Encoding multiple unnatural amino acids via evolution of a quadruplet-decoding ribosome

Protein-designing ribosomes Although chemists can devise novel amino acids with desirable properties, only a few of these amino acids have been successfully introduced into proteins by the cellular machinery. Even then, it is possible to add only one unnatural amino acid to a protein at a time. In theory the use of quadruplet codons, rather than the triplets used in natural protein synthesis, provides added flexibility in the form of extra blank codons available for assignment to unusual amino acids. Natural ribosomes are very inefficient at decoding quadruplets, and cannot be evolved to do it better as they would then misread the entire proteome. Jason Chin and colleagues get around this problem by creating and synthetically evolving parallel or 'orthogonal' ribosomes that efficiently decode quadruple codons using unnatural tRNA synthase/tRNA pairs. This system has the potential to allow the incorporation of up to 200 novel amino acids in genetically encoded designer proteins.