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

Abstract

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 surprises 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 either form globules or conformations with ensemble averages that are reminiscent of ideal chains wherein intra-chain and chain-solvent interactions are counterbalanced. 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 intra-chain 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. This stems from intrinsic differences in free energies of hydration between arginine and lysine. We also identify differences between aspartate and glutamate containing sequences, whereby the shorter aspartate sidechain 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.

Distribution of Charged Residues Affects the Average Size and Shape of Intrinsically Disordered Proteins

“…Overall, our experimental data, complemented by the ellipsoid model, indicate that the extent of compaction and shape remodeling triggered by charge separation is modulated by multiple parameters that can concur, either individually or collectively, to counteract the expected response. Among the possible sequence features affecting IDP conformational responsiveness to charge clustering, the Lys/Arg and Asp/Glu ratio, recently reported by Zeng and co-authors [48], is a plausible factor that deserves further investigation. Many additional ones are probably at play and still remain elusive, thereby preventing our ability to fully rationalize and model the conformational behavior of IDPs.…”

From isolated polyelectrolytes to star-like assemblies: the role of sequence heterogeneity on the statistical structure of the intrinsically disordered neurofilament-low tail domain

“…Specifically, polymer scaling theories allow us to derive the statistical structure of IDPs given sequence-derived parameters, such as charge density and hydrophobicity [11,12,[19][20][21]. However, due to the heterogeneity of the IDP primary structure (i.e., the amino-acid sequence), some systems showed contradictions with the behavior theorized by standard heterogeneous polymer physics [17,19,[22][23][24].…”