期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 138, 期 42, 页码 13911-13922出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.6b06433
关键词
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Self-assembly of proteins into ordered, fibrilar 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 A beta 42. 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.
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