Defining a Physical Basis for Diversity in Protein Self-Assemblies Using a Minimal Model.

Self-assembly of proteins into ordered, fibrillar structures is a commonly observed theme in biology. It has been observed that diverse set of proteins (e.g., alpha-synuclein, insulin, TATA-box binding protein, Sup35, p53), independent of their sequence, native structure, or function could self-assemble into highly ordered structures known as amyloids. What are the crucial features underlying amyloidogenesis that make it so generic? Using coarse-grained simulations of peptide self-assembly, we argue that variation in two physical parameters-bending stiffness of the polypeptide and strength of intermolecular interactions-can give rise to many of the structural features typically associated with amyloid self-assembly. We show that the interplay between these two factors gives rise to a rich phase diagram displaying high diversity in aggregated states. For certain parameters, we find a bimodal distribution for the order parameter implying the coexistence of ordered and disordered aggregates. Our findings may explain the experimentally observed variability including the "off-pathway" aggregated structures. Further, we demonstrate that sequence-dependence and protein-specific signatures could be mapped to our coarse-grained framework to study self-assembly behavior of realistic systems such as the STVIIE peptide and Aβ42. The work also provides certain guiding principles that could be used to design novel peptides with desired self-assembly properties, by tuning a few physical parameters.