Challenges in studying the liquid-to-solid phase transitions of proteins using computer simulations

Szała-Mendyk, Beata; Phan, Tien M.; Mohanty, Priyesh; Mittal, Jeetain

doi:10.1016/j.cbpa.2023.102333

Cited by 7 publications

(5 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As stated in the previous section, the favorable interdomain contacts from our singlechain, atomistic simulations may also contribute toward intermolecular interactions within the condensed phase of TDP-43. As an example, the positive correlation between the intra-monomer contacts and inter-chain interactions implicated in phase separation was demonstrated recently in case of the HP1 paralogs where CG phase-coexistence simulations were used to complement the AA simulations and study the protein phase behavior at longer timescales (Her et al, 2022;Phan et al, 2023). We used the HPS model based on the Urry hydrophobicity scale (Regy et al, 2021) to study the phase behavior of TDP-43 at a single-bead per amino acid resolution.…”

Section: Cg Simulations Of Tdp-43 Condensates Reveal a Complex Networ...mentioning

confidence: 99%

“…Independent of SGs, TDP‐43 can undergo cytoplasmic de‐mixing in association with the HSP70 chaperone—HSPB1 (Lu et al, 2022 ). Transient oxidative stress, ATP depletion or proteasome inhibition promotes liquid‐to‐solid transition (Mathieu et al, 2020 ; Szała‐Mendyk et al, 2023 ) of TDP‐43 condensates (Chang et al, 2013 ; Gu et al, 2021 ; Lu et al, 2022 ; Yu et al, 2021 ) which may be related to the onset of TDP‐43 proteinopathies.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Cg Simulations Of Tdp-43 Condensates Reveal a Complex Networ...mentioning

confidence: 99%

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although proposed to not play major roles in driving phase separation, polar residues have been proposed to regulate the liquid-to-solid (LST) transitions of phase separating proteins 6,41 . Many proteins containing prion-like domains are associated with neurodegenerative diseases where they form inclusions 42–47 . In test tubes, these proteins can form liquid-like droplets that can convert to solid-like aggregates over time 4,48,49 .…”

Section: Introductionmentioning

confidence: 99%

Expanding the molecular grammar of polar residues and arginine in FUS prion-like domain phase separation and aggregation

Wake,

Weng,

Zheng

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

A molecular grammar governing low-complexity prion-like domains phase separation (PS) has been proposed based on mutagenesis experiments that identified tyrosine and arginine as primary drivers of phase separation via aromatic-aromatic and aromatic-arginine interactions. Here we show that additional residues make direct favorable contacts that contribute to phase separation, highlighting the need to account for these contributions in PS theories and models. We find that tyrosine and arginine make important contacts beyond only tyrosine-tyrosine and tyrosine-arginine, including arginine-arginine contacts. Among polar residues, glutamine in particular contributes to phase separation with sequence/position-specificity, making contacts with both tyrosine and arginine as well as other residues, both before phase separation and in condensed phases. For glycine, its flexibility, not its small solvation volume, favors phase separation by allowing favorable contacts between other residues and inhibits the liquid-to-solid (LST) transition. Polar residue types also make sequence-specific contributions to aggregation that go beyond simple rules, which for serine positions is linked to formation of an amyloid-core structure by the FUS low-complexity domain. Hence, here we propose a revised molecular grammar expanding the role of arginine and polar residues in prion-like domain protein phase separation and aggregation.

show abstract

“…Addressing the challenges of timescales and length scales inherent in protein LLPS, a recent coarse-grain (CG) framework ( Dignon et al, 2018b ; Regy et al, 2021b ; Szała-Mendyk et al, 2023 ) has emerged as a powerful computational tool to provide insights into the molecular interactions behind phase separation of multidomain and intrinsically disordered proteins (IDPs). Here, we use this CG simulation framework to uncover the underlying forces driving phase separation of HP1 paralogs.…”

Section: Introductionmentioning

confidence: 99%

Interplay between charge distribution and DNA in shaping HP1 paralog phase separation and localization

Phan,

Kim,

Debelouchina

et al. 2024

eLife

Self Cite

View full text Add to dashboard Cite

The heterochromatin protein 1 (HP1) family is a crucial component of heterochromatin with diverse functions in gene regulation, cell cycle control, and cell differentiation. In humans, there are three paralogs, HP1α, HP1β, and HP1γ, which exhibit remarkable similarities in their domain architecture and sequence properties. Nevertheless, these paralogs display distinct behaviors in liquid-liquid phase separation (LLPS), a process linked to heterochromatin formation. Here, we employ a coarse-grained simulation framework to uncover the sequence features responsible for the observed differences in LLPS. We highlight the significance of the net charge and charge patterning along the sequence in governing paralog LLPS propensities. We also show that both highly conserved folded and less-conserved disordered domains contribute to the observed differences. Furthermore, we explore the potential co-localization of different HP1 paralogs in multicomponent assemblies and the impact of DNA on this process. Importantly, our study reveals that DNA can significantly reshape the stability of a minimal condensate formed by HP1 paralogs due to competitive interactions of HP1α with HP1β and HP1γ versus DNA. In conclusion, our work highlights the physicochemical nature of interactions that govern the distinct phase-separation behaviors of HP1 paralogs and provides a molecular framework for understanding their role in chromatin organization. Distinct interaction patterns of HP1 paralogs, in concert with DNA modulation, induce the organization of chromatin via liquid-liquid phase separation.

show abstract

Challenges in studying the liquid-to-solid phase transitions of proteins using computer simulations

Cited by 7 publications

References 89 publications

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

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

Expanding the molecular grammar of polar residues and arginine in FUS prion-like domain phase separation and aggregation

Interplay between charge distribution and DNA in shaping HP1 paralog phase separation and localization

Contact Info

Product

Resources

About