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Science 3 October 1997:
Vol. 278. no. 5335, pp. 82 - 87
DOI: 10.1126/science.278.5335.82
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Research Articles

De Novo Protein Design: Fully Automated Sequence Selection

Bassil I. Dahiyat, dagger Stephen L. Mayo *

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 × 1027 possible amino acid sequences for compatibility with the design target, a beta beta alpha 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.

B I. Dahiyat, Division of Chemistry and Chemical Engineering, California Institute of Technology, mail code 147-75, Pasadena, CA 91125, USA.
S. L. Mayo, Howard Hughes Medical institute and Division of Biology, California Institute of Technology, mail code 147-75, Pasadena, CA 91125, USA.
*   To whom correspondence should be addressed. E-mail: steve{at}mayo.caltech.edu

dagger    Present address: Xencor, Pasadena, CA 91106, USA.

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Recent improvements in prediction of protein structure by global optimization of a potential energy function.
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