Protein evolution with an expanded genetic code

Chang C. Liu, Antha V. Mack, Meng Lin Tsao, Jeremy H. Mills, Soo Lee Hyun, Hyeryun Choe, Michael Farzan, Peter G. Schultz, Vaughn V. Smider

Research output: Contribution to journalArticlepeer-review

120 Scopus citations


We have devised a phage display system in which an expanded genetic code is available for directed evolution. This system allows selection to yield proteins containing unnatural amino acids should such sequences functionally outperform ones containing only the 20 canonical amino acids. We have optimized this system for use with several unnatural amino acids and provide a demonstration of its utility through the selection of anti-gp120 antibodies. One such phage-displayed antibody, selected from a naïve germline scFv antibody library in which six residues in VH CDR3 were randomized, contains sulfotyrosine and binds gp120 more effectively than a similarly displayed known sulfated antibody isolated from human serum. These experiments suggest that an expanded "synthetic" genetic code can confer a selective advantage in the directed evolution of proteins with specific properties.

Original languageEnglish (US)
Pages (from-to)17688-17693
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number46
StatePublished - Nov 18 2008
Externally publishedYes


  • Directed evolution
  • Phage display
  • Unnatural amino acids

ASJC Scopus subject areas

  • General


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