Guilt by Association: The Physical Chemistry and Biology of Protein Aggregation

Aggregation T aggregation of proteins and polypeptides is a major problem in the laboratory and in biotechnology, and is a serious issue in biology and human health. Protein aggregation is a topic that is ripe for investigation by physical chemical and biophysical methods, as well as by molecular dynamics (MD) simulations, and by more coarse grained modeling and analytical theory. Much recent attention in the physical chemistry community has focused on the process of amyloid fibril formation, motivated in part by its role in human disease. More than 30 different diseases involve amyloid formation, including devastating neurodegenerative disorders, but the mechanism of amyloid formation is not well understood, and there are very few viable therapeutic approaches. Amyloids are partially ordered aggregates of proteins that contain significant β-sheet structure arrayed in a cross-β structure in which the individual peptide chains are oriented perpendicular to the long axis of the fibril (Figure 1). The formation of amyloid is a fascinating and challenging problem in molecular self-assembly. However, it is worthwhile reminding ourselves that the importance of amyloids is directly related to their role in human disease, and thus experiments and simulations conducted under simplified conditions need to connect to biology to remain relevant. Fortunately, recent developments in methodology and experimental design, as well as growing collaborations between biophysicists and biologists hold the promise of providing a more rigorous, biologically relevant description of amyloid formation. Several of these advances are highlighted in the Perspectives included in this issue. Protein aggregation is not limited to amyloid formation, and new methods and approaches are also needed to study nonamyloidogenic aggregation. For example, considerable resources are invested in optimizing protein solubility and preventing aggregation of potential therapeutic proteins. Aggregation and poor solubility have limited the development of many monoclonal antibodies and other protein-based drugs and can lead to problems with immunogenicity, as well as loss of active protein. Protein aggregation can take other guises in biology beyond just amyloid. A classical example, and still arguably the best understood case of pathological protein aggregation, is the polymerization of sickle cell hemoglobin to form polymeric fibers. Elegant spectroscopic measurements together with detailed modeling have defined the mechanism of sickle cell polymerization, illustrating the power of physical chemical approaches. There are numerous other examples of deleterious aggregation that does not involve amyloid, including interesting mechanisms by which certain viruses subvert host defenses. Protein aggregation and/or polymerization in vivo and in vitro is not always bad. The discovery of functional amyloids highlights the beneficial effects of controlled amyloid formation in vivo. Recent work also spotlights the importance of controlled aggregation and self-assembly in cell signaling, the generation of signalosomes, the production of other intracellular bodies, and the potential role of liquid−liquid demixing transitions in biology. The controlled self-assembly of designed peptides into biocompatible hydrogels provides one example of the benefits of controlled aggregation in vitro, as does the design of amyloid-inspired biomaterials. At an even more basic level, we still lack a general, predictive theory of protein solubility. In contrast, the interactions that control protein stability are generally well understood, and there are well-documented approaches for rationally enhancing protein stability, but understanding protein solubility is arguably even more important. One of the most significant challenges in the study of amyloid formation is that the kinetics of self-assembly are complex and likely involve distributions of heterogeneous oligomers and possibly multiple pathways. In addition, there are