The ability to design highly specific protein binders to disrupt protein-protein interactions would have immediate application to treatment of many diseases and for the dissection of protein-interaction networks. We recently developed a general computational method for the generation of de novo protein binders. Our methods focus on the incorporation of �hot-spot� residues onto protein scaffolds to generate protein binders to specific epitopes on proteins of interest. We demonstrate how combinations of a small number of newly generated high-affinity sidechain interactions with the target epitope of human IgG result in a new set of Fc binding proteins with new characteristics. By applying directed evolution methodologies via yeast surface display and deep sequencing, we optimized successful designs and explored their propensity for new properties, such as pH dependence and specificity for antibodies of different species. Our computationally designed and evolved proteins will have direct practical applications, such as providing new material for affinity chromatography for the purification of various antibodies or Fc-fusion proteins.

De novo design of protein binders: Targeting human IgG (Fc)

243rd National Meeting (2012)

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