1997/10/03 by Bassil I. Dahiyat, Stephen L. Mayo · 7 citations
Biochemistry, Genetics and Molecular Biology · Materials Science · #Protein Structure and Dynamics #Enzyme Structure and Function #RNA and protein synthesis mechanisms
paper · doi:10.1126/science.278.5335.82
openalex publication_date 1997/10/03 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
The first fully automated design and experimental validation of a novel sequence for an entire protein is described. A computational design algorithm based on physical chemical potential functions and stereochemical constraints was used to screen a combinatorial library of 1.9 x 10(27) possible amino acid sequences for compatibility with the design target, a betabetaalpha protein motif based on the polypeptide backbone structure of a zinc finger domain. A BLAST search shows that the designed sequence, full sequence design 1 (FSD-1), has very low identity to any known protein sequence. The solution structure of FSD-1 was solved by nuclear magnetic resonance spectroscopy and indicates that FSD-1 forms a compact well-ordered structure, which is in excellent agreement with the design target structure. This result demonstrates that computational methods can perform the immense combinatorial search required for protein design, and it suggests that an unbiased and quantitative algorithm can be used in various structural contexts.