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Thermodynamic Forces from Protein and Water Govern Condensate Formation of an Intrinsically Disordered Protein Domain

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Mukherjee, Saumyak, Schäfer, Lars V.·2023·Nature Communications
DOI 10.1101/2023.09.05.556343PMC PMC10514047

Preprint — published as 10.1038/s41467-023-41586-y

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Abstract

Liquid-liquid phase separation (LLPS) can drive a multitude of cellular processes by compartmentalizing biological cells via the formation of dense liquid biomolecular condensates, which can function as membraneless organelles. Despite its importance, the molecular-level understanding of the underlying thermodynamics of this process remains incomplete. In this study, we use atomistic molecular dynamics simulations of the low complexity domain (LCD) of human fused in sarcoma (FUS) protein to investigate the contributions of water and protein molecules to the free energy changes that govern LLPS. Both protein and water components are found to have comparably sizeable thermodynamic contributions to the formation of FUS condensates. Moreover, we quantify the counteracting effects of water molecules that are released into the bulk upon condensate formation and the waters retained within the protein droplets. Among the various factors considered, solvation entropy and protein interaction enthalpy are identified as the most important contributions, while solvation enthalpy and protein entropy changes are smaller. These insights provide detailed molecular insights on the intricate thermodynamic interplay between protein- and solvation-related forces underlying the formation of biomolecular condensates.

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Metadata

Authors
Mukherjee, S., & Schäfer, L. V.
Affiliations
Ruhr University Bochum (DE)
Corresponding author
Schäfer, Lars V.
ORCID
Venue
Nature Communications
Publisher
openRxiv
Published
2023-09-06
Volume
14
Issue
1
Pages
5892-5892
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2023.09.05.556343
PMC
PMC10514047
OpenAlex
W4386915691
Cited by
118
References
1
Citations by year
2026: 41 · 2025: 44 · 2024: 30 · 2023: 3
FWCI
10.51
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Dokumentenrepositorium der RUB (Ruhr University Bochum) (submittedVersion, cc-by)
Funders
  • Arizona State University
  • European Commission (801459, HORIZON2020)
  • Deutsche Forschungsgemeinschaft (390677874, EXC2033390677874, EXC2033, 2033390677874‐RESOLV, EXC-2033390677874-RESOLV)
  • Horizon 2020 Framework Programme (801459-FP-RESOMUS)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
liquid-liquid phase separation, biomolecular condensates, intrinsically disordered proteins, FUS protein, low-complexity domains, solvation entropy, free energy change, atomistic molecular dynamics
MeSH terms
Biomolecular Condensates, Humans, Thermodynamics, Water, Entropy, Intrinsically Disordered Proteins

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