Complete Diagram of Conformational Regimes for Polyampholytic Disordered Proteins

AM Rumyantsev and AA Gavrilov and A Johner, MACROMOLECULES, 57, 5533-5544 (2024).

DOI: 10.1021/acs.macromol.4c00429

Conformations of polyampholytic intrinsically disordered proteins (IDPs) are controlled by the interplay between Coulomb attractions of the opposite charges and long-range Coulomb repulsions due to the chain net charge. In salt-free solutions, as the charge imbalance increases, the polyampholyte (PA) structure changes from globular to necklace-like and further to highly stretched. Here, we consider the behavior of PAs in the presence of salt to predict IDP conformations under physiological conditions. The scaling approach and coarse-grained simulations are combined to demonstrate that (i) for globular PAs, salt-induced screening of Coulomb attractions leads to the globule swelling; (ii) PA necklaces exhibit a nonmonotonic response to salt: the initial necklace shortening and necklace-to-globule transition are followed by reentrant swelling of the globule; (iii) PAs with a high net charge demonstrate polyelectrolyte-like contraction upon the addition of salt. These results, consistent with the experimental studies of IDPs and synthetic PAs, are summarized in the complete scaling diagram of the PA conformational regimes constructed in the coordinates of salt concentration and net charge per monomer. The point where the regions of globular, necklace, and highly swollen conformations meet is analogous to a Lifshitz multicritical point, suggesting strong size and shape fluctuations of IDPs and PAs near it. We discuss if the composition of IDPs could have been tuned by evolution accordingly to provide their highest conformational susceptibility. Generalization to PAs with different charge blockiness is provided. Our findings contribute to a fundamental understanding of IDP structure from the polymer physics perspective.

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