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Science 20 November 1998:
Vol. 282. no. 5393, pp. 1462 - 1467
DOI: 10.1126/science.282.5393.1462
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Research Articles

High-Resolution Protein Design with Backbone Freedom

Pehr B. Harbury, * Joseph J. Plecs, Bruce Tidor, Tom Alber, Peter S. Kim dagger

Recent advances in computational techniques have allowed the design of precise side-chain packing in proteins with predetermined, naturally occurring backbone structures. Because these methods do not model protein main-chain flexibility, they lack the breadth to explore novel backbone conformations. Here the de novo design of a family of alpha -helical bundle proteins with a right-handed superhelical twist is described. In the design, the overall protein fold was specified by hydrophobic-polar residue patterning, whereas the bundle oligomerization state, detailed main-chain conformation, and interior side-chain rotamers were engineered by computational enumerations of packing in alternate backbone structures. Main-chain flexibility was incorporated through an algebraic parameterization of the backbone. The designed peptides form alpha -helical dimers, trimers, and tetramers in accord with the design goals. The crystal structure of the tetramer matches the designed structure in atomic detail.

P. B. Harbury is at the Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, MA 02142, USA, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. J. J. Plecs is in the Department of Molecular and Cell Biology and Department of Physics, University of California at Berkeley, Berkeley, CA 94720, USA. B. Tidor is in the Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. T. Alber is in the Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA. P. S. Kim is at the Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, MA 02142, USA.
*   Present address: Department of Biochemistry, Stanford University, Stanford, CA 94305, USA.

dagger    To whom correspondence should be addressed. E-mail: dvorak{at}wi.mit.edu

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