The Role of Small Oligomers on an Amyloidogenic Free Energy Landscape

Abstract

We combine atomic force microscopy particle size distribution measurements with earlier measurements on 1-anilino-8-naphthalene sulfonate, thioflavin T and dynamic light scattering to develop a quantitative kinetic model for the aggregation of beta-lactoglobulin into amyloid. We directly compare our simulations to the population distributions provided by dynamic light scattering and atomic force microscopy. We combine species in the simulation according to structural type to compare with the fluorescence fingerprint results. The kinetic model of amyloidogenesis leads to an aggregation free energy landscape. We define the roles of and propose a classification scheme for different oligomeric species based on their location on the aggregation free energy landscape. We relate the different types of oligomers to the amyloid cascade hypothesis and the toxic oligomer hypothesis for amyloid-related diseases. We discuss existing kinetic mechanisms in terms of the different types of oligomers. We provide a possible resolution to the toxic oligomer-amyloid coincidence.