Research Article

High-Resolution Protein Design with Backbone Freedom

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Science  20 Nov 1998:
Vol. 282, Issue 5393, pp. 1462-1467
DOI: 10.1126/science.282.5393.1462

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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 α-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 α-helical dimers, trimers, and tetramers in accord with the design goals. The crystal structure of the tetramer matches the designed structure in atomic detail.

  • * Present address: Department of Biochemistry, Stanford University, Stanford, CA 94305, USA.

  • To whom correspondence should be addressed. E-mail: dvorak{at}

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