  Liquid liquid phase separation (LLPS) mediated by pi-cation bonds between
tyrosine and arginine residues 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 reveal that this energy of
complexation comes primarily from pi-cation bonds. On running free energy
calculation for the second binding step of complex coacervation, we find
striking similarities between this process and pi-mediated LLPS. These
calculations lead us to believe that contrary to the common notion, complex
coacervation as whole, which involves an entropic complexation followed by an
energetic aggregation is not invoked by proteins containing arginine and
tyrosine residues. Rather, the latter step in itself, in which neutral polyion
pairs aggregate together is the correct mechanism for pi-cation mediated LLPS.
