Title: Conformations of Polyampholytic Disordered Proteins: Does Nature Use Multicriticality

Abstract: Recent advancements in understanding intracellular organization have been significantly attributed to the application of polymer physics methods. A notable example is the formation of membraneless organelles from intrinsically disordered proteins (IDPs), which can be described as liquid-liquid phase separation in a polyampholyte (PA) solution. This inspired us to apply the similar theoretical framework to single-chain PAs. We constructed a comprehensive scaling diagram of PA conformations, covering a broad range of salt concentrations and charge imbalances—from net-neutral PAs to polyelectrolytes carrying charges of only one sign. Theoretically predicted scaling laws were quantitatively confirmed through simulations.
The most intriguing feature of the conformational diagram is the presence of the point where regimes of swollen chains, globules, and necklaces meet. It is analogous to the multicritical Lifshitz point in macroscopic systems of ionic polymers (e.g. solutions and coacervates), where disordered, homogeneous ordered, and periodically modulated ordered phases coexist. Although our scaling estimates are inevitably approximate, they demonstrate that at intracellular salt concentration, the composition of real IDPs places them near this (single-chain analog of) Lifshitz point. We hypothesize that these strong, critical fluctuations in IDPs’ shape and size provide them with the high conformational heterogeneity and susceptibility necessary for their functions in signaling and regulation. A related question is whether the IDP composition could have been evolutionarily tuned for this purpose. In other words, does nature intentionally employ multicriticality?