Amyloid Fibril Nucleation in Reverse Micelles

Abstract

Aβ is 40-residue peptide, unstructured and present in all brain tissue. In Alzheimer's disease, Aβ peptides spontaneously aggregate and form fibrils. Fibril formation begins with a nucleation step that is poorly understood. Factors that cause nucleation are likely to be related with the cause of Alzheimer's disease. To understand the nucleation step, while preventing protein aggregation into fibrils, we have encapsulated Aβ peptides in reverse micelles (RMs) - nanometer-sized droplets of water, surrounded by a surfactant, immersed in an organic solvent. In addition to preventing aggregation, RMs may mimic aspects of the in vivo circumstances where Aβ peptides form fibrils, such as molecular crowding, confinement, and high ionic strength. MD simulations were performed to better understand RM properties, and the behavior of Aβ peptides in an RM. This computational study provides a detailed molecular model for an AOT RM. Our results show that 64 AOT molecules and a Wo = 7.5 yields an RM with dimensions that are consistent with experimental data. When Wo = 7.5 and the number of AOT molecules is greater than 64, the RM shape becomes markedly non-spherical and begins to split. When Wo = 7.5 and the number of AOT molecules is less than 64, the resulting RM has an insufficient number of AOT molecules to separate water from isooctane. Even with 64 AOT per RM, there is an overlap of water and isooctane phases that facilitates both the escape of waters from the RM core, and their re-entry. These processes - observable now in a detailed simulation - account for the narrow size distribution of RM at equilibrium. When incorporated in an RM, Aβ peptides may locate in the surfactant layer and increase RM surface area as well as volume.