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bioRxiv · 10.1101/2025.07.09.663981

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

Polyansky, A. A.·Fruehbauer, B.·Zagrovic, B.
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Abstract

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 condensate composed of 24 copies of a C-terminal 73-residue arginine- and glycine-rich IDR (RGG3) of fused in sarcoma (FUS) protein. Specifically, 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. The results demonstrate how a well-defined organization of the disordered protein dense phase across scales emerges from highly heterogenous, transient interactions.

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Polyansky, A. A., Fruehbauer, B., Zagrovic, B.. 2025-07-15. Dynamic, yet well-defined organization of the FUS RGG3 dense phase. https://doi.org/10.1101/2025.07.09.663981

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