The role of water in amyloid aggregation kinetics.

• Water and protein mobility are inextricably linked and therefore water itself plays an essential role in protein function. • IDPs have a larger solvent accessible area compared to globular proteins, making them more sensitive to changes in the surrounding environment. • Retardation of water mobility and subsequent protein mobility may lead to an increased propensity of proteins to aggregate. • Environments vary inside different cells and compartments and can directly affect water mobility and therefore protein aggregation. • Water is the rate limiting step of the 'dock and lock' mechanism of fibril elongation. The role of water in protein function and aggregation is highly important and may hold some answers to understanding initiation of misfolding diseases such as Parkinson's, Alzheimer's and Huntington's where soluble intrinsically disordered proteins (IDPs) aggregate into fibrillar structures. IDPs are highly dynamic and have larger solvent exposed areas compared to globular proteins, meaning they make and break hydrogen bonds with the surrounding water more frequently. The mobility of water can be altered by presence of ions, sugars, osmolytes, proteins and membranes which differ in different cell types, cell compartments and also as cells age. A reduction in water mobility and thus protein mobility enhances the probability that IDPs can associate to form intermolecular bonds and propagate into aggregates. This poses an interesting question as to whether localised water mobility inside cells can influence the propensity of an IDP to aggregate and furthermore whether it can influence fibril polymorphism and disease outcome. [ABSTRACT FROM AUTHOR]