Functional protein-protein interaction design was first accomplished in 2011 by Fleishman et al[ ]. The method begins by detecting where on the surface of a protein to bind which is done by copying an antibody binding site. From there hotspots are extracted from the antibody and protein scaffolds are selected in the PDB. The proteins are selected based on what shape can accommodate the hot-spots. Additional interactions on the protein scaffold are designed. The protein is then experimentally refined using directed evolution and verified using X-ray crystallography.