Phase behaviour and structure of a model biomolecular condensate

Shillcock, Julian C.; Brochut, Maelick; Chénais, Etienne; Ipsen, John Hjort

doi:10.1039/d0sm00813c

Cited by 14 publications

(34 citation statements)

References 74 publications

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“…We hypothesize that the domain formed by short IDPs is broken up by the conformational entropy of the longer IDP backbones. Previous work has shown that B 16 IDPs assemble into a structured network when they phase separate in the bulk solvent with a spatial structure whose length scale is selected by the length of the IDPs [55]. When these associated IDPs adsorb to the minority lipid headgroups, they maintain this structure which keeps the adsorbed minority lipids farther apart and unable to form a single domain.…”

Section: Increasing Idp Length Results In Patchy Domainsmentioning

confidence: 99%

“…Additionally, a dissipative force (characterized by the parameter γ ij ) and random force (whose strength σ ij is related to the dissipative force parameter by the fluctuation-dissipation theorem σ 2 ij = 2γ ij k B T) provide a thermostat that keeps the system temperature k B T constant. More details of the force field are given in previous work [55]. Beads are connected into molecules with Hookean springs, and a bending stiffness may be applied via an additional bond angle-dependent potential.…”

Section: Dissipative Particle Dynamics Simulationsmentioning

confidence: 99%

“…The tails are connected to the final two adjacent head beads as shown in Figure 2. The IDPs are modeled as linear, semi-flexible polymers (backbone beads of type B) with self-associating endcaps containing four beads (bead type E) [55]. Water was represented by a single bead W. Both backbone and endcap beads in the IDPs are hydrophilic, and it is only the self-attraction of their endcaps that drives their phase separation.…”

Section: Dissipative Particle Dynamics Simulationsmentioning

confidence: 99%

“…A similar potential was applied to the lipid tails with parameters k 3 = 15 k B T and ϕ 0 = 0,. Further details of the simulation technique are given in the literature [40,55,61]. 1.…”

Section: Dissipative Particle Dynamics Simulationsmentioning

confidence: 99%

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Coupling Bulk Phase Separation of Disordered Proteins to Membrane Domain Formation in Molecular Simulations on a Bespoke Compute Fabric

et al. 2021

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Phospholipid membranes surround the cell and its internal organelles, and their multicomponent nature allows the formation of domains that are important in cellular signalling, the immune system, and bacterial infection. Cytoplasmic compartments are also created by the phase separation of intrinsically disordered proteins into biomolecular condensates. The ubiquity of lipid membranes and protein condensates raises the question of how three-dimensional droplets might interact with two-dimensional domains, and whether this coupling has physiological or pathological importance. Here, we explore the equilibrium morphologies of a dilute phase of a model disordered protein interacting with an ideal-mixing, two-component lipid membrane using coarse-grained molecular simulations. We find that the proteins can wet the membrane with and without domain formation, and form phase separated droplets bound to membrane domains. Results from much larger simulations performed on a novel non-von-Neumann compute architecture called POETS, which greatly accelerates their execution compared to conventional hardware, confirm the observations. Reducing the wall clock time for such simulations requires new architectures and computational techniques. We demonstrate here an inter-disciplinary approach that uses real-world biophysical questions to drive the development of new computing hardware and simulation algorithms.

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Section: Increasing Idp Length Results In Patchy Domainsmentioning

confidence: 99%

Section: Dissipative Particle Dynamics Simulationsmentioning

confidence: 99%

Section: Dissipative Particle Dynamics Simulationsmentioning

confidence: 99%

“…A similar potential was applied to the lipid tails with parameters k 3 = 15 k B T and ϕ 0 = 0,. Further details of the simulation technique are given in the literature [40,55,61]. 1.…”

Section: Dissipative Particle Dynamics Simulationsmentioning

confidence: 99%

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Coupling Bulk Phase Separation of Disordered Proteins to Membrane Domain Formation in Molecular Simulations on a Bespoke Compute Fabric

et al. 2021

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“…DPD is a coarse-grained, explicit-solvent molecular simulation technique designed to study the hydrodynamic behaviour of complex fluids,[28-30] and soft materials. [62-64] Its advantage over both atomistic and coarse-grained molecular dynamics are its speed of execution and retention of the correct hydrodynamic behaviour of the solvent. The speedup is obtained by grouping several atoms or atomic groups into beads that interact via soft forces.…”

Section: Methodsmentioning

confidence: 99%

Non-monotonic fibril surface occlusion by GFP tags from coarse-grained molecular simulations

Shillcock

Hastings

Riguet

et al. 2021

Preprint

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The pathological growth of amyloid fibrils in neurons underlies the progression of neurodegenerative diseases including Alzheimer’s and Parkinson’s disease. Fibrils form when soluble monomers oligomerise in the cytoplasm. Their subsequent growth occurs via nucleated polymerization mechanisms involving the free ends of the fibrils augmented by secondary nucleation of new oligomers at their surface. Amyloid fibrils possess a complex interactome with diffusing cytoplasmic proteins that regulates many aspects of their growth, seeding capacity, biochemical activity and transition to pathological inclusions in diseased brains. Changes to their surface are also expected to modify their interactome, pathogenicity and spreading in the brain. Many assays visualise fibril formation, growth and inclusion formation by decorating monomeric proteins with fluorescent tags such as GFP. Recent studies from our group suggest that tags with sizes comparable to the fibril radius may modify the fibril surface accessibility and thus their PTM pattern, interactome and ability to form inclusions. Using coarse-grained molecular simulations of a single alpha synuclein fibril tagged with GFP we find that thermal fluctuations of the tags create a non-monotonic, size-dependent sieve around the fibril that perturbs its interactome with diffusing species. Our results indicate that experiments using tagged and untagged monomers to study the growth and interactome of fibrils should be compared with caution, and the confounding effects of the tags are more complex than a reduction in surface accessibility. The prevalence of fluorescent tags in amyloid fibril growth experiments suggests this has implications beyond the specific alpha synuclein fibrils we model here.

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Assembly of model postsynaptic densities involves interactions auxiliary to stoichiometric binding

Lin

Jia

et al. 2022

Biophysical Journal

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Phase behaviour and structure of a model biomolecular condensate

Abstract: Associative polymers phase separate into a porous phase that mimics the structural features of biomolecular condensates of intrinsically-disordered proteins.

Cited by 14 publications

References 74 publications

Coupling Bulk Phase Separation of Disordered Proteins to Membrane Domain Formation in Molecular Simulations on a Bespoke Compute Fabric

Coupling Bulk Phase Separation of Disordered Proteins to Membrane Domain Formation in Molecular Simulations on a Bespoke Compute Fabric

Non-monotonic fibril surface occlusion by GFP tags from coarse-grained molecular simulations

Assembly of model postsynaptic densities involves interactions auxiliary to stoichiometric binding

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