What keeps protein interactions in line? Scientists have contributed to knowledge regarding the factors involved in the maintenance of protein solubility. Project results are important for understanding what conditions influence dysfunctional protein interactions. Health © Shutterstock Most proteins have evolved in their ability to convert from soluble states to distinctive and well-defined functional states under physiological conditions. Recent findings indicate that even under physiological conditions, the aggregated states of proteins can be more thermodynamically stable than native states. An example of this is the highly ordered amyloid form; it points to the key importance of kinetic factors in enabling the maintenance of protein homeostasis. Rarely, despite their inherent tendency to do so in vitro, proteins in vivo convert into aberrant aggregated states such as those identified in Alzheimer's disease and type II diabetes. The EU-funded project 'The structural and dynamical ensemble of an amyloidogenic intermediate' (Amyloidintermediate) combined nuclear magnetic resonance (NMR) experiments and simulations of molecular dynamics to identify factors allowing the majority of proteins to avoid aggregation under physiological conditions. Project partners chose to use the acylphosphatase from Drosophila melanogaster (AcPDro2) to investigate the molecular strategies involved in maintaining protein solubility. Study efforts afforded the opportunity to analyse differences in the structures, dynamics and energy surfaces of the protein in its soluble state or in situations of aggregation. This led to identification of the nature of the energy barriers that stop the protein ensemble from populating dangerous aggregation-prone states under normal physiological conditions. The identified barriers allow the protein to remain soluble while undergoing functional dynamics, and remove the risk of misfolding and aggregation into non-functional and potentially toxic agents. Results of the Amyloidintermediate project succeeded in enhancing scientific knowledge of factors significant to the development of degenerative diseases.
