Conformations of Polyampholytic Disordered Proteins: Does Nature Use Multicriticality?

Recent progress in understanding intracellular organization has been largely due to applying polymer physics methods. A striking example is how the formation of membraneless organelles from intrinsically disordered proteins (IDPs) depends on the primary sequence of ionic monomers in the latter and external conditions such as salt concentration. In the polymer physics language, biocondensate formation is nothing but liquid-liquid phase separation in a polyampholyte (PA) solution. Conceptually, this effect and sequence specificity in it were theoretically described long before the actual experimental observation in vivo.

This inspired us to apply the same theoretical framework to single-chain PAs. The comprehensive scaling diagram of PA conformations is constructed, which covers the broad range of salt concentrations and charge imbalances, from net-neutral PAs to polyelectrolytes carrying charges of only one sign. Scaling laws have been derived for all the regimes identified. For chains with moderate charge imbalance, the non-monotonic response to salt, with the necklace to globule to coil transitions, is predicted theoretically and quantitatively (scaling exponents values) confirmed in simulations.

The most interesting 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. Albeit inevitably approximate, our scaling estimates demonstrate that, at the intracellular salt concentration, the composition of real IDPs places them close to this single-chain analog of the Lifshitz point. We conjecture that these strong, critical fluctuations in IDPs shape and size provide them with high conformational heterogeneity and susceptibility necessary for their functioning in signaling and regulation. The related question is whether the IDP composition could have been tuned accordingly during evolution. In other words, does nature intentionally use multicriticality?

* This work has been performed in collaboration with Albert Johner and Alexey A Gavrilov.