Determining macromolecular assembly structures by molecular docking and fitting into an electron density map

Authors

  • Keren Lasker,

    1. Raymond and Beverly Sackler Faculty of Exact Sciences, Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel
    2. Department of Bioengineering and Therapeutic Sciences, University of California at San Francisco, San Francisco, California 94158-2230
    3. Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California 94158-2230
    4. California Institute for Quantitative Biosciences (QB3), University of California at San Francisco, San Francisco, California 94158-2230
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  • Andrej Sali,

    Corresponding author
    1. Department of Bioengineering and Therapeutic Sciences, University of California at San Francisco, San Francisco, California 94158-2230
    2. Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California 94158-2230
    3. California Institute for Quantitative Biosciences (QB3), University of California at San Francisco, San Francisco, California 94158-2230
    • UCSF MC 2552, Byers Hall at Mission Bay, Suite 503B, University of California at San Francisco, 1700 4th Street, San Francisco, CA 94158
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  • Haim J. Wolfson

    Corresponding author
    1. Raymond and Beverly Sackler Faculty of Exact Sciences, Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel
    • School of Computer Science, Tel Aviv University, Tel-Aviv 69978, Israel
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  • The authors state no conflict of interest.

Abstract

Structural models of macromolecular assemblies are instrumental for gaining a mechanistic understanding of cellular processes. Determining these structures is a major challenge for experimental techniques, such as X-ray crystallography, NMR spectroscopy and electron microscopy (EM). Thus, computational modeling techniques, including molecular docking, are required. The development of most molecular docking methods has so far been focused on modeling of binary complexes. We have recently introduced the MultiFit method for modeling the structure of a multisubunit complex by simultaneously optimizing the fit of the model into an EM density map of the entire complex and the shape complementarity between interacting subunits. Here, we report algorithmic advances of the MultiFit method that result in an efficient and accurate assembly of the input subunits into their density map. The successful predictions and the increasing number of complexes being characterized by EM suggests that the CAPRI challenge could be extended to include docking-based modeling of macromolecular assemblies guided by EM. Proteins 2010. © 2010 Wiley-Liss, Inc.

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