Celebrating the evolution of protein design throughthe lenses of the Protein Data Bank

It is not a coincidence that protein design beganin the late 1970s, few years after the institution of the Protein Data Bank (PDB), the archive servingas the global repository for open access of biological macromolecules. Back then, the opportunityof exploring available 3D structures of macromolecules inspired protein designers to drawsmall sequences that could fold in simple secondary structures, such as an alpha helix. Sincethe first structure of a short alpha helix named ALPHA-1 protein (1986), protein designers learnedmore complex folding rules.The design of sequences that could fold in entire newproteins, comprised of more than one secondary structure, and assembled together representsa great achievement. These days protein designers use the PDB beyond gatheringof new macromolecular structures. They explore the archive to get new structuralpatterns, or any information to compile libraries, or as needed for their designs. Then, theyassemble novel configurations of secondary structures not present in natural proteins. We explored the PDB to find unique structures of designedsequences not longer than 50 residues.We aimed to understand how protein designersare using strategies from de novo design and miniaturization, or by computational methods.This set of structures led us to understand the evolution of protein design architectureover the years and identify among them trends of function by analyzing the binding detailsof prosthetic groups. Our analysis shows that protein designers are still learning new rules tomake computational design more reliable. On the other hand, they are making available examplesthat represent the application of protein design across several disciplines. These outstandingdesigned proteins include use in medicine (designed antibodies), nanotechnology (proteins ableto interact with nanoparticles), advanced materials (minienzymes), bio- and environmental-technologies(designed photosynthetic proteins). Similar to a roundtrip journey that beginsfrom exploring the PDB, protein designers are reaching continuously new goals, including theallosteric cooperation in the newest de novo designed protein.