Influence of electrostatic forces on the association kinetics and conformational ensemble of an intrinsically disordered protein

Erik C. Cook, Trevor P. Creamer

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Recent work has revealed that the association of a disordered region of a protein with a folded binding partner can occur as rapidly as association between two folded proteins. This is the case for the phosphatase calcineurin (CaN) and its association with its activator calmodulin. Calmodulin binds to the intrinsically disordered regulatory domain of CaN. Previous studies have shown that electrostatic steering can accelerate the binding of folded proteins with disordered ligands. Given that electrostatic forces are strong determinants of disordered protein ensembles, the relationship between electrostatics, conformational ensembles, and quaternary interactions is unclear. Here, we employ experimental approaches to explore the impact of electrostatic interactions on the association of calmodulin with the disordered regulatory region of CaN. We find that estimated association rate constants of calmodulin with our chosen calmodulin-substrates are within the diffusion-limited regime. The association rates are dependent on the ionic strength, indicating that favorable electrostatic forces increase the rate of association. Further, we show that charged amino acids outside the calmodulin-binding site modulate the binding rate. Conformational ensembles obtained from computer simulations suggest that electrostatic interactions within the regulatory domain might bias the conformational ensemble such that the calmodulin binding region is readily accessible. Given the prevalence of charged residues in disordered protein chains, our findings are likely relevant to many protein-protein interactions.

Original languageEnglish
Pages (from-to)1607-1619
Number of pages13
JournalProteins: Structure, Function and Bioinformatics
Issue number12
StatePublished - Dec 1 2020

Bibliographical note

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© 2020 Wiley Periodicals LLC.


  • calcineurin
  • calmodulin
  • electrostatics
  • kinetics

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology


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