Cooperative nature of residue interactions in biomolecular condensates.

Atomistic simulations of intrinsically disordered protein condensates reveal cooperative residue interactions as 3–5 residue motifs whose lifetimes are three orders of magnitude longer than residue contacts.

• Why it matters: It remains unclear whether cooperativity in residue interactions persists in IDPs and their assembled condensates, limiting mechanistic understanding of condensate cohesion and properties.
• What they did: Using atomistic molecular dynamics, the study identifies higher-order interactions with significant nonadditive free energy tied to a local low-dielectric environment and sequence patterns like “Y-X-Q”, “D-X-R”, and “S-Y-X”.
• The result: Higher-order interactions dominate cohesive energy, enabling condensates to be modeled as HOI-crosslinked networks that reproduce experimental saturation concentration, viscoelasticity, and interfacial tension.