Multiscale simulations reveal molecular dynamics of TDP-43 assemblies

Ingólfsson, Helgi I.; Rizuan, Azamat; Mohanty, Priyesh; Mittal, Jeetain; Berry, Joel

doi:10.1016/j.bpj.2021.11.2420

Cited by 4 publications

(5 citation statements)

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“…Between these options is the Martini force field, which uses a transferable building block approach representing 2-4 heavy atoms by a single bead, combining beads to build entire molecules, parameterized based on underlying chemical properties (26,57,58). Martini has already shown promise in simulating several condensate systems (28,59–61). Building on this, we showed that Martini resolution simulations can reproduce the phase separation of [Q 5,8 ]-20 IDPs as expected ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…MD Simulations: Topologies and initial conformations for Martini 3 models of [Q5,8]-20 IDPs were generated using Polyply, including updated bonded parameters for disordered proteins (25,26). Additionally, non-bonded protein-water interactions were increased by a factor of 1.04 to both improve the global dimensions of disordered proteins, and reduce protein-protein interactions to avoid aggregates (27,28). A factor of 1.04 was used instead of the generally recommended 1.10 as this degree of increase was found to produce homogeneous systems with no protein phase separation.…”

Section: Phosphorescence Lifetime Imaging Microscopy (Plim): Samples ...mentioning

confidence: 99%

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Oxygen partitioning into biomolecular condensates is governed by excluded volume

Garg,

Brasnett,

Marrink

et al. 2024

Preprint

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Biomolecular condensates form through the self-assembly of proteins and nucleic acids to create dynamic compartments in cells. By concentrating specific molecules, condensates establish distinct microenvironments that regulate biochemical reactions in time and space. Macromolecules and metabolites partition into condensates depending on their interactions with the macromolecular constituents, however, the partitioning of gases has not been explored. We investigated oxygen partitioning into condensates formed by intrinsically disordered repeat proteins with systematic sequence variations using phosphorescence lifetime imaging microscopy (PLIM). Unlike other hydrophobic metabolites, oxygen is partially excluded from the condensate with partitioning constants more strongly modulated by changes in protein length than hydrophobicity. For repeat proteins, the dense phase protein concentration drops with chain length resulting in a looser condensate with less excluded volume. We found that oxygen partitioning is anti-correlated with dense phase protein concentration, suggesting that oxygen concentration is mainly determined by the solvent accessible volume. This suggests that oxygen partitioning is determined by the physical organization of the condensates rather than the chemical properties of the scaffold. Molecular dynamics simulations suggest that oxygen does not form strong and specific interactions with the scaffold and is dynamic on the nanosecond timescale. Biomolecular condensates thus result in variation of oxygen concentrations on nanometer length-scales, which can tune the oxygen concentration available for biochemical reactions within the cell.

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Section: Resultsmentioning

confidence: 99%

Section: Phosphorescence Lifetime Imaging Microscopy (Plim): Samples ...mentioning

confidence: 99%

Oxygen partitioning into biomolecular condensates is governed by excluded volume

Garg,

Brasnett,

Marrink

et al. 2024

Preprint

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“…The role of the different protein domains in the intra-and intermolecular interactions that give rise to LLPS is not yet fully understood [56]. In this context, multi-scale simulations are a suitable approach to rationalize experimental results [57,58].…”

Section: Characterization Of Tar Dna-binding Protein 43 (Tdp-43)mentioning

confidence: 99%

WARIO: Weighted families of contact maps to characterize conformational ensembles of (highly-)flexible proteins

González-Delgado,

Bernadó,

Neuvial

et al. 2024

Preprint

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Characterizing the structure of flexible proteins, particularly within the realm of intrinsic disorder, presents a formidable challenge due to their high conformational variability. Currently, their structural representation relies on (possibly large) conformational ensembles derived from a combination of experimental and computational methods. The detailed structural analysis of these ensembles is a difficult task, for which existing tools have limited effectiveness. This study proposes an innovative extension of the concept of contact maps to the ensemble framework, incorporating the intrinsic probabilistic nature of disordered proteins. Within this framework, a conformational ensemble is characterized through a weighted family of contact maps. To achieve this, conformations are first described using a refined definition of contact that appropriately accounts for the geometry of the inter-residue interactions and the sequence context. Representative structural features of the ensemble naturally emerge from the subsequent clustering of the resulting contact-based descriptors. Importantly, transiently-populated structural features are readily identified within large ensembles. The performance of the method is illustrated by several use cases and compared with other existing approaches, highlighting its superiority in capturing relevant structural features of highly flexible proteins. An open-source implementation of the method is provided together with an easy-to-use Jupyter notebook, available at https://gitlab.laas.fr/moma/WARIO.

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“…Molecular dynamics (MD) simulations can serve as a valuable complement to experiments (Fawzi et al, 2021), particularly in the case of multidomain proteins such as TDP‐43, which are difficult to characterize in vitro due to their low solubility (Wright et al, 2020). Previous studies utilized all‐atom (AA) and coarse‐grained (CG) molecular dynamics (MD) simulations to characterize the structure, dynamics and interactions implicated in the phase of separation of TDP‐43 CTD and full‐length protein (Conicella et al, 2016, 2020; Ingólfsson et al, 2023; Mohanty et al, 2023). Here, we employ a multiscale simulation approach which utilizes both AA and CG simulations to characterize the monomeric (dilute phase) TDP‐43 full‐length ensemble and nature of inter‐domain interactions which underlie its phase separation.…”

Section: Introductionmentioning

confidence: 99%

A complex network of interdomain interactions underlies the conformational ensemble of monomeric TDP‐43 and modulates its phase behavior

Mohanty,

Rizuan,

Kim

et al. 2024

Protein Science

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TAR DNA‐binding protein 43 (TDP‐43) is a multidomain protein involved in the regulation of RNA processing, and its aggregates have been observed in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Numerous studies indicate TDP‐43 can undergo liquid‐liquid phase separation (LLPS) in vitro and is a component of biological condensates. Homo‐oligomerization via the folded N‐terminal domain (aa:1‐77) and the conserved helical region (aa:319‐341) of the disordered, C‐terminal domain is found to be an important driver of TDP‐43 phase separation. However, a comprehensive molecular view of TDP‐43 phase separation, particularly regarding the nature of heterodomain interactions, is lacking due to the challenges associated with its stability and purification. Here, we utilize all‐atom and coarse‐grained (CG) molecular dynamics (MD) simulations to uncover the network of interdomain interactions implicated in TDP‐43 phase separation. All‐atom simulations uncovered the presence of transient, interdomain interactions involving flexible linkers, RNA‐recognition motif (RRM) domains and a charged segment of disordered C‐terminal domain (CTD). CG simulations indicate these inter‐domain interactions which affect the conformational landscape of TDP‐43 in the dilute phase are also prevalent in the condensed phase. Finally, sequence and surface charge distribution analysis coupled with all‐atom simulations (at high salt) confirmed that the transient interdomain contacts are predominantly electrostatic in nature. Overall, our findings from multiscale simulations lead to a greater appreciation of the complex interaction network underlying the structural landscape and phase separation of TDP‐43.This article is protected by copyright. All rights reserved.

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Multiscale simulations reveal molecular dynamics of TDP-43 assemblies

Cited by 4 publications

References 0 publications

Oxygen partitioning into biomolecular condensates is governed by excluded volume

Oxygen partitioning into biomolecular condensates is governed by excluded volume

WARIO: Weighted families of contact maps to characterize conformational ensembles of (highly-)flexible proteins

A complex network of interdomain interactions underlies the conformational ensemble of monomeric TDP‐43 and modulates its phase behavior

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