Biophysics of Phase Separation of Disordered Proteins Is Governed by Balance between Short- And Long-Range Interactions

[Image: see text] Intrinsically disordered proteins play a crucial role in cellular phase separation, yet the diverse molecular forces driving phase separation are not fully understood. It is of utmost importance to understand how peptide sequence, and particularly the balance between the peptides’ short- and long-range interactions with other peptides, may affect the stability, structure, and dynamics of liquid–liquid phase separation in protein condensates. Here, using coarse-grained molecular dynamics simulations, we studied the liquid properties of the condensate in a series of polymers in which the ratio of short-range dispersion interactions to long-range electrostatic interactions varied. As the fraction of mutations that participate in short-range interactions increases at the expense of long-range electrostatic interactions, a significant decrease in the critical temperature of phase separation is observed. Nevertheless, sequences with a high fraction of short-range interactions exhibit stabilization, which suggests compensation for the loss of long-range electrostatic interactions. Decreased condensate stability is coupled with decreased translational diffusion of the polymers in the condensate, which may result in the loss of liquid characteristics in the presence of a high fraction of uncharged residues. The effect of exchanging long-range electrostatic interactions for short-range interactions can be explained by the kinetics of breaking intermolecular contacts with neighboring polymers and the kinetics of intramolecular fluctuations. While both time scales are coupled and increase as electrostatic interactions are lost, for sequences that are dominated by short-range interactions, the kinetics of intermolecular contact breakage significantly slows down. Our study supports the contention that different types of interactions can maintain protein condensates, however, long-range electrostatic interactions enhance its liquid-like behavior.