Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 40, Pages E5478-E5485Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1509508112
Keywords
de novo design; protein design; ideal protein; control protein shape
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Funding
- Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology
- National Institutes of General Medical Science Protein Structure Initiative program [U54 GM094597]
- Defense Threat Reduction Agency
- Howard Hughes Medical Institute
- Research Center for Computational Science
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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, beta-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.
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