Macromolecular crowding Is surprisingly unable to deform the structure of a model biomolecular condensate
Macromolecular crowding Is surprisingly unable to deform the structure of a model biomolecular condensate
The crowded interior of a living cell makes performing experiments on simpler in vitro systems attractive. Although these reveal interesting phenomena, their biological relevance can be questionable. A topical example is the phase separation of intrinsically disordered proteins into biomolecular condensates, which is proposed to underlie the membrane-less compartmentalization of many cellular functions. How a cell reliably controls biochemical reactions in compartments open to the compositionally-varying cytoplasm is an important question for understanding cellular homeostasis. Computer simulations are often used to study the phase behavior of model biomolecular condensates, but the number of relevant parameters increases as the number of protein components increases. It is unfeasible to exhaustively simulate such models for all parameter combinations, although interesting phenomena are almost certainly hidden in their high-dimensional parameter space. Here, we have studied the phase behavior of a model biomolecular condensate in the presence of a polymeric crowding agent. We used a novel compute framework to execute dozens of simultaneous simulations spanning the protein/crowder concentration space. We then combined the results into a graphical representation for human interpretation, which provided an efficient way to search the model’s high-dimensional parameter space. We found that steric repulsion from the crowder drives a near-critical system across the phase boundary, but the molecular arrangement within the resulting biomolecular condensate is rather insensitive to the crowder concentration and molecular weight. We propose that a cell may use the local cytoplasmic concentration to assist the formation of biomolecular condensates, while relying on the dense phase to reliably provide a stable, structured, fluid milieu for cellular biochemistry despite being open to its changing environment.
biomolecular condensate, coarse-grained simulation, crowding, event-based computing, hardware-accelerated simulation, liquid–liquid phase separation
Shillcock, Julian
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Thomas, David B.
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Ipsen, John H.
978b42a1-11a9-4c38-9744-5c7e496e9510
Brown, Andrew
5c19e523-65ec-499b-9e7c-91522017d7e0
25 January 2023
Shillcock, Julian
5fcb7cf0-914e-46d2-b4c8-963fc3f05d77
Thomas, David B.
5701997d-7de3-4e57-a802-ea2bd3e6ab6c
Ipsen, John H.
978b42a1-11a9-4c38-9744-5c7e496e9510
Brown, Andrew
5c19e523-65ec-499b-9e7c-91522017d7e0
Shillcock, Julian, Thomas, David B., Ipsen, John H. and Brown, Andrew
(2023)
Macromolecular crowding Is surprisingly unable to deform the structure of a model biomolecular condensate.
Biology, 12 (2), [181].
(doi:10.3390/biology12020181).
Abstract
The crowded interior of a living cell makes performing experiments on simpler in vitro systems attractive. Although these reveal interesting phenomena, their biological relevance can be questionable. A topical example is the phase separation of intrinsically disordered proteins into biomolecular condensates, which is proposed to underlie the membrane-less compartmentalization of many cellular functions. How a cell reliably controls biochemical reactions in compartments open to the compositionally-varying cytoplasm is an important question for understanding cellular homeostasis. Computer simulations are often used to study the phase behavior of model biomolecular condensates, but the number of relevant parameters increases as the number of protein components increases. It is unfeasible to exhaustively simulate such models for all parameter combinations, although interesting phenomena are almost certainly hidden in their high-dimensional parameter space. Here, we have studied the phase behavior of a model biomolecular condensate in the presence of a polymeric crowding agent. We used a novel compute framework to execute dozens of simultaneous simulations spanning the protein/crowder concentration space. We then combined the results into a graphical representation for human interpretation, which provided an efficient way to search the model’s high-dimensional parameter space. We found that steric repulsion from the crowder drives a near-critical system across the phase boundary, but the molecular arrangement within the resulting biomolecular condensate is rather insensitive to the crowder concentration and molecular weight. We propose that a cell may use the local cytoplasmic concentration to assist the formation of biomolecular condensates, while relying on the dense phase to reliably provide a stable, structured, fluid milieu for cellular biochemistry despite being open to its changing environment.
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biology-12-00181
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Accepted/In Press date: 17 January 2023
e-pub ahead of print date: 25 January 2023
Published date: 25 January 2023
Additional Information:
Funding Information:
The DPD source code used in this work is available on GitHub ( https://github.com/Osprey-DPD/osprey-dpd , accessed on 16 January 2023) []. The authors acknowledge the use of the IRIDIS High Performance Computing Facility and associated support services at the University of Southampton in the completion of this work. The computational aspect of this research was supported by the EPSRC-funded POETS project (EP/N031768/1). Snapshots and movies of the simulations were produced using the open source VMD software ( http://www.ks.uiuc.edu/Research/vmd/ , accessed on 16 January 2023) [] and ImageJ ( https://imagej.net/ij/index.html accessed on 16 January 2023) [].
Funding Information:
J.C.S. was supported by funding to the Blue Brain Project, a research center of the École polytechnique fédérale de Lausanne (EPFL), from the Swiss government’s ETH Board of the Swiss Federal Institutes of Technology. D.B.T. and A.D.B. were supported by the UK EPSRC Grant EP/N031768/1 (POETS).
Publisher Copyright:
© 2023 by the authors.
Keywords:
biomolecular condensate, coarse-grained simulation, crowding, event-based computing, hardware-accelerated simulation, liquid–liquid phase separation
Identifiers
Local EPrints ID: 474808
URI: http://eprints.soton.ac.uk/id/eprint/474808
ISSN: 2079-7737
PURE UUID: 6299a006-9cce-46a8-8a60-2054e17dc0f1
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Date deposited: 03 Mar 2023 17:32
Last modified: 06 Jun 2024 02:12
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Author:
Julian Shillcock
Author:
David B. Thomas
Author:
John H. Ipsen
Author:
Andrew Brown
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