Higher-order Residue Interactions Encode Diversified Physical Properties of Biomolecular Condensates

Biomolecular condensates often formed by proteins containing extended intrinsic disordered regions (IDPs) can coordinate versatile cellular processes. The biological functions of condensates are attributed to a variety of physical properties, including viscoelasticity, interfacial tension and saturation concentration. Comprehensive understanding of biological functions of protein condensates and the corresponding sequence encoding requires unified interpretation of the diverse physical properties by a single model. Here we report the diversified physical properties of condensate and the interactions between constituent IDPs can be interpreted on the basis of higher-order residue interactions. These findings are based on s-scale atomistic molecular dynamics simulations of three homogeneous IDP condensates (FUS PLD, ARF6 PLD, LAF-1 RGG) combined with the reported simulation trajectories of two heterogeneous condensates. In all interacting IDPs, there are residue interactions between finite motifs (3[~]5 residues) that organize in a highly cooperative way: residues form multivalent interactions and their remaking is localized. The sequence features of higher-order interactions (HOIs) are identified: tyrosine, arginine, glutamine and aspartic acid are essential, and their consecutive sequence position is also important. The interaction between corresponding motifs is highly sustained and dominates the cohesive energy of IDP. IDP condensate can be modeled as a HOI-crosslinked network. This model can successfully reproduce all reported experimental results of condensate viscoelasticity, interfacial tension and saturation concentration, and expand our insights into the molecular grammar of IDP interactions. Significance StatementThe biological functions of biomolecular condensates involve various physical properties of condensate. A unified model that describes all these physical properties is essential for the understanding of condensate functions. Our research reveals the prevalence of higher-order residue interactions in all IDP condensates we considered, which leads to extremely sustained interaction between corresponding residue motifs. Accordingly, we propose a physically crosslinked network based on higher-order residue interactions as a simplified model for condensate. This model can quantitively reproduce all reported experimental results of condensate physical properties, including viscoelasticity, interfacial tension and saturation concentration.