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. 2024 Nov 14;15(45):11244-11251.
doi: 10.1021/acs.jpclett.4c02142. Epub 2024 Nov 1.

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

Saumyak Mukherjee  1 , Lars V Schäfer  1
Affiliations

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

Saumyak Mukherjee et al. J Phys Chem Lett. .

Abstract

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. Here, we use atomistic molecular dynamics (MD) simulations of the intrinsically disordered low complexity domain (LCD) of the human fused in sarcoma (FUS) RNA-binding protein to study how self-crowding inside a condensate affects the dynamic motions of the protein. We found a heterogeneous retardation of the protein dynamics in the condensate with respect to the dilute phase, with large-amplitude motions being strongly slowed by up to 2 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 motions respond differently to the environment.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(A) MSDs of Cα atoms in the protein backbones in the dilute (red) and condensate (blue) systems plotted as a function of the lag time t. The solid lines represent the mean MSD, and the error bars denote the standard deviations over all of the Cα atoms considered. The black dashed line represents the condensate MSD multiplied by 100. (B) Ratio of the mean MSDs of Cα atoms in the condensate and dilute systems at selected lag times (10, 50, 100, 200, 300, 400, 500, and 600 ns) plotted against the number of Cα atoms in a group. The error bars denote the standard deviations over the eight protein chains in the simulation system.
Figure 2
Figure 2
Protein backbone dynamics for FUS-LCD chains. (A and B) Time scales of orientational dynamics as a function of Cα–Cα separation for the dilute and condensate systems, respectively. (C) Ratio of these two time scales. (D–F) Analogous properties for the Cα–Cα distance fluctuations. The error bars denote the standard errors over the eight proteins in the condensate system.
Figure 3
Figure 3
Time scales of side-chain dihedral angle rotations in the (A) dilute and (B) condensate systems. (C) Ratio of the time constants in the two systems. The χ1, χ2, and χ3 dihedral angles of the respective residues are plotted in blue, orange, and green, respectively. The error bars denote the standard errors over all of the respective residues present in the system.
Figure 4
Figure 4
Dynamics of the PHL in the dilute (red) and condensate (blue) phases. The PHL is defined by a cutoff distance of 0.5 nm from the protein. (A) Distributions of rotational correlation times. (B) ACFs of total dipole moment (and triexponential fits, solid lines) of PHL water molecules in the dilute and condensate phases plotted on a semi-log scale.
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