Nucleoprotein\nPhase-Separation Affinities Revealed\nvia Atomistic Simulations of Short Peptide and RNA Fragments

Liquid–liquid phase separation of proteins and\nnucleic acids\ninto condensate phases is a versatile mechanism for ensuring the compartmentalization\nof cellular biochemistry. RNA molecules play critical roles in these\ncondensates, particularly in transcriptional regulation and stress\nresponses, exhibiting a wide range of thermodynamic and dynamic behaviors.\nHowever, deciphering the molecular grammar that governs the stability\nand dynamics of protein–RNA condensates remains challenging\ndue to the multicomponent and heterogeneous nature of condensates.\nIn this study, we employ atomistic simulations of 20 distinct mixtures\ncontaining minimal RNA and peptide fragments which allows us to dissect\nthe phase-separating affinities of all 20 amino acids in the presence\nof RNA. Our findings elucidate chemically specific interactions, hydration\nprofiles, and ionic effects that synergistically promote or suppress\nprotein–RNA phase separation. We map a ternary phase diagram\nof interactions, identifying four distinct groups of residues that\npromote, maintain, suppress, and disrupt protein–RNA clusters.