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Unifying mechanical and thermodynamic descriptions across the thioredoxin protein family

Authors

  • James M. Mottonen,

    1. Department of Physics and Optical Science, University of North Carolina at Charlotte, Charlotte, North Carolina 28223
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  • Minli Xu,

    1. Department of Computer Science, University of North Carolina at Charlotte, Charlotte, North Carolina 28223
    2. Bioinformatics Research Center, University of North Carolina at Charlotte, Charlotte, North Carolina 28223
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  • Donald J. Jacobs,

    Corresponding author
    1. Department of Physics and Optical Science, University of North Carolina at Charlotte, Charlotte, North Carolina 28223
    • Department of Physics and Optical Science, University of North Carolina, 9201 University City Blvd, Charlotte, NC 28223
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  • Dennis R. Livesay

    Corresponding author
    1. Department of Computer Science, University of North Carolina at Charlotte, Charlotte, North Carolina 28223
    2. Bioinformatics Research Center, University of North Carolina at Charlotte, Charlotte, North Carolina 28223
    • Department of Computer Science and Bioinformatics Research Center, University of North Carolina, 9201 University City Blvd, Charlotte, NC 28223
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Abstract

We compare various predicted mechanical and thermodynamic properties of nine oxidized thioredoxins (TRX) using a Distance Constraint Model (DCM). The DCM is based on a nonadditive free energy decomposition scheme, where entropic contributions are determined from rigidity and flexibility of structure based on distance constraints. We perform averages over an ensemble of constraint topologies to calculate several thermodynamic and mechanical response functions that together yield quantitative stability/flexibility relationships (QSFR). Applied to the TRX protein family, QSFR metrics display a rich variety of similarities and differences. In particular, backbone flexibility is well conserved across the family, whereas cooperativity correlation describing mechanical and thermodynamic couplings between the residue pairs exhibit distinctive features that readily standout. The diversity in predicted QSFR metrics that describe cooperativity correlation between pairs of residues is largely explained by a global flexibility order parameter describing the amount of intrinsic flexibility within the protein. A free energy landscape is calculated as a function of the flexibility order parameter, and key values are determined where the native-state, transition-state, and unfolded-state are located. Another key value identifies a mechanical transition where the global nature of the protein changes from flexible to rigid. The key values of the flexibility order parameter help characterize how mechanical and thermodynamic response is linked. Variation in QSFR metrics and key characteristics of global flexibility are related to the native state X-ray crystal structure primarily through the hydrogen bond network. Furthermore, comparison of three TRX redox pairs reveals differences in thermodynamic response (i.e., relative melting point) and mechanical properties (i.e., backbone flexibility and cooperativity correlation) that are consistent with experimental data on thermal stabilities and NMR dynamical profiles. The results taken together demonstrate that small-scale structural variations are amplified into discernible global differences by propagating mechanical couplings through the H-bond network. Proteins 2009. © 2008 Wiley-Liss, Inc.

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