The sequence-ensemble relationships in fuzzy protein complexes

San Hadzi, Remy Loris, Jurij Lah

Research output: Contribution to journalArticle


Intrinsically disordered proteins (IDPs) interact with globular proteins through variety of mechanisms, resulting in structurally heterogeneous ensembles known as fuzzy complexes. While there exists a reasonable comprehension on how IDP sequence determines the unbound IDP ensemble, little is known about what shapes the structural ensembles of IDPs bound to their targets. Using a statistical-thermodynamic model we show that the target-bound ensembles are determined by a simple code combining IDP sequence and the distribution of IDP-target interaction hotspots. These two parameters define the conformational phase space target-bound IDPs and rationalize the observed structural heterogeneity of fuzzy complexes. The presented model successfully reproduces dynamical signatures form the NMR relaxation experiments and changes in the average helicity and interaction affinity induced by mutations. The model explains how target-bound IDP ensembles modulate their conformation in response mutations in order to achieve an optimal balance between conformational freedom and interaction energy. Taken together, the presented sequence-ensemble relationship of fuzzy complexes explains the different manifestations of IDP disorder in folding-upon-binding processes.
Original languageEnglish
JournalProc Natl Acad Sci USA
Publication statusAccepted/In press - 2021


  • Intrinsic diorder
  • Protein Binding
  • Fuzzy complexes
  • IDP
  • Allostery
  • Toxin-antitoxin module

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