An all-atom structure-based potential for proteins: Bridging minimal models with all-atom empirical forcefields

Authors

  • Paul C. Whitford,

    1. Center for Theoretical Biological Physics and Department of Physics, University of California at San Diego, La Jolla, California 92093
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  • Jeffrey K. Noel,

    1. Center for Theoretical Biological Physics and Department of Physics, University of California at San Diego, La Jolla, California 92093
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  • Shachi Gosavi,

    1. Center for Theoretical Biological Physics and Department of Physics, University of California at San Diego, La Jolla, California 92093
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  • Alexander Schug,

    1. Center for Theoretical Biological Physics and Department of Physics, University of California at San Diego, La Jolla, California 92093
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  • Kevin Y. Sanbonmatsu,

    1. Theoretical Biology and Biophysics, Theoretical Division, Los Alamos National Laboratory, MS K710, Los Alamos, New Mexico 87545
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  • José N. Onuchic

    Corresponding author
    1. Center for Theoretical Biological Physics and Department of Physics, University of California at San Diego, La Jolla, California 92093
    • Center for Theoretical Biological Physics and Department of Physics, University of California at San Diego, 9500 Gilman Drive, LaJolla, CA 92093
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Abstract

Protein dynamics take place on many time and length scales. Coarse-grained structure-based equation image models utilize the funneled energy landscape theory of protein folding to provide an understanding of both long time and long length scale dynamics. All-atom empirical forcefields with explicit solvent can elucidate our understanding of short time dynamics with high energetic and structural resolution. Thus, structure-based models with atomic details included can be used to bridge our understanding between these two approaches. We report on the robustness of folding mechanisms in one such all-atom model. Results for the B domain of Protein A, the SH3 domain of C-Src Kinase, and Chymotrypsin Inhibitor 2 are reported. The interplay between side chain packing and backbone folding is explored. We also compare this model to a Cα structure-based model and an all-atom empirical forcefield. Key findings include: (1) backbone collapse is accompanied by partial side chain packing in a cooperative transition and residual side chain packing occurs gradually with decreasing temperature, (2) folding mechanisms are robust to variations of the energetic parameters, (3) protein folding free-energy barriers can be manipulated through parametric modifications, (4) the global folding mechanisms in a Cα model and the all-atom model agree, although differences can be attributed to energetic heterogeneity in the all-atom model, and (5) proline residues have significant effects on folding mechanisms, independent of isomerization effects. Because this structure-based model has atomic resolution, this work lays the foundation for future studies to probe the contributions of specific energetic factors on protein folding and function. Proteins 2009. © 2008 Wiley-Liss, Inc.

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