Phase behaviour of hnRNPA1 low-complexity domain mutants described by different sequence-dependent models

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 29, 2024

Intracellular liquid–liquid phase separation (LLPS) of proteins and nucleic acids is a fundamental mechanism by which cells compartmentalize their components perform essential biological functions. Molecular simulations play crucial role in providing microscopic insights into the physicochemical processes driving this phenomenon. In study, we systematically compare six state-of-the-art sequence-dependent, residue-resolution models to evaluate performance reproducing behaviour material properties condensates formed seven variants low-complexity domain (LCD) hnRNPA1 protein (A1-LCD)—a implicated pathological liquid-to-solid transition stress granules. Specifically, assess HPS, HPS-cation– π , HPS-Urry, CALVADOS2, Mpipi, Mpipi-Recharged predictions condensate saturation concentration, critical solution temperature, viscosity for A1-LCD variants. Our analyses demonstrate that, among tested models, Mpipi-Recharged, CALVADOS2 provide accurate descriptions temperatures concentrations various tested. Regarding prediction its variants, stands out as most reliable model. Overall, study benchmarks range coarse-grained thermodynamic stability establishes direct link between ranking intermolecular interactions these consider.

Language: Английский

Structural and Functional Relevance of Charge Based Transient Interactions inside Intrinsically Disordered Proteins

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Abstract Intrinsically disordered proteins (IDPs) perform a wide range of biological functions without adopting stable, well-defined, three-dimensional structures. Instead, IDPs exist as dynamic ensembles flexible conformations, traditionally thought to be governed by weak, nonspecific interactions, which are well described homopolymer theory. However, recent research highlights the presence transient, specific interactions in several IDPs, suggesting that factors beyond overall size influence their conformational behavior. In this study, we investigate how spatial arrangement charged amino acids within IDP sequences shapes prevalence interactions. Through series model peptides, establish quantitative empirical relationship between fraction transient and novel sequence metric, termed effective patch length, characterizes ability patches drive these By examining with varying levels further explore heteropolymeric structural behavior phase-separated condensates, where observe formation condensate-spanning network structure. Additionally, proteome-wide scan for charge-based regions human proteome, revealing approximately 10% exhibit such charge-driven leading behaviors ensembles. Finally, examine correlate molecular functions, identifying roles enriched.

Language: Английский

Electrostatics of Salt-Dependent Reentrant Phase Behaviors Highlights Diverse Roles of ATP in Biomolecular Condensates

Published: Dec. 30, 2024

Liquid-liquid phase separation (LLPS) involving intrinsically disordered protein regions (IDRs) is a major physical mechanism for biological membraneless compartmentalization. The multifaceted electrostatic effects in these biomolecular condensates are exemplified here by experimental and theoretical investigations of the different salt- ATP-dependent LLPSs an IDR messenger RNA-regulating Caprinl its phosphorylated variant pY-Caprinl, exhibiting, e.g., reentrant behaviors some instances but not others. Experimental data rationalized modeling using analytical theory, molecular dynamics, polymer field-theoretic simulations, indicating that interchain ion bridges enhance LLPS polyelectrolytes such as high valency ATP-magnesium significant factor colocalization with condensed phases, similar trends observed other IDRs. nature features complements ATP’s involvement π-related interactions amphiphilic hydrotrope, underscoring general role modulating concentrations functional ramifications.

Language: Английский