Phosphorylation of disordered proteins tunes local and global intramolecular interactions DOI Creative Commons
Emery T. Usher, Martin J. Fossat, Alex S. Holehouse

и другие.

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

Опубликована: Июнь 12, 2024

ABSTRACT Protein post-translational modifications, such as phosphorylation, are important regulatory signals for diverse cellular functions. In particular, intrinsically disordered protein regions (IDRs) subject to phosphorylation a means modulate their interactions and Toward understanding the relationship between in IDRs specific functional outcomes, we must consider how affects IDR conformational ensemble. Various experimental techniques suited interrogate features of ensembles; molecular simulations can provide complementary insights even illuminate ensemble that may be experimentally inaccessible. Therefore, sought expand tools available study phosphorylated by all-atom Monte Carlo simulations. To this end, implemented parameters phosphoserine (pSer) phosphothreonine (pThr) into OPLS version continuum solvent model, ABSINTH, assessed performance compared published findings. We simulated short (< 20 residues) long (> 80 phospho-IDRs that, collectively, survey both local global phosphorylation-induced changes Our four well-studied show near-quantitative agreement with findings these systems via metrics including radius gyration, transient helicity, persistence length. also leveraged inherent advantage sequence control explore effects combinations phospho-sites two multi-phosphorylated IDRs. results support on prior observations connect Herein, describe alter chemistry, net charge patterning, intramolecular interactions, which collectively features. SIGNIFICANCE Spatially temporally controlled is critical many facets function broader health. Intrinsically overrepresented targets but structural consequences modifications remain elusive systems. rigorous modeling using simulations, present new ABSINTH implicit paradigm. Through example phospho-IDRs, demonstrate excellent our phospho-IDR datasets.

Язык: Английский

Structure Characterization of a Disordered Peptide Using In-Droplet Hydrogen/Deuterium Exchange Mass Spectrometry and Molecular Dynamics DOI Creative Commons
Mohammad Ashiqur Rahman,

Mst Nigar Sultana,

Daud Sharif

и другие.

ACS Physical Chemistry Au, Год журнала: 2024, Номер 5(1), С. 17 - 29

Опубликована: Ноя. 13, 2024

In-droplet hydrogen/deuterium exchange (HDX)-mass spectrometry (MS) experiments have been conducted for peptides of highly varied conformational type. A new model is presented that combines the use protection factors (PF) from molecular dynamics (MD) simulations with intrinsic HDX rates (kint) to obtain a structure-to-reactivity calibration curve. Using model, relationship peptide structural flexibility and reactivity different elucidated. Additionally, used describe degree bias disease-relevant Nt17 peptide; although flexible, intrinsically primed facile conversion α-helical conformation upon binding partners imparts significant in-droplet this peptide. In future, scale may be developed whereby predictive (propensity form 2° elements such as α-helix, β-sheet, β-turn) disordered regions (IDRs). Such resolution ultimately high-throughput screening IDR transformation(s) ligands drug candidates.

Язык: Английский

Процитировано

1
Phosphorylation of disordered proteins tunes local and global intramolecular interactions DOI Creative Commons
Emery T. Usher, Martin J. Fossat, Alex S. Holehouse

и другие.

Biophysical Journal, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

Protein post-translational modifications, such as phosphorylation, are important regulatory signals for diverse cellular functions. In particular, intrinsically disordered protein regions (IDRs) subject to phosphorylation a means modulate their interactions and Toward understanding the relationship between in IDRs specific functional outcomes, we must consider how affects IDR conformational ensemble. Various experimental techniques suited interrogate features of ensembles; molecular simulations can provide complementary insights even illuminate ensemble that may be experimentally inaccessible. Therefore, sought expand tools available study phosphorylated by all-atom Monte Carlo simulations. To this end, implemented parameters phosphoserine (pSer) phosphothreonine (pThr) into OPLS version continuum solvent model, ABSINTH, assessed performance compared with published findings. We simulated short (<20 residues) long (>80 phospho-IDRs that, collectively, survey both local global phosphorylation-induced changes Our four well-studied show near-quantitative agreement findings these systems via metrics including radius gyration, transient helicity, persistence length. also leveraged inherent advantage sequence control explore effects combinations phospho-sites two multiphosphorylated IDRs. results support on previous observations connect Herein, describe alter chemistry, net charge patterning, intramolecular interactions, which collectively features.

Язык: Английский

Процитировано

1
Identifying Sequence Effects on Chain Dimensions of Disordered Proteins by Integrating Experiments and Simulations DOI Creative Commons

Andrea Holla,

Erik Martin, Thomas Dannenhoffer-Lafage

и другие.

JACS Au, Год журнала: 2024, Номер 4(12), С. 4729 - 4743

Опубликована: Ноя. 14, 2024

It has become increasingly evident that the conformational distributions of intrinsically disordered proteins or regions are strongly dependent on their amino acid compositions and sequence. To facilitate a systematic investigation these sequence-ensemble relationships, we selected set 16 naturally occurring identical length but with large differences in composition, hydrophobicity, charge patterning. We probed ensembles single-molecule Förster resonance energy transfer (FRET), complemented by circular dichroism (CD) nuclear magnetic (NMR) spectroscopy as well small-angle X-ray scattering (SAXS). The shows strong dependence chain dimensions sequence volumes differing up to factor 6. residue-specific intrachain interaction networks underlie pronounced were identified using atomistic simulations combined ensemble reweighting, revealing important role charged, aromatic, polar residues. advance transferable description protein regions, further employed experimental data parametrize coarse-grained model for includes an explicit representation FRET fluorophores successfully describes experiments different dye pairs. Our findings demonstrate value integrating advancing our quantitative understanding features determine proteins.

Язык: Английский

Процитировано

1
The evolution and exploration of intrinsically disordered and phase-separated protein states DOI
Chi Fung Willis Chow, Ágnes Tóth-Petróczy

Elsevier eBooks, Год журнала: 2024, Номер unknown, С. 353 - 379

Опубликована: Ноя. 22, 2024

Язык: Английский

Процитировано

1
Phosphorylation of disordered proteins tunes local and global intramolecular interactions DOI Creative Commons
Emery T. Usher, Martin J. Fossat, Alex S. Holehouse

и другие.

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

Опубликована: Июнь 12, 2024

ABSTRACT Protein post-translational modifications, such as phosphorylation, are important regulatory signals for diverse cellular functions. In particular, intrinsically disordered protein regions (IDRs) subject to phosphorylation a means modulate their interactions and Toward understanding the relationship between in IDRs specific functional outcomes, we must consider how affects IDR conformational ensemble. Various experimental techniques suited interrogate features of ensembles; molecular simulations can provide complementary insights even illuminate ensemble that may be experimentally inaccessible. Therefore, sought expand tools available study phosphorylated by all-atom Monte Carlo simulations. To this end, implemented parameters phosphoserine (pSer) phosphothreonine (pThr) into OPLS version continuum solvent model, ABSINTH, assessed performance compared published findings. We simulated short (< 20 residues) long (> 80 phospho-IDRs that, collectively, survey both local global phosphorylation-induced changes Our four well-studied show near-quantitative agreement with findings these systems via metrics including radius gyration, transient helicity, persistence length. also leveraged inherent advantage sequence control explore effects combinations phospho-sites two multi-phosphorylated IDRs. results support on prior observations connect Herein, describe alter chemistry, net charge patterning, intramolecular interactions, which collectively features. SIGNIFICANCE Spatially temporally controlled is critical many facets function broader health. Intrinsically overrepresented targets but structural consequences modifications remain elusive systems. rigorous modeling using simulations, present new ABSINTH implicit paradigm. Through example phospho-IDRs, demonstrate excellent our phospho-IDR datasets.

Язык: Английский

Процитировано

0