Single-Chain Conformational Fluctuation Regulates Phase Separation of Intrinsically Disordered Proteins.
4 affiliations
- 1Advanced Materials Thrust, Function Hub, The Hong Kong University of Science and Technology (Guangzhou), Guangzhou 511453, China.
- 2Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR 999077, China.
- 3Guangzhou Municipal Key Laboratory of Materials Informatics, The Hong Kong University of Science and Technology (Guangzhou), Guangzhou 511453, China.
- 4Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR 999077, China.
Abstract
Intrinsically disordered proteins (IDPs) form biomolecular condensates through weak multivalent interactions, but the ensemble variables that control condensate stability and material properties remain incompletely defined. Most current descriptions emphasize sequence features or mean single-chain descriptors, such as the radius of gyration Rg. Here, we ask whether the breadth of the single-chain ensemble can regulate liquid-liquid phase separation when the amino-acid sequence and mean chain size are fixed. We develop an all-atom-informed maximum-entropy coarse-grained model of the low-complexity domain of Fused in sarcoma (FUS-LCD) that preserves atomistic contact propensities while tuning the width of the isolated-chain Rg distribution. This design yields dynamically quenched (Qch), middle (Mid), and flexible (Flx) models with nearly identical ⟨Rg⟩ but increasing conformational fluctuation. Increasing fluctuation produces chains that are locally compact yet globally extensible, and decouples condensate density from thermodynamic stability: Flx forms a dense low-temperature phase but has lower critical temperature and surface tension. Flx condensates also show faster diffusion, shorter contact lifetimes, accelerated stress relaxation, delayed early nucleation, and faster late-stage coalescence. This more dynamic state also exhibits weaker orientational organization, with Flx showing the lowest orientational order among the three models. Our results identify single-chain conformational fluctuation as an ensemble-level control variable that links local IDP organization to condensate thermodynamics, transport, viscoelasticity, assembly, and mesoscopic order.
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BibTeX
@article{feng2026singlechain,
title = {{Single-Chain Conformational Fluctuation Regulates Phase Separation of Intrinsically Disordered Proteins.}},
author = {Cibo Feng and Shiqinrui Xu and Haibin Su and Xiakun Chu},
journal = {JACS Au},
year = {2026},
month = sep,
doi = {10.1021/jacsau.6c01044},
url = {https://europepmc.org/article/MED/42953606},
note = {CC BY},
}
RIS
TY - JOUR
TI - Single-Chain Conformational Fluctuation Regulates Phase Separation of Intrinsically Disordered Proteins.
AU - Cibo Feng
AU - Shiqinrui Xu
AU - Haibin Su
AU - Xiakun Chu
PY - 2026
DA - 2026/09/24
JO - JACS Au
DO - 10.1021/jacsau.6c01044
UR - https://europepmc.org/article/MED/42953606
AB - Intrinsically disordered proteins (IDPs) form biomolecular condensates through weak multivalent interactions, but the ensemble variables that control condensate stability and material properties remain incompletely defined. Most current descriptions emphasize sequence features or mean single-chain descriptors, such as the radius of gyration Rg. Here, we ask whether the breadth of the single-chain ensemble can regulate liquid-liquid phase separation when the amino-acid sequence and mean chain size are fixed. We develop an all-atom-informed maximum-entropy coarse-grained model of the low-complexity domain of Fused in sarcoma (FUS-LCD) that preserves atomistic contact propensities while tuning the width of the isolated-chain Rg distribution. This design yields dynamically quenched (Qch), middle (Mid), and flexible (Flx) models with nearly identical ⟨Rg⟩ but increasing conformational fluctuation. Increasing fluctuation produces chains that are locally compact yet globally extensible, and decouples condensate density from thermodynamic stability: Flx forms a dense low-temperature phase but has lower critical temperature and surface tension. Flx condensates also show faster diffusion, shorter contact lifetimes, accelerated stress relaxation, delayed early nucleation, and faster late-stage coalescence. This more dynamic state also exhibits weaker orientational organization, with Flx showing the lowest orientational order among the three models. Our results identify single-chain conformational fluctuation as an ensemble-level control variable that links local IDP organization to condensate thermodynamics, transport, viscoelasticity, assembly, and mesoscopic order.
SN - 2691-3704
ER -