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Proc Natl Acad Sci U S A. 2015 Oct 6;112(40):E5478-85. doi: 10.1073/pnas.1509508112. Epub 2015 Sep 22.

Control over overall shape and size in de novo designed proteins.

Author information

1
Department of Biochemistry, University of Washington and Howard Hughes Medical Institute, Seattle, WA 98195;
2
Department of Biochemistry, University of Washington and Howard Hughes Medical Institute, Seattle, WA 98195; Research Center of Integrative Molecular Systems, Institute for Molecular Science, National Institutes of Natural Sciences, Okazaki, Aichi 444-8585, Japan; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan; dabaker@u.washington.edu nkoga@ims.ac.jp.
3
Department of Biochemistry, University of Washington and Howard Hughes Medical Institute, Seattle, WA 98195; Research Center of Integrative Molecular Systems, Institute for Molecular Science, National Institutes of Natural Sciences, Okazaki, Aichi 444-8585, Japan;
4
Center for Advanced Biotechnology and Medicine, Department of Molecular Biology and Biochemistry, and Northeast Structural Genomics Consortium, Rutgers, The State University of New Jersey, Piscataway, NJ 08854;
5
Center for Advanced Biotechnology and Medicine, Department of Molecular Biology and Biochemistry, and Northeast Structural Genomics Consortium, Rutgers, The State University of New Jersey, Piscataway, NJ 08854; Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ 08854.
6
Department of Biochemistry, University of Washington and Howard Hughes Medical Institute, Seattle, WA 98195; dabaker@u.washington.edu nkoga@ims.ac.jp.

Abstract

We recently described general principles for designing ideal protein structures stabilized by completely consistent local and nonlocal interactions. The principles relate secondary structure patterns to tertiary packing motifs and enable design of different protein topologies. To achieve fine control over protein shape and size within a particular topology, we have extended the design rules by systematically analyzing the codependencies between the lengths and packing geometry of successive secondary structure elements and the backbone torsion angles of the loop linking them. We demonstrate the control afforded by the resulting extended rule set by designing a series of proteins with the same fold but considerable variation in secondary structure length, loop geometry, β-strand registry, and overall shape. Solution NMR structures of four designed proteins for two different folds show that protein shape and size can be precisely controlled within a given protein fold. These extended design principles provide the foundation for custom design of protein structures performing desired functions.

KEYWORDS:

control protein shape; de novo design; ideal protein; protein design

PMID:
26396255
PMCID:
PMC4603489
DOI:
10.1073/pnas.1509508112
[Indexed for MEDLINE]
Free PMC Article

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