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Science 21 November 2003:
Vol. 302. no. 5649, pp. 1364 - 1368
DOI: 10.1126/science.1089427
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Research Articles

Design of a Novel Globular Protein Fold with Atomic-Level Accuracy

Brian Kuhlman,1*{dagger} Gautam Dantas,1* Gregory C. Ireton,4 Gabriele Varani,1,2 Barry L. Stoddard,4 David Baker1,3{ddagger}

A major challenge of computational protein design is the creation of novel proteins with arbitrarily chosen three-dimensional structures. Here, we used a general computational strategy that iterates between sequence design and structure prediction to design a 93-residue {alpha}/ß protein called Top7 with a novel sequence and topology. Top7 was found experimentally to be folded and extremely stable, and the x-ray crystal structure of Top7 is similar (root mean square deviation equals 1.2 angstroms) to the design model. The ability to design a new protein fold makes possible the exploration of the large regions of the protein universe not yet observed in nature.

1 Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
2 Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
3 Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
4 Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.



* These authors contributed equally to this work.

{dagger} Present address: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.

{ddagger} To whom correspondence should be addressed. E-mail: dabaker{at}u.washington.edu

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