Abstract Phase separation of intrinsically disordered prion-like low-complexity domains (PLCDs) derived from RNA-binding proteins enable the formation of biomolecular condensates in cells. PLCDs have distinct amino acid compositions, and here we decipher the physicochemical impact of conserved compositional biases on the driving forces for phase separation. We find that tyrosine residues make for stronger drivers of phase separation than phenylalanine. Depending on their sequence contexts, arginine residues enhance or weaken phase separation, whereas lysine residues weaken cohesive interactions within PLCDs. Increased net charge per residue (NCPR) weakens the driving forces for phase separation of PLCDs and this effect can be modeled quantitatively. The effects of NCPR also weaken known correlations between the dimensions of single chains in dilute solution and the driving forces for phase separation. We build on experimental data to develop a coarse-grained model for accurate simulations of phase separation that yield novel insights regarding PLCD phase behavior.

Deciphering how naturally occurring sequence features impact the phase behaviors of disordered prion-like domains