A De Novo Protein Binding Pair By Computational Design and Directed Evolution

This article presents an effective combination of computational design and directed evolution to synthesize a de novo protein binding pair. Karanicolas and coworkers first selected two proteins with complementary surface features but no natural affinity to bind one another, then using a 'motif based' strategy were able to model new favorable binding interactions. This method differs from the standard technique of importing known binding elements from natural protein binding pairs. The computational models can then be synthesized and enhanced. Using directed evolution, the binding affinity of the protein complex was increased, yielding a KD of 180 pM. This result is better than any previous computer-designed protein binding pair and highlights the strength of combining computational and directed evolution techniques.