developed in the Hall group, PRIME20, were applied to a peptide/crowder system. The systems contained 192 Aβ(16-22) peptides and crowders of diameters 5Å, 20Å, and 40Å, represented here by simple hard spheres, at volume fractions of φc=0.00, 0.05, 0.10, 0.15, and 0.20. The effects of varying the number and size of the spheres were examined. Preliminary results indicate that aggregation is promoted when the crowder volume fraction is increased, leading to an increase in effective concentration. An additional effect of increased crowder volume fraction is more rapid oligomer formation and fibril seeding, ultimately decreasing or eliminating the lag phase of aggregation and altering the mechanism of aggregation. The aggregation mechanism appears to shift from the reaction limited dock-lock mechanism in dilute solution to a mechanism more characteristic of hydrophobic collapse followed by subsequent rearrangement into fibrils in a crowded environment. When the size of the crowding spheres at fixed crowding volume fraction is increased, aggregation is decreased because the increased mass decreases peptide diffusion.
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