Phase Separation and Single-Chain Compactness of Charged Disordered Proteins Are Strongly Correlated

Liquid-liquid phase separation of intrinsically disordered proteins (IDPs) is a major undergirding factor in the regulated formation of membraneless organelles in the cell. The phase behavior of an IDP is sensitive to its amino acid sequence. Here we apply a recent random-phase-approximation polymer theory to investigate how the tendency for multiple chains of a protein to phase-separate, as characterized by the critical temperature T^∗_cr, is related to the protein's single-chain average radius of gyration 〈R_g〉. For a set of sequences containing different permutations of an equal number of positively and negatively charged residues, we found a striking correlation T^∗_cr ∼ 〈R_g〉^-γ with γ as large as ∼6.0, indicating that electrostatic effects have similarly significant impact on promoting single-chain conformational compactness and phase separation. Moreover, T^∗_cr ∝ -SCD, where SCD is a recently proposed "sequence charge decoration" parameter determined solely by sequence information. Ramifications of our findings for deciphering the sequence dependence of IDP phase separation are discussed.