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

TitleThe Thermodynamic Basis of the Fuzzy Interaction of an Intrinsically Disordered Protein.
Publication TypeJournal Article
Year of Publication2017
AuthorsHadži, S., A. Mernik, Č. Podlipnik, R. Loris, and J. Lah
JournalAngew Chem Int Ed Engl
Date Published2017 11 13
KeywordsAmino Acid Sequence, Calorimetry, Circular Dichroism, Fuzzy Logic, Intrinsically Disordered Proteins, Kinetics, Models, Molecular, Molecular Dynamics Simulation, Protein Binding, Protein Folding, Thermodynamics

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.

Alternate JournalAngew. Chem. Int. Ed. Engl.
PubMed ID28914483
Research group: