Modeling large regions in proteins: Applications to loops, termini, and folding

Authors

  • Aashish N. Adhikari,

    1. Department of Chemistry, The University of Chicago, Chicago, Illinois 60637
    2. The James Franck Institute, The University of Chicago, Chicago, Illinois 60637
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  • Jian Peng,

    1. Toyota Technological Institute at Chicago, Chicago, Illinois 60637
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  • Michael Wilde,

    1. Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois 60637
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  • Jinbo Xu,

    1. Toyota Technological Institute at Chicago, Chicago, Illinois 60637
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  • Karl F. Freed,

    Corresponding author
    1. Department of Chemistry, The University of Chicago, Chicago, Illinois 60637
    2. The James Franck Institute, The University of Chicago, Chicago, Illinois 60637
    3. Computation Institute, The University of Chicago and Argonne National Laboratory, Chicago, Illinois 60637
    • Karl F. Freed, Department of Chemistry, The James Frank Institute, Computation Institute, The University of Chicago, Chicago, Il 60637

      Tobin R. Sosnick, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Computation Institute, The University of Chicago, Chicago, Il 60637

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  • Tobin R. Sosnick

    Corresponding author
    1. Computation Institute, The University of Chicago and Argonne National Laboratory, Chicago, Illinois 60637
    2. Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois 60637
    3. Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois 60637
    • Karl F. Freed, Department of Chemistry, The James Frank Institute, Computation Institute, The University of Chicago, Chicago, Il 60637

      Tobin R. Sosnick, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Computation Institute, The University of Chicago, Chicago, Il 60637

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Abstract

Template-based methods for predicting protein structure provide models for a significant portion of the protein but often contain insertions or chain ends (InsEnds) of indeterminate conformation. The local structure prediction “problem” entails modeling the InsEnds onto the rest of the protein. A well-known limit involves predicting loops of ≤12 residues in crystal structures. However, InsEnds may contain as many as ∼50 amino acids, and the template-based model of the protein itself may be imperfect. To address these challenges, we present a free modeling method for predicting the local structure of loops and large InsEnds in both crystal structures and template-based models. The approach uses single amino acid torsional angle “pivot” moves of the protein backbone with a Cβ level representation. Nevertheless, our accuracy for loops is comparable to existing methods. We also apply a more stringent test, the blind structure prediction and refinement categories of the CASP9 tournament, where we improve the quality of several homology based models by modeling InsEnds as long as 45 amino acids, sizes generally inaccessible to existing loop prediction methods. Our approach ranks as one of the best in the CASP9 refinement category that involves improving template-based models so that they can function as molecular replacement models to solve the phase problem for crystallographic structure determination.

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