Heterogeneous Slowdown of Dynamics in the Condensate of an Intrinsically Disordered Protein

The high concentration of proteins and other biological macromolecules inside biomolecular condensates leads to dense and confined environments, which can affect the dynamic ensembles and the time scales of the conformational transitions of the biomolecules. Here we use atomistic molecular dynamics (MD) simulations on the intrinsically disordered low complexity domain (LCD) of the human fused in sarcoma (FUS) RNA-binding protein as a model system to study how self-crowding inside a condensate affects the dynamic motions of the protein. We found a heterogeneous retardation of the protein dynamics, with large-amplitude motions being strongly slowed by up to two orders of magnitude, whereas small-scale motions, such as local backbone fluctuations and side chain rotations, are less affected. The results support the notion of a liquid-like character of the condensates and show that different protein dynamic modes exhibit differential sensitivity to the crowded environment.