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De novo protein design: fully automated sequence selection

Dahiyat, Bassil I. and Mayo, Stephen L. (1997) De novo protein design: fully automated sequence selection. Science, 278 (5335). pp. 82-87. ISSN 0036-8075. doi:10.1126/science.278.5335.82.

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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 ββα 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.

Item Type:Article
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Mayo, Stephen L.0000-0002-9785-5018
Additional Information:© 1997 American Association for the Advancement of Science. Received 16 June 1997; accepted 8 September 1997. We thank P. Poon and T. Laue for sedimentation equilibrium measurements and discussions, A. Su for assistance calculating super-secondary structure parameters, S. Ross for assistance with NMR measurements, G. Hathaway for mass spectrometry, J. Abelson and P. Bjorkman for critical reading of the manuscript, and R. A. Olofson for helpful discussions. Supported by the Howard Hughes Medical Institute (S.L.M.), the Rita Allen Foundation, the Chandler Family Trust, the Booth Ferris Foundation, the David and Lucile Packard Foundation, the Searle Scholars Program and The Chicago Community Trust, and grant GM08346 from the National Institutes of Health (B.I.D.). Coordinates and NMR restraints have been deposited in the Brookhaven Protein Data Bank with accession numbers 1FSD and R1FSDMR, respectively.
Funding AgencyGrant Number
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Rita Allen FoundationUNSPECIFIED
Chandler Family TrustUNSPECIFIED
Booth Ferris FoundationUNSPECIFIED
David and Lucile Packard FoundationUNSPECIFIED
Searle Scholars ProgramUNSPECIFIED
Chicago Community TrustUNSPECIFIED
Subject Keywords:DNA-Binding Proteins; Protein Engineering; Sequence Alignment; Hydrogen Bonding; Amino Acid Sequence; Models: Molecular; Zinc Fingers; Transcription Factors; Crystallography: X-Ray; Protein Folding; Protein Conformation; Computer Simulation; Protein Structure: Tertiary; Protein Structure: Secondary; Magnetic Resonance Spectroscopy; Solutions; Molecular Sequence Data; Algorithms
Issue or Number:5335
Record Number:CaltechAUTHORS:20110928-132632399
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Official Citation:De Novo Protein Design: Fully Automated Sequence Selection Bassil I. Dahiyat and Stephen L. Mayo. Science 3 October 1997: 278 (5335), 82-87. [DOI:10.1126/science.278.5335.82]
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:25472
Deposited By: Tony Diaz
Deposited On:28 Sep 2011 20:43
Last Modified:09 Nov 2021 16:33

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