Direct computations of viscoelastic moduli of biomolecular condensates

Cohen, Samuel R.; Banerjee, Priya R.; Pappu, Rohit V.

doi:10.1101/2024.06.11.598543

Cited by 3 publications

(1 citation statement)

References 110 publications

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“…This weakening of pairwise associations enables networking that enables percolation within dense phases. Indeed, recent studies 49 have shown evidence for condensates being percolated network fluids 11,15,28,50 . Furthermore, the network structures directly explain the measured, sequence-specific viscoelastic moduli of different PLCD-based condensates 11 .…”

Section: Discussionmentioning

confidence: 99%

Backbone-mediated weakening of pairwise interactions enables percolation in mimics of protein condensates

Zeng,

Pappu

2024

Preprint

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Intrinsically disordered regions (IDRs) of proteins with specific sequence grammars can be drivers of phase separation and percolation that enable the formation of biomolecular condensates. Measurements have shown that dense phases of protein-based condensates are semidilute solutions. In these solutions, the probability of realizing intermolecular interactions is higher than the probability of intramolecular interactions. Accordingly, to zeroth order, dense phases may be viewed as concentrated solutions of peptide-sized motifs. Here, we report results from all-atom molecular dynamics simulations that were used to quantify differences between inter-residue interactions in mimics of dense versus dilute phases. The simulations use the polarizable AMOEBA forcefield for peptides, ions, and water molecules. In simulations that treat coexisting phases as solutions of model compounds, we find that the interactions between aromatic residues are stronger than interactions between cationic and aromatic residues. Cooperativity within dense phases formed by freely diffusing model compounds is manifest as enhanced pairwise interactions and the formation of nanoscale clusters of aromatic sidechains. Simulations that account for the effects of peptide backbones reveal contrasting results. While peptide backbones maintain or enhance pairwise inter-residue interactions in dilute phases, these interactions are weakened within dense phases. Backbone-mediated weakening of pairwise inter-residue interactions within dense phases is accompanied by the gain of higher-order interactions that enables percolation, whereby molecules within a dense phase become part of a system-spanning network. Our findings provide a physico-chemical rationale for phase separation and percolation as joint drivers of condensate formation.

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Section: Discussionmentioning

confidence: 99%

Backbone-mediated weakening of pairwise interactions enables percolation in mimics of protein condensates

Zeng,

Pappu

2024

Preprint

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Sequence-Encoded Spatiotemporal Dependence of Viscoelasticity of Protein Condensates Using Computational Microrheology

Sundaravadivelu Devarajan,

Mittal

2024

JACS Au

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Many biomolecular condensates act as viscoelastic complex fluids with distinct cellular functions. Deciphering the viscoelastic behavior of biomolecular condensates can provide insights into their spatiotemporal organization and physiological roles within cells. Although there is significant interest in defining the role of condensate dynamics and rheology in physiological functions, the quantification of their time-dependent viscoelastic properties is limited and is mostly done through experimental rheological methods. Here, we demonstrate that a computational passive probe microrheology technique, coupled with continuum mechanics, can accurately characterize the linear viscoelasticity of condensates formed by intrinsically disordered proteins (IDPs). Using a transferable coarsegrained protein model, we first provide a physical basis for choosing optimal values that define the attributes of the probe particle, namely, its size and interaction strength with the residues in an IDP chain. We show that the technique captures the sequencedependent viscoelasticity of heteropolymeric IDPs that differ in either sequence charge patterning or sequence hydrophobicity. We also illustrate the technique's potential in quantifying the spatial dependence of viscoelasticity in heterogeneous IDP condensates. The computational microrheology technique has important implications for investigating the time-dependent rheology of complex biomolecular architectures, resulting in the sequence−rheology−function relationship for condensates.

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Decoding Biomolecular Condensate Dynamics: An Energy Landscape Approach

Biswas,

Potoyan

2024

Preprint

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A significant fraction of eukaryotic proteins contain low-complexity sequence elements with unknown functions. Many of these sequences are prone to form biomolecular condensates with unique material and dynamic properties. Mutations in low-complexity regions often result in abnormal phase transitions into pathological solid-like states. Therefore, understanding how the low-complexity sequence patterns encode the material properties of condensates is crucial for uncovering the cellular functions and evolutionary forces behind the emergence of low-complexity regions in proteins. In this work, we employ an alphabet-free energy landscape framework of the stickers and spacers to dissect how the low complexity patterns of proteins encode the material properties of condensates. We find a broad phase diagram of material properties determined by distinct energy landscape features, showing that periodic repeat motifs promote elastic-dominated while random sequences are viscous-dominated properties. We find that a certain degree of sticker periodicity is necessary to maintain the fluidity of condensates, preventing them from forming glassy or solid-like states. Finally, we show that the energy landscape framework captures viscoelastic trends seen in the recent experiments on prion domains and makes predictions for systematic variation of protein condensate viscoelasticity via altering the periodicity and strength of sticker motifs.

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Direct computations of viscoelastic moduli of biomolecular condensates

Cited by 3 publications

References 110 publications

Backbone-mediated weakening of pairwise interactions enables percolation in mimics of protein condensates

Backbone-mediated weakening of pairwise interactions enables percolation in mimics of protein condensates

Sequence-Encoded Spatiotemporal Dependence of Viscoelasticity of Protein Condensates Using Computational Microrheology

Decoding Biomolecular Condensate Dynamics: An Energy Landscape Approach

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