3 years ago

The Thermodynamic Basis of the Fuzzy Interaction of an Intrinsically Disordered Protein

The Thermodynamic Basis of the Fuzzy Interaction of an Intrinsically Disordered Protein
Andrej Mernik, San Hadži, Remy Loris, Črtomir Podlipnik, Jurij Lah
Many intrinsically disordered proteins (IDP) that fold upon binding retain conformational heterogeneity in IDP-target complexes. The thermodynamics of such fuzzy interactions is poorly understood. Herein we introduce a thermodynamic framework, based on analysis of ITC and CD spectroscopy data, that provides experimental descriptions of IDP association in terms of folding and binding contributions which can be predicted using sequence folding propensities and molecular modeling. We show how IDP can modulate the entropy and enthalpy by adapting their bound-state structural ensemble to achieve optimal binding. This is explained in terms of a free-energy landscape that provides the relationship between free-energy, sequence folding propensity, and disorder. The observed “fuzzy” behavior is possible because of IDP flexibility and also because backbone and side-chain interactions are, to some extent, energetically decoupled allowing IDP to minimize energetically unfavorable folding. Fuzz box: A thermodynamic framework rationalizes the energetics of intrinsically disordered protein (IDP)–target interactions in terms of folding and binding contributions and clarifies the relationship between IDP sequence folding propensity, helix fraction, and the free energy of IDP–target association. The IDPs respond to sequence perturbations by adjusting fuzziness of the bound-state ensemble in a manner similar to the Le Châtelier's principle.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/anie.201707853

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