De Novo Design of alpha-Helical Bundles Protein folding is a remarkable process of molecular recognition in which a random coil with an astronomically large number of rapidly interconverting conformers assembles into a functional, fully folded unique three-dimensional structure. De novo design, in which one attempts to design proteins from scratch, has recently emerged as an attractive approach for investigating this process. In the previous period, we designed and characterized the structures of several three and four-helix bundle proteins that mimic the properties of natural proteins. This work led to a greater understanding of the balance of forces that are required for the stabilization of uniquely folded proteins. The current proposal focuses on the extension of these principles to the design of very large helical bundles as well as functional polypeptides. Specifically, we will design and characterize hexameric assemblies of three-helix bundles. Further, helical bundles will be designed to tightly and specifically associate with the alpha-subunit of the IL-4 receptor. Finally, we will use de novo design to understand how proteins bind and tune the properties of transition metal ions. In particular, proteins that bind dinuclear zinc, manganese, and iron will be prepared, and the influence of the protein matrix on the physical and chemical properties of the metal ions will be characterized.
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