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

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 twostate behavior, compact states are highly favored by such systems.

Automated summary

Polyampholytes are the most common type of intrinsically disordered proteins (IDPs), characterized by low net charge and high fractions of charged residues. Recent experiments have revealed differences in conformational preferences for different sequences of polyampholytic IDPs, as well as the existence of various conformations including globules and self-avoiding walks. Atomistic simulations have shown that these IDPs generally sample two stable states, with globules favored by electrostatic attractions and self-avoiding walks favored by favorable hydration energies. The temperature at which these states coexist depends on the sequence, with arginine-rich sequences preferring globular conformations and lysine-rich sequences preferring self-avoiding walks. The length of the side chain also affects the conformational preferences, with shorter side chains favoring necklace-like conformations. Overall, these findings provide insights into the relationship between sequence and conformation in polyampholytic IDPs.