Driving Forces for Nonnative Protein Aggregation and Approaches to Predict Aggregation-Prone Regions

Nonnative protein aggregation is the process by which otherwise folded, monomeric proteins are converted to stable aggregates composed of protein chains that have undergone some degree of unfolding. Often, a conformational change is needed to allow certain sequences of amino acids-so-called aggregation-prone regions (APRs)-to form stable interprotein contacts such as β-sheet structures. In addition to APRs that are needed to stabilize aggregates, other factors or driving forces are also important in inducing aggregation in practice. This review focuses first on the overall process and mechanistic drivers for nonnative aggregation, followed by a more detailed summary of the factors currently thought to be important for determining which amino acid sequences most greatly stabilize nonnative protein aggregates, as well as a survey of many of the existing algorithms that are publicly available to attempt to predict APRs. Challenges with experimental validation of predicted APRs for proteins are briefly discussed.