Delineating Structural Propensities of the 4E-BP2 Protein via Integrative Modeling and Clustering

The Journal of Physical Chemistry B, Journal Year: 2023, Volume and Issue: 127(34), P. 7472 - 7486

Published: Aug. 18, 2023

The intrinsically disordered 4E-BP2 protein regulates mRNA cap-dependent translation through interaction with the predominantly folded eukaryotic initiation factor 4E (eIF4E). Phosphorylation of dramatically reduces level eIF4E binding, in part by stabilizing a binding-incompatible domain. Here, we used Rosetta-based sampling algorithm optimized for IDRs to generate initial ensembles two phospho forms 4E-BP2, non- and 5-fold phosphorylated (NP 5P, respectively), 5P domain flanked N- C-terminal (N-IDR C-IDR, respectively). We then applied an integrative Bayesian approach obtain NP conformational that agree experimental data from nuclear magnetic resonance, small-angle X-ray scattering, single-molecule Förster resonance energy transfer (smFRET). For state, inter-residue distance scaling 2D maps revealed role charge segregation pi interactions driving contacts between distal regions chain (∼70 residues apart). ensemble shows prominent N-IDR region phosphosites domain, pT37 pT46, and, lesser extent, delocalized C-IDR region. Agglomerative hierarchical clustering led partitioning each into four clusters different global dimensions contact maps. This helped delineate cluster that, based on our smFRET data, is compatible eIF4E-bound state. were differentiated Our study provides both better visualization fundamental structural poses set falsifiable insights intrachain bias folding binding this protein.

Language: Английский

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SPEADI: Accelerated Analysis of IDP-Ion Interactions from MD-Trajectories

Biology, Journal Year: 2023, Volume and Issue: 12(4), P. 581 - 581

Published: April 10, 2023

The disordered nature of Intrinsically Disordered Proteins (IDPs) makes their structural ensembles particularly susceptible to changes in chemical environmental conditions, often leading an alteration normal functions. A Radial Distribution Function (RDF) is considered a standard method for characterizing the environment surrounding particles during atomistic simulations, commonly averaged over entire or part trajectory. Given high variability, such information might not be reliable IDPs. We introduce Time-Resolved (TRRDF), implemented our open-source Python package SPEADI, which able characterize dynamic environments around use SPEADI distribution ions IDPs Alpha-Synuclein (AS) and Humanin (HN) from Molecular Dynamics (MD) some selected mutants, showing that local ion-residue interactions play important role structures behaviors

Language: Английский

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Interplay of the folded domain and disordered low-complexity domains along with RNA sequence mediate efficient binding of FUS with RNA

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Nov. 10, 2022

Abstract RNA binding ability of Fused in Sarcoma (FUS) protein is crucial to its cellular function. Our molecular simulation study on FUS-RNA complex provides atomic resolution insights into the observations from biochemical studies and also illuminate our understanding driving forces that mediate structure, stability, interaction RRM RGG domains FUS with a stem-loop junction RNA. We observe clear cooperativity division labour among ordered (RRM) disordered (RGG1 RGG2 domain) leads an organized tighter binding. Irrespective length RGG2, RGG2-RNA confined proximal stem regions. On other hand, RGG1-RNA interactions are primarily longer stem. find C-terminus RRM, which make up “boundary residues” connect folded long stretch protein, plays critical role domain. high-resolution forms basis for origins full-length

Language: Английский

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Delineating Structural Propensities of the 4E-BP2 Protein via Integrative Modelling and Clustering

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 22, 2023

ABSTRACT The intrinsically disordered 4E-BP2 protein regulates mRNA cap-dependent translation through the interaction with predominantly folded eukaryotic initiation factor 4E (eIF4E). Phosphorylation of dramatically reduces eIF4E binding, in part by stabilizing a binding- incompatible domain (REF). Here, we used Rosetta-based sampling algorithm optimized for IDRs to generate initial ensembles two phospho forms 4E-BP2, non- and five-fold phosphorylated (NP 5P, respectively), 5P flanked N- C-terminal (N-IDR C-IDR, respectively). We then applied an integrative Bayesian approach obtain NP conformational that agree experimental data from nuclear magnetic resonance, small-angle X-ray scattering single-molecule Förster resonance energy transfer (smFRET). For state, inter-residue distance scaling 2D maps revealed role charge segregation pi interactions driving contacts between distal regions chain (∼70 residues apart). ensemble shows prominent N-IDR region phosphosites domain, pT37 pT46, and, lesser extent, delocalized C-IDR region. Agglomerative hierarchical clustering led partitioning each into four clusters, different global dimensions contact maps. This helped delineate cluster that, based on our smFRET data, is compatible eIF4E-bound state. clusters were differentiated domain. Our study provides both better visualization fundamental structural poses set falsifiable insights intrachain bias folding binding this protein.

Language: Английский

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Covalent adducts formed by the androgen receptor transactivation domain and small molecule drugs remain disordered

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

Published: Nov. 15, 2024

Abstract Intrinsically disordered proteins are implicated in many human diseases. Small molecules that target the androgen receptor transactivation domain have entered trials for treatment of castration-resistant prostate cancer. These been shown to react with cysteine residues and form covalent adducts under physiological conditions. It is currently unclear how attachment these alters conformational ensemble receptor. Here, we utilize all-atom molecular dynamics computer simulations simulate small molecule ligands EPI-002 EPI-7170 bound domain. Our reveal ensembles heterogeneous disordered. We find increases population collapsed helical conformations relative populations observed non-covalent binding identify networks protein-ligand interactions stabilize adduct ensembles. compare those ligand-bound substantial differences. results provide atomically detailed descriptions formed by an intrinsically protein suggest strategies developing more potent inhibitors proteins.

Language: Английский

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Manifold Learning in Atomistic Simulations: A Conceptual Review

arXiv (Cornell University), Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 1, 2023

Analyzing large volumes of high-dimensional data requires dimensionality reduction: finding meaningful low-dimensional structures hidden in their observations. Such practice is needed atomistic simulations complex systems where even thousands degrees freedom are sampled. An abundance such makes gaining insight into a specific physical problem strenuous. Our primary aim this review to focus on unsupervised machine learning methods that can be used simulation find manifold providing collective and informative characterization the studied process. manifolds for sampling long-timescale processes free-energy estimation. We describe work datasets from standard enhanced simulations. Unlike recent reviews simulations, we consider only construct based Markov transition probabilities between samples. discuss these techniques conceptual point view, including underlying theoretical frameworks possible limitations.

Language: Английский

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