A coarse‐grained model for disordered and multi‐domain proteins

Protein Science, Год журнала: 2024, Номер 33(11)

Опубликована: Окт. 16, 2024

Many proteins contain more than one folded domain, and such modular multi-domain help expand the functional repertoire of proteins. Because their larger size often substantial dynamics, it may be difficult to characterize conformational ensembles by simulations. Here, we present a coarse-grained model for that is both fast provides an accurate description global properties in solution. We show accuracy one-bead-per-residue depends on how interaction sites domains are represented. Specifically, find excessive domain-domain interactions if located at position C

Язык: Английский

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Expanding the molecular grammar of polar residues and arginine in FUS phase separation

Nature Chemical Biology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 7, 2025

Язык: Английский

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Biological condensates form percolated networks with molecular motion properties distinctly different from dilute solutions

eLife, Год журнала: 2023, Номер 12

Опубликована: Июнь 1, 2023

Formation of membraneless organelles or biological condensates via phase separation and related processes hugely expands the cellular organelle repertoire. Biological are dense viscoelastic soft matters instead canonical dilute solutions. To date, numerous different have been discovered, but mechanistic understanding remains scarce. In this study, we developed an adaptive single-molecule imaging method that allows simultaneous tracking individual molecules their motion trajectories in both condensed phases various condensates. The enables quantitative measurements concentrations, boundary, behavior, speed phases, as well scale molecular exchanges between two phases. Notably, do not undergo uniform Brownian motion, constantly switch a (class of) confined state(s) random diffusion-like state. Transient confinement is consistent with strong interactions associated large networks (i.e., percolation) phase. way, behave distinctly from those methods findings described herein should be generally applicable for deciphering mechanisms underlying assembly, dynamics, consequently functional implications

Язык: Английский

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Theory and Simulation of Multiphase Coexistence in Biomolecular Mixtures

Journal of Chemical Theory and Computation, Год журнала: 2023, Номер 19(12), С. 3429 - 3445

Опубликована: Июнь 5, 2023

Biomolecular condensates constitute a newly recognized form of spatial organization in living cells. Although many are believed to as result phase separation, the physicochemical properties that determine behavior heterogeneous biomolecular mixtures only beginning be explored. Theory and simulation provide invaluable tools for probing relationship between molecular determinants, such protein RNA sequences, emergence phase-separated complex environments. This review covers recent advances prediction computational design phase-separate into coexisting phases. First, we efforts understand with hundreds or thousands species using theoretical models statistical approaches. We then describe progress developing analytical theories coarse-grained predict multiphase detail required make contact biophysical experiments. conclude by summarizing challenges ahead modeling inhomogeneous

Язык: Английский

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Cross-Talk of Cation−π Interactions with Electrostatic and Aromatic Interactions: A Salt-Dependent Trade-off in Biomolecular Condensates

The Journal of Physical Chemistry Letters, Год журнала: 2023, Номер 14(38), С. 8460 - 8469

Опубликована: Сен. 18, 2023

Biomolecular condensates are essential for cellular functionality, yet the complex interplay among diverse molecular interactions that mediate their formation remains poorly understood. Here, using coarse-grained dynamics simulations, we address contribution of cation-π to stability formed via liquid-liquid phase separation. We found greater stabilization up 80% in from peptides with higher aromatic residue content or less charge clustering. The droplet increases increasing ionic strength, suggesting a trade-off between and electrostatic interactions. Cation-π interactions, therefore, can compensate reduced such as occurs at salt concentrations sequences charged Designing desired biophysical characteristics therefore requires quantification not only individual but also cross-talks involving charge-charge, π-π,

Язык: Английский

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Toward Accurate Simulation of Coupling between Protein Secondary Structure and Phase Separation

Journal of the American Chemical Society, Год журнала: 2023, Номер 146(1), С. 342 - 357

Опубликована: Дек. 19, 2023

Intrinsically disordered proteins (IDPs) frequently mediate phase separation that underlies the formation of a biomolecular condensate. Together with theory and experiment, efficient coarse-grained (CG) simulations have been instrumental in understanding sequence-specific IDPs. However, widely used Cα-only models are limited capturing peptide nature IDPs, particularly backbone-mediated interactions effects secondary structures, separation. Here, we describe hybrid resolution (HyRes) protein model toward more accurate description backbone transient structures With an atomistic side chains, HyRes can semiquantitatively capture residue helical propensity overall chain dimension monomeric Using GY-23 as system, show is enough for direct simulation spontaneous and, at same time, appears to resolve single His Lys mutations. also successfully predict increased β-structure condensate, consistent available experimental CD data. We further utilize study TPD-43, where several disease-related mutants conserved region (CR) shown affect residual helicities modulate measured by saturation concentration. The recapitulate effect these on helicity TDP-43 CR. Analyses reveal balance between chain-mediated interactions, but not itself, actually determines propensity. These results support represents effective molecular IDP will help elucidate coupling

Язык: Английский

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Differential Effects of Sequence-Local versus Nonlocal Charge Patterns on Phase Separation and Conformational Dimensions of Polyampholytes as Model Intrinsically Disordered Proteins

The Journal of Physical Chemistry Letters, Год журнала: 2024, Номер 15(32), С. 8248 - 8256

Опубликована: Авг. 6, 2024

Conformational properties of intrinsically disordered proteins (IDPs) are governed by a sequence-ensemble relationship. To differentiate the impact sequence-local versus sequence-nonlocal features an IDP's charge pattern on its conformational dimensions and phase-separation propensity, "blockiness" κ nonlocality-weighted sequence decoration (SCD) parameters compared for their correlations with isolated-chain radii gyration (Rgs) upper critical solution temperatures (UCSTs) polyampholytes modeled random phase approximation, field-theoretic simulation, coarse-grained molecular dynamics. SCD is superior to in predicting Rg because accounts effects contact order, i.e., nonlocality, isolated chains. In contrast, comparably good, though nonideal, predictors UCST frequencies interchain contacts multiple-chain condensed less sensitive positions than intrachain chain, as reflected correlating better condensed-phase interaction energy SCD.

Язык: Английский

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A coarse-grained model for disordered and multi-domain proteins

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Фев. 7, 2024

Abstract Many proteins contain more than one folded domain, and such modular multi-domain help expand the functional repertoire of proteins. Because their larger size often substantial dynamics, it may be difficult to characterize conformational ensembles by simulations. Here, we present a coarse-grained model for that is both fast provides an accurate description global properties in solution. We show accuracy one-bead-per-residue depends on how interaction sites domains are represented. Specifically, find excessive domain-domain interactions if located at position C α atoms. also centre mass residue, obtain good agreement between simulations experiments across wide range then optimize our previously described CALVADOS using this centre-of-mass representation, validate resulting independent data. Finally, use revised simulate phase separation disordered proteins, examine stability differ dilute dense phases. Our results provide starting point understanding regions these affect propensity self-associate undergo separation.

Язык: Английский

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Chemically Informed Coarse-Graining of Electrostatic Forces in Charge-Rich Biomolecular Condensates

ACS Central Science, Год журнала: 2025, Номер 11(2), С. 302 - 321

Опубликована: Фев. 11, 2025

Biomolecular condensates composed of highly charged biomolecules, such as DNA, RNA, chromatin, and nucleic-acid binding proteins, are ubiquitous in the cell nucleus. The biophysical properties these charge-rich largely regulated by electrostatic interactions. Residue-resolution coarse-grained models that describe solvent ions implicitly widely used to gain mechanistic insights into condensates, offering transferability, computational efficiency, accurate predictions for multiple systems. However, their predictive accuracy diminishes due implicit treatment ions. Here, we present Mpipi-Recharged, a residue-resolution model improves description charge effects biomolecular containing disordered multidomain and/or single-stranded RNAs. Mpipi-Recharged introduces pair-specific asymmetric Yukawa potential, informed atomistic simulations. We show this coarse-graining forces captures intricate effects, blockiness, stoichiometry variations complex coacervates, modulation salt concentration, without requiring explicit solvation. provides excellent agreement with experiments predicting phase behavior condensates. Overall, tools available investigate physicochemical mechanisms regulating enhancing scope computer simulations field.

Язык: Английский

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Coacervation drives morphological diversity of mRNA encapsulating nanoparticles

The Journal of Chemical Physics, Год журнала: 2025, Номер 162(7)

Опубликована: Фев. 19, 2025

The spatial arrangement of components within an mRNA encapsulating nanoparticle has consequences for its thermal stability, which is a key parameter therapeutic utility. mesostructure nanoparticles formed with cationic polymers several distinct putative structures: here, we develop field theoretic simulation model to compute the phase diagram amphiphilic block copolymers that balance coacervation and hydrophobicity as driving forces assembly. We predict morphologies these nanoparticles, depending on salt conditions hydrophobicity. compare our predictions cryogenic-electron microscopy images encapsulated by charge altering releasable transporters. In addition, provide graphics processing unit-accelerated, open-source codebase general purpose simulations, anticipate will be useful tool community.

Язык: Английский

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