Dynamic yet well-defined organization of the FUS RGG3 dense phase.

Intrinsically disordered protein regions (IDRs) play a key role in the formation of biomolecular condensates, a ubiquitous mode of cellular compartmentalization, but the underlying microscopic details remain unclear. Here, microsecond-level molecular dynamics simulations and fractal formalism are employed to study at atomistic resolution a model dense phase composed of 24 copies of a C-terminal 73-residue arginine- and glycine-rich IDR (RGG3) of fused in sarcoma (FUS) protein in the absence of RNA. RGG3 displays a highly dynamic behavior in the dense phase with only a small configurational entropy loss and a minor slowdown in diffusion as compared to the dilute phase. Despite rapid mixing, short contact residence times and structurally heterogenous binding interfaces in the dense phase, RGG3 exhibits a distinct dynamic binding mode, with statistically defined interaction motifs and a robust multi-scale topology of self-associated protein clusters. An analysis of bound water suggests that solvent entropy may significantly contribute to the thermodynamics of condensate formation. Our results demonstrate how a well-defined organization of the disordered protein dense phase across scales emerges from highly heterogenous, transient interactions at the molecular level.