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The Thermodynamic Basis of the Fuzzy Interaction of an Intrinsically Disordered Protein
Author(s) -
Hadži San,
Mernik Andrej,
Podlipnik Črtomir,
Loris Remy,
Lah Jurij
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201707853
Subject(s) - intrinsically disordered proteins , folding (dsp implementation) , enthalpy , chemistry , entropy (arrow of time) , energy landscape , sequence (biology) , protein folding , conformational ensembles , conformational entropy , thermodynamics , chemical physics , molecular dynamics , computational chemistry , molecule , physics , biochemistry , organic chemistry , electrical engineering , engineering
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.