Role of conformational dynamics in pathogenic protein aggregation

The accumulation of pathogenic protein oligomers and ag-gregates is associated with several devastating amyloid dis-eases. As protein aggregation is a multi-step nucleation-dependent process beginning with unfolding or misfolding of the native state, it is important to understand how innate pro-tein dynamics influence aggregation propensity. Kinetic in-ter mediates composed of heterogeneous ensembles of oligomers are frequently formed on the aggregation pathway. Characterization of the structure and dynamics of these in-ter mediates is critical to the understanding of amyloid diseases since oligomers appear to be the main cytotoxic agents. In this review, we highlight recent biophysical studies of the roles of protein dynamics in driving pathogenic protein aggregation, yielding new mechanistic insights that can be leveraged for design of aggregation inhibitors.