Structure and Intermolecular Dynamics of Aggregates Populated during Amyloid Fibril Formation Studied by Hydrogen/Deuterium Exchange

摘要

Tnhe aggregation of proteins into amyloid fibrils is a com-nplex and fascinating process associated with debilitatingnclinical disorders such as Alzheimer’s and Parkinson’s diseases.nThe process of aggregation involves a series of steps duringnwhich many intermediate aggregation states are populated.nRecent evidence points to these intermediate states as the toxicnmoieties primarily responsible for cell damage or cell death,nwhich are critical steps in the origin and progression of these disorders. To understand the molecular basis of these diseases, itnis crucial to investigate and define the details of the aggregation process, and to achieve this objective, researchers need the toolsnto characterize the structure and kinetics of interconversion of the various species present during amyloid fibril formation.nHydrogen deuterium (HD) exchange experiments are based on solvent accessibilities and provide one means by which this kindnof information may be acquired. In this Account, we describe research based on HD exchange processes that is directed towardnbetter understanding the dynamics and structural reorganizations involved in the formation of amyloid fibrils.