(32d) Conformations of Polyampholytic Disordered Proteins: Could Multicritical Behavior be an Outcome of Evolution?

Scaling theory is employed to consider single-chain conformations of charge-imbalanced polyampholytic disordered proteins in the presence of salt. In the salt-free case, the competition between Coulomb attractions and repulsions leads to compact globular, necklace-like, or highly swollen conformations, depending on how large the global charge imbalance of the chain. The latter also controls the response of synthetic polyampholytes (PAs) and intrinsically disordered proteins (IDPs) to the addition of salt: (i) For initially globular PAs with low net charge, salt-induced screening of Coulomb attractions leads to the globule swelling; (ii) PAs with moderate charge imbalance form necklaces, which exhibit a non-monotonic response to salt. The necklace shortening and merging of the necklace beads into the spherical globule due to the weakening Coulomb repulsions are followed by reentrant globule swelling; (iii) PAs with a high net charge demonstrate polyelectrolyte-like contraction. These theoretical predictions are quantitatively supported by coarse-grained simulations. A complete diagram of PA/IDP conformations is constructed in the coordinates of salt concentration and the chain charge imbalance per one monomer. The point where the regimes of necklaces, spherical globules, and swollen chains meet resembles the Lifshitz multicritical point. Strong conformational fluctuations are expected near it. Interestingly, under physiological conditions, the composition of many IDPs places them near this special point, in the fluctuation-dominated region of the constructed conformational diagram. One can reason if the composition of IDPs was selected by nature (evolution) intentionally, to achieve the highest conformational plasticity and heterogeneity.