KCS

As the number of people suffering from neurodegenerative diseases, such as dementia, grows, they have become a serious social burden. Nevertheless, the majority of dementia treatments aim to alleviate symptoms in the short term. Understanding the nature of a protein identified as a pathogen is required for developing a more effective treatment. However, intrinsically disordered proteins, which have been identified as the cause of dementia, can exist in a heterogeneous states and do not have a specific favorable structure, particularly at the early stage of aggregation. As a result, an analysis method capable of comprehensively analyzing various structure ensembles in which proteins may exist is required. Herein, we investigated the conformation ensemble of amyloid-β (1-42) and tau, which are closely related to the pathological hallmarks in Alzheimer’s disease using replica exchange molecular dynamics simulations. We identified protein interactions that play an active role on the early stages of amyloid aggregation by in silico analyses. Furthermore, combined with an interdisciplinary biophysical approach, we observed how the theoretically identified structural properties were expressed in vitro. Overall, this methodology, based on the structural dynamics of pathologically disordered proteins, could be applied to theoretically predict and inhibit self-assembly properties.