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Among all biomolecules in living cells, proteins represent a group with highly divergent biological functions. These include maintaining structural integrity, catalyzing most chemical reactions in vivo, regulating cellular responses via signal transduction, and targeting foreign molecules via the immune system. Because of these diverse functions and associated applications, protein engineering has been a field for intense academic research and biopharmaceutical drug development. However, proteins made by nature are generally composed of only 20 canonical amino acids. The recently developed technology to incorporate non-natural amino acids (NNAAs) into proteins at specifically chosen sites represents an extremely powerful tool for protein engineering. Unlike traditional protein engineering with the 20 canonical amino acids as building blocks, protein engineering with NNAAs has nearly unlimited novel side-chain structures to choose from. Coupled with rapid advances in protein structure computation and bioorthogonal chemical reactions, proteins with tailored properties or novel functions beyond natural or directed evolution are becoming a reality.

Protein Engineering with Non-Natural Amino Acids