Adaptation of a fast Fourier transform-based docking algorithm for protein design

Authors

  • Po-Ssu Huang,

    1. Howard Hughes Medical Institute and Division of Biology, California Institute of Technology, Pasadena, California 91125
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  • John J. Love,

    1. Howard Hughes Medical Institute and Division of Biology, California Institute of Technology, Pasadena, California 91125
    Current affiliation:
    1. Department of Chemistry, San Diego State University, 5500 Campanile Dr., San Diego, CA 92182-1030
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  • Stephen L. Mayo

    Corresponding author
    1. Howard Hughes Medical Institute and Divisions of Biology and Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125
    • Howard Hughes Medical Institute and Division of Biology, California Institute of Technology, Pasadena, California 91125
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Abstract

Designing proteins with novel protein/protein binding properties can be achieved by combining the tools that have been developed independently for protein docking and protein design. We describe here the sequence-independent generation of protein dimer orientations by protein docking for use as scaffolds in protein sequence design algorithms. To dock monomers into sequence-independent dimer conformations, we use a reduced representation in which the side chains are approximated by spheres with atomic radii derived from known C2 symmetry-related homodimers. The interfaces of C2-related homodimers are usually more hydrophobic and protein core-like than the interfaces of heterodimers; we parameterize the radii for docking against this feature to capture and recreate the spatial characteristics of a hydrophobic interface. A fast Fourier transform-based geometric recognition algorithm is used for docking the reduced representation protein models. The resulting docking algorithm successfully predicted the wild-type homodimer orientations in 65 out of 121 dimer test cases. The success rate increases to ∼70% for the subset of molecules with large surface area burial in the interface relative to their chain length. Forty-five of the predictions exhibited less than 1 Å Cα RMSD compared to the native X-ray structures. The reduced protein representation therefore appears to be a reasonable approximation and can be used to position protein backbones in plausible orientations for homodimer design. © 2005 Wiley Periodicals, Inc. J Comput Chem 26: 1222–1232, 2005

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