De novo design of helical bundles as models for understanding protein folding and function

De novo protein design has proven to be a powerful tool for understanding p rotein folding, structure, and function. In this Account, we highlight aspe cts of our research on the design of dimeric, four-helix bundles. Dimeric, four-helix bundles are found throughout nature, and the history of their de sign in our laboratory illustrates our hierarchic approach to protein desig n. This approach has been successfully applied to create a completely nativ e-like protein. Structural and mutational analysis allowed us to explore th e determinants of native protein structure. These determinants were then ap plied to the design of a dinuclear metal-binding protein that can now serve as a model for this important class of proteins.