A polymer physics perspective on driving forces and mechanisms for protein aggregation.

Protein aggregation is a commonly occurring problem in biology. Cells have evolved stress-response mechanisms to cope with problems posed by protein aggregation. Yet, these quality control mechanisms are overwhelmed by chronic aggregation-related stress and the resultant consequences of aggregation become toxic to cells. As a result, a variety of systemic and neurodegenerative diseases are associated with various aspects of protein aggregation and rational approaches to either inhibit aggregation or manipulate the pathways to aggregation might lead to an alleviation of disease phenotypes. To develop such approaches, one needs a rigorous and quantitative understanding of protein aggregation. Much work has been done in this area. However, several unanswered questions linger, and these pertain primarily to the actual mechanism of aggregation as well as to the types of inter-molecular associations and intramolecular fluctuations realized at low protein concentrations. It has been suggested that the concepts underlying protein aggregation are similar to those used to describe the aggregation of synthetic polymers. Following this suggestion, the relevant concepts of polymer aggregation are introduced. The focus is on explaining the driving forces for polymer aggregation and how these driving forces vary with chain length and solution conditions. It is widely accepted that protein aggregation is a nucleation-dependent process. This view is based mainly on the presence of long times for the accumulation of aggregates and the elimination of these lag times with "seeds". In this sense, protein aggregation is viewed as being analogous to the aggregation of colloidal particles. The theories for polymer aggregation reviewed in this work suggest an alternative mechanism for the origin of long lag times in protein aggregation. The proposed mechanism derives from the recognition that polymers have unique dynamics that distinguish them from other aggregation-prone systems such as colloidal particles.