Higher-Order Interactions and Water-Driven Fluctuations Affect Condensate Mechanics and Longevity

On the basis of simulation trajectories of five distinct IDP condensates we show that the same physical principle—cooperative, higher-order residue contacts acting as transient, multi-valent cross-links—affects both the static mechanical response the droplet. In this picture each protein segment can engage three or more partners simultaneously; the average number of such higher-order interactions per residue sets the instantaneous elastic modulus and surface tension without additional fit parameters. When explicit solvent is present the continual exchange of water molecules imports kinetic energy that repeatedly disrupts the residue interaction, maintaining the system near a steady state of residue interaction breaking and reformation and postponing the slow relaxation that would otherwise drive the condensate toward a gel like structure. Removing the solvent flux eliminates the energy input, causing the same universal aging behaviour observed in all systems studied. Thus a single, motif-based higher-order interaction model quantitatively links sequence, mechanics and lifetime by separating the roles of network connectivity and non-equilibrium energy supply, providing a minimal physical framework applicable to any phase-separated protein fluid.