De novo protein design: fully automated sequence selection
- Creators
- Dahiyat, Bassil I.
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Mayo, Stephen L.
Abstract
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.
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.Additional details
- Eprint ID
- 25472
- Resolver ID
- CaltechAUTHORS:20110928-132632399
- Howard Hughes Medical Institute (HHMI)
- Rita Allen Foundation
- Chandler Family Trust
- Booth Ferris Foundation
- David and Lucile Packard Foundation
- Searle Scholars Program
- Chicago Community Trust
- NIH
- GM08346
- Created
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2011-09-28Created from EPrint's datestamp field
- Updated
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2021-11-09Created from EPrint's last_modified field