Competing interactions give rise to two-state behavior and switch-like transitions in charge-rich intrinsically disordered proteins

Xiangze Zeng, Kiersten M. Ruff, Rohit V. Pappu*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

28 Citations (Scopus)


The most commonly occurring intrinsically disordered proteins (IDPs) are polyampholytes, which are defined by the duality of low net charge per residue and high fractions of charged residues. Recent experiments have uncovered nuances regarding sequence–ensemble relationships of model polyampholytic IDPs. These include differences in conformational preferences for sequences with lysine vs. arginine and the suggestion that well-mixed sequences form a range of conformations, including globules, conformations with ensemble averages that are reminiscent of ideal chains, or self-avoiding walks. Here, we explain these observations by analyzing results from atomistic simulations. We find that polyampholytic IDPs generally sample two distinct stable states, namely, globules and self-avoiding walks. Globules are favored by electrostatic attractions between oppositely charged residues, whereas self-avoiding walks are favored by favorable free energies of hydration of charged residues. We find sequence-specific temperatures of bistability at which globules and self-avoiding walks can coexist. At these temperatures, ensemble averages over coexisting states give rise to statistics that resemble ideal chains without there being an actual counterbalancing of intrachain and chain-solvent interactions. At equivalent temperatures, arginine-rich sequences tilt the preference toward globular conformations whereas lysine-rich sequences tilt the preference toward self-avoiding walks. We also identify differences between aspartate- and glutamate-containing sequences, whereby the shorter aspartate side chain engenders preferences for metastable, necklace-like conformations. Finally, although segregation of oppositely charged residues within the linear sequence maintains the overall two-state behavior, compact states are highly favored by such systems.

Original languageEnglish
Article numbere2200559119
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number19
Publication statusPublished - 10 May 2022

Scopus Subject Areas

  • General

User-Defined Keywords

  • bistable
  • intrinsically disordered proteins
  • polyampholyte
  • polyzwitterion


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