Crossover in Aromatic Amino Acid Interaction Strength: Tyrosine vs. Phenylalanine in Biomolecular Condensates

Biomolecular condensates often form through the self-assembly of disordered proteins with low-complexity sequences. In these polypeptides, the aromatic amino acids phenylalanine and tyrosine act as key “sticker” residues, driving the cohesion of dense phases. Recent studies on condensates suggest a hierarchy in sticker strength, with tyrosine being more adhesive than phenylalanine. This hierarchy aligns with experimental data on amino acid solubilities and potentials of mean force derived from atomistic simulations. However, it contradicts conventional chemical intuition based on hydrophobicity scales and pairwise contact statistics from experimental structures of proteins, which suggest phenylalanine should be the stronger sticker. In this work, we use molecular dynamics simulations and quantum chemistry calculations to resolve this apparent discrepancy. Using simple model peptides and side-chain analogues, we demonstrate that the experimentally observed hierarchy arises from the lower free energy of transfer of tyrosine into the condensate, mediated by both stronger protein-protein interactions and solvation effects in the condensate environment. Notably, as the dielectric constant of the media surrounding the stickers approaches that of an apolar solvent, the trend reverses, and phenylalanine becomes the stronger sticker. These findings highlight the role of the chemical environment in modulating protein-protein interactions, providing a clear explanation for the crossover in sticker strength between tyrosine and phenylalanine in different media.