Kinetics and Morphology of Self-Associating Beta-Sheet Peptides

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0330537MurphyMany peptides and proteins spontaneously self-associate into large aggregates of cross beta-sheet structure and fibrillar morphology, which may be toxic to a wide number of cell types, due simply to their morphology and not to their specific sequence. Thus, elucidation of the factors that control peptide self-association into fibrillar aggregates is needed to understand mechanisms of disease, to develop therapeutic strategies for these diseases, and to design efficient processes for protein manufacture and formulation. The objectives of this research are: (1) to develop a detailed mathematical model of the kinetics of assembly of fibril-forming peptides and proteins, (2) to design and synthesize fibril-forming peptides in which morphology is controlled by judicious balancing of backbone hydrogen-bonding and side chain-side chain interactions, and (3) to develop rules to predict whether pairs of interacting peptides will have greater or lesser aggregation propensity than each peptide in isolation. Three model systems will be used in pursuing these objectives: (1) Insulin and insulin analogs, (2) Apomyoglobin truncation mutants, and (3) Polyglutamine and other expanded-domain peptides. Kinetics of assembly are monitored using several complementary experimental techniques: static and dynamic light scattering,