Microscopic Model of a Biological Condensate

Liquid-liquid phase separation governs the intracellular organization of biological molecules into membraneless organelles also known as biological condensates. Fused in Sarcoma (FUS), an RNA-binding protein, is the principle component of a biological condensate involved in DNA repair. The intrinsically disordered nature of FUS eludes structural characterization using conventional methods. Here, we report a fully-atomistic structure of a FUS condensate obtained through a combination of coarse-grained and all-atom simulations. Using existing structural and biochemical information, we constructed a coarse-grained model of the FUS protein. An ensemble of such proteins was found to undergo phase separation into a liquid-like condensate in a temperature and composition-dependent manner. The final configurations obtained through the coarse-grained simulations were used to construct an all-atom model of the condensate, including the surrounding solvent. The microscopic structure was refined using atomistic simulations and used to probe the condensate’s viscoelastic behavior and identify specific interactions that control its viscosity. The resulting structural model sets the stage for subsequent systematic inquiry into the sequence-structure-function relationship of the condensate.