Combining Design and Selection to Create Novel Protein-Peptide Interactions

The ability to design new protein-protein interactions (PPIs) has many applications in biotechnology and medicine. The goal of designed PPIs is to achieve both high affinity and specificity for the target protein. A great challenge in protein design is to identify such proteins from an enormous number of potential sequences. Many computational and experimental methods have been developed to contend with this challenge. Here we describe one particularly powerful approach-semirational design-that combines design and selection. This approach has been applied to generate new PPIs for many applications, including novel affinity reagents for protein detection/purification and bioorthogonal modules for synthetic biology (Jackrel, Valverde, & Regan, 2009; Sawyer et al., 2014; Speltz, Brown, Hajare, Schlieker, & Regan, 2015; Speltz, Nathan, & Regan, 2015).