Physics-driven coarse-grained model for biomolecular phase separation with near-quantitative accuracy

Joseph, Jerelle A.; Reinhardt, Aleks; Aguirre, Anne; Chew, Pin Yu; Russell, Kieran O.; Espinosa, Jorge R.; Garaizar, Adiran; Collepardo-Guevara, Rosana

doi:10.1038/s43588-021-00155-3

Cited by 187 publications

(371 citation statements)

References 90 publications

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“…Instead, coarse-grained models including mean field simulations [78][79][80][81][82]111], lattice-based models [74][75][76][77], and high-resolution sequence-dependent approaches [56,[64][65][66][67]112], are becoming the go-to simulation methods for characterizing the mechanistic and molecular details of biomolecular condensates. Here, we employ two protein/RNA coarse-grained models of different resolutions, previously developed by us, to elucidate the role of RNA length in modulating LLPS of RBPs: (1) the Mpipi sequencedependent residue-resolution coarse-grained force field for proteins and RNA [57], and (2) a minimal model in which proteins are represented as patchy particles, and RNA as selfrepulsive flexible polymers [69,91] (Fig 1).…”

Section: Multiscale Modelling Approach For Rbp-rna Phase Separationmentioning

confidence: 99%

“…We employ a rectangular box, with an elongated side perpendicular to the interfaces (long enough to capture the bulk density of each phase), while the parallel sides are Coarse-grained models used to investigate phase-separation of RBP-RNA mixtures. Left: Residue-resolution sequence-dependent coarse-grained representation of full FUS, PR 25 , and a 400-mer polyU RNA strand, using the Mpipi model [57]. The Mpipi model represents each amino acid and nucleotide by a single bead and describes the solvent implicitly.…”

Section: Multiscale Modelling Approach For Rbp-rna Phase Separationmentioning

confidence: 99%

“…Using MD simulations of our protein/RNA sequence-specific Mpipi model [57], we first investigate the effect of adding disordered PolyU single-stranded RNA chains to RBPs condensates, and varying the length of the PolyU (while keeping the total amount of U nucleotides and protein constant). Specifically, we compare the effects of RNA-length in the phase behaviour of two different RBPs: (1) FUS, which can phase separate on its own at physiological conditions via homotypic protein-protein interactions, and (2) PR 25 , which only undergoes LLPS at physiological conditions in the presence of RNA (Fig A in the S1 Text) via heterotypic RNA-protein interactions [48,103,114].…”

Section: Impact Of Rna Length In the Phase Behaviour Of Fus Versus Pr...mentioning

confidence: 99%

“…phosphorylated [10,11,53] or methylated [18,54,55]) are of great value. Alongside, sequencedependent molecular simulations can help uncover how specific protein regions, amino acid-RNA interactions, or RNA properties influence the experimentally observed behavior [49,50,[56][57][58].…”

Section: Introductionmentioning

confidence: 99%

“…In this work, we seek to address another pertinent open question on the role of RNA in RBP LLPS [110]: What is the function of RNA strand length in biomolecular LLPS? For this, we use our recently developed residue/nucleotide-resolution coarse-grained protein/RNA model [57], which predicts biomolecular phase diagrams in quantitative agreement with experiments. We demonstrate striking and contrasting effects of RNA length on the phase behaviour of RBPs.…”

Section: Introductionmentioning

confidence: 99%

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RNA length has a non-trivial effect in the stability of biomolecular condensates formed by RNA-binding proteins

et al. 2022

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Biomolecular condensates formed via liquid–liquid phase separation (LLPS) play a crucial role in the spatiotemporal organization of the cell material. Nucleic acids can act as critical modulators in the stability of these protein condensates. To unveil the role of RNA length in regulating the stability of RNA binding protein (RBP) condensates, we present a multiscale computational strategy that exploits the advantages of a sequence-dependent coarse-grained representation of proteins and a minimal coarse-grained model wherein proteins are described as patchy colloids. We find that for a constant nucleotide/protein ratio, the protein fused in sarcoma (FUS), which can phase separate on its own—i.e., via homotypic interactions—only exhibits a mild dependency on the RNA strand length. In contrast, the 25-repeat proline-arginine peptide (PR25), which does not undergo LLPS on its own at physiological conditions but instead exhibits complex coacervation with RNA—i.e., via heterotypic interactions—shows a strong dependence on the length of the RNA strands. Our minimal patchy particle simulations suggest that the strikingly different effect of RNA length on homotypic LLPS versus RBP–RNA complex coacervation is general. Phase separation is RNA-length dependent whenever the relative contribution of heterotypic interactions sustaining LLPS is comparable or higher than those stemming from protein homotypic interactions. Taken together, our results contribute to illuminate the intricate physicochemical mechanisms that influence the stability of RBP condensates through RNA inclusion.

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Section: Multiscale Modelling Approach For Rbp-rna Phase Separationmentioning

confidence: 99%

Section: Multiscale Modelling Approach For Rbp-rna Phase Separationmentioning

confidence: 99%

Section: Impact Of Rna Length In the Phase Behaviour Of Fus Versus Pr...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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RNA length has a non-trivial effect in the stability of biomolecular condensates formed by RNA-binding proteins

et al. 2022

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Biomolecular phase separation through theoretical and computational microscope

Kumar,

Koo,

Eom

et al. 2024

Bulletin Korean Chem Soc

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Biomolecular phase separation is a vital mechanism for orchestrating biomolecules within living cells. This crucial role has spurred an intense pursuit to comprehend the molecular underpinnings governing and regulating these processes. Computational methodologies offer a unique perspective, augmenting experimental techniques by providing detailed information that cannot be obtained otherwise. In this review, we briefly overview the theoretical and computational approaches to investigate biomolecular phase separation. As a short primer, we explain the factors driving and affecting phase separation of biomolecules, and then we delve into analytical and simulation methods used to study phase separation. We explain how analytical methods like the Flory–Huggins theory, random phase approximation, and graph‐based methods have been used to study phase behaviors of various proteins. We also discuss principles and applications of all‐atom simulations, coarse‐grained simulations, and field‐theoretical approaches. Additionally, we explore the recent advances in machine learning approach to predict phase separation of biomolecules.

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Mesoscience in cell biology and cancer research

Qian

Beltran

2022

Cancer Innovation

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Mesoscale characteristics and their interdimensional correlation are the focus of contemporary interdisciplinary research. Mesoscience is a discipline that has the potential to radically update the existing knowledge structure, which differs from the conventional unit-scale and system-scale research models, revealing a previously untouchable area for scientific research. Integrative biology research aims to dissect the complex problems of life systems by conducting comprehensive research and integrating various disciplines from all biological levels of the living organism.However, the mesoscientific issues between different research units are neglected and challenging. Mesoscale research in biology requires the integration of research theories and methods from other disciplines (mathematics, physics, engineering, and even visual imaging) to investigate theoretical and frontier questions of biological processes through experiments, computations, and modeling. We reviewed integrative paradigms and methods for the biological mesoscale problems (focusing on oncology research) and prospected the potential of their multiple dimensions and upcoming challenges. We expect to establish an interactive and collaborative theoretical platform for further expanding the depth and width of our understanding on the nature of biology.

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Physics-driven coarse-grained model for biomolecular phase separation with near-quantitative accuracy

Cited by 187 publications

References 90 publications

RNA length has a non-trivial effect in the stability of biomolecular condensates formed by RNA-binding proteins

RNA length has a non-trivial effect in the stability of biomolecular condensates formed by RNA-binding proteins

Biomolecular phase separation through theoretical and computational microscope

Mesoscience in cell biology and cancer research

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