Liquid–Liquid Phase Separation As the Second Step of Complex Coacervation

Liquid–liquid phase separation (LLPS) between tyrosine- and arginine-rich peptides are of biological importance. To understand the interactions between proteins in the condensed phase in close analogy to complex coacervation, we run multiple umbrella calculations between oligomers containing tyrosine (pY) and arginine (pR). We find pR-pY complexation to be energetically driven. Metadynamics simulations on monomers suggest that this energy of complexation is correlated with the number of π-cation bonds. Free energy calculations for the binding between pairs of poly glutamate-pR dimers show striking similarities between this process and LLPS. These calculations suggest that proteins containing arginine and tyrosine residues do not undergo complexation followed by coacervation. The mechanism, rather, is akin to phase separation of neutral polyion pairs.