Cited by Impact of Phosphorylation on the Structural Ensemble of alpha-Synuclein in Aqueous Solution

An integrated machine learning approach delineates an entropic expansion mechanism for the binding of a small molecule to α-synuclein DOI

Sneha Menon,

Subinoy Adhikari,

Jagannath Mondal

et al.

eLife, Journal Year: 2024, Volume and Issue: 13

Published: June 3, 2024

The mis-folding and aggregation of intrinsically disordered proteins (IDPs) such as α-synuclein (αS) underlie the pathogenesis various neurodegenerative disorders. However, targeting αS with small molecules faces challenges due to lack defined ligand-binding pockets in its structure. Here, we implement a deep artificial neural network-based machine learning approach, which is able statistically distinguish fuzzy ensemble conformational substates neat water from those aqueous fasudil (small molecule interest) solution. In particular, presence solvent either modulates pre-existing states or gives rise new αS, akin an ensemble-expansion mechanism. ensembles display strong conformation-dependence residue-wise interaction molecule. A thermodynamic analysis indicates that small-molecule structural repertoire by tuning protein backbone entropy, however entropy remains unperturbed. Together, this study sheds light on intricate interplay between IDPs, offering insights into entropic modulation expansion key biophysical mechanisms driving potential therapeutics.

Language: Английский

Citations

Interplay between phosphorylation and oligomerization tunes the conformational ensemble of SWEET transporters DOI

Austin T. Weigle, Diwakar Shukla

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

Published: June 14, 2024

SWEET sugar transporters are desirable biotechnological targets for improving plant growth. One engineering strategy includes modulating how regulated. Phosphorylation and oligomerization have been shown to positively regulate function, leading increased transport activity. However, constitutive phosphorylation may not be beneficial health under basal conditions. Structural mechanistic understanding of the interplay between in functional regulation SWEETs remains limited. Using extensive molecular dynamics simulations coupled with Markov state models, we demonstrate thermodynamic kinetic effects using OsSWEET2b as a model. We report that these regulatory mechanisms bias outward-facing states improved extracellular gating, which complement published experimental findings. Our results offer insights guide strategies throughout family.

Language: Английский

Citations

Virtual Special Issue on Machine Learning in Physical Chemistry Volume 2 DOI

Andrew L. Ferguson, Jim Pfaendtner

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: 128(27), P. 6435 - 6438

Published: July 11, 2024

Language: Английский

Citations

Impact of Phosphorylation on the Physiological Form of Human alpha-Synuclein in Aqueous Solution DOI

Emile De Bruyn, Anton Emil Dorn, Giulia Rossetti

et al.

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(21), P. 8215 - 8226

Published: Oct. 28, 2024

Serine 129 can be phosphorylated in pathological inclusions formed by the intrinsically disordered protein human α-synuclein (AS), a key player Parkinson's disease and other synucleinopathies. Here, molecular simulations provide insight into structural ensemble of AS. The allow us to suggest that phosphorylation significantly impacts content physiological AS conformational aqueous solution, as phosphate group is mostly solvated. hydrophobic region contains β-hairpin structures, which may increase propensity undergo amyloid formation, seen nonphysiological (nonacetylated) form recent simulation study. Our findings are consistent with existing experimental data caveat observed limitations force field for moiety.

Language: Английский

Citations

Phosphorylation of disordered proteins tunes local and global intramolecular interactions DOI

Emery T. Usher, Martin J. Fossat, Alex S. Holehouse

et al.

Biophysical Journal, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 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.

Language: Английский

Citations

An Integrated Machine Learning Approach Delineates Entropy-mediated Conformational Modulation ofα-synuclein by Small Molecule DOI

Sneha Menon,

Subinoy Adhikari,

Jagannath Mondal

et al.

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

Published: Jan. 16, 2024

Abstract The mis-folding and aggregation of intrinsically disordered proteins (IDPs) such as α -synuclein ( S) underlie the pathogenesis various neurodegenerative disorders. However, targeting S with small molecules faces challenges due to its lack defined ligand-binding pockets in structure. Here, we implement a deep artificial neural network based machine learning approach, which is able statistically distinguish fuzzy ensemble conformational substates neat water from those aqueous fasudil (small molecule interest) solution. In particular, presence solvent either modulates pre-existing states or gives rise new S, akin an ensemble-expansion mechanism. ensembles display strong conformation-dependence residue-wise interaction molecule. A thermodynamic analysis indicates that small-molecule structural repertoire by tuning protein backbone entropy, however entropy remains unperturbed. Together, this study sheds light on intricate interplay between IDPs, offering insights into entropic modulation expansion key biophysical mechanisms driving potential therapeutics.

Language: Английский

Citations

A Transformer Based Machine Learning of Molecular Grammar Inherent in Proteins Prone to Liquid Liquid Phase Separation DOI

Abdul Wasim, Ushasi Pramanik, Anirban Das

et al.

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

Published: March 6, 2024

Abstract Understanding the molecular grammar that governs protein phase separation is essential for advancements in bioinformatics and engineering. This study leverages Generative Pre-trained Transformer (GPT)-based Protein Language Models (PLMs) to decode complex of proteins prone liquid-liquid (LLPS). We trained three distinct GPT models on datasets comprising amino acid sequences with varying LLPS propensities: highly predisposed (LLPS+ GPT), moderate (LLPS-GPT), resistant (PDB* GPT). As training progressed, LLPS-prone model began learn embeddings were from those LLPS-resistant sequences. These generated 18,000 ranging 20 200 acids, which exhibited low similarity known SwissProt database. Statistical analysis revealed subtle but significant differences occurrence probabilities between models, suggesting underlying their abilities. Notably, LLPS+ showed fewer aromatic residues a higher fraction charge decoration. Short peptides (20-25 acids) underwent computational wet-lab validation, demonstrating ability form phase-separated states vitro. The enriched existing database enabled development robust classifier accurately distinguishes non-LLPS research marks advancement using explore engineer vast sequence space associated proteins.

Language: Английский

Citations

Phosphorylation of disordered proteins tunes local and global intramolecular interactions DOI

Emery T. Usher, Martin J. Fossat, Alex S. Holehouse

et al.

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

Published: June 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.

Language: Английский

Citations

Virtual Special Issue on Machine Learning in Physical Chemistry Volume 2 DOI

Andrew L. Ferguson, Jim Pfaendtner

The Journal of Physical Chemistry A, Journal Year: 2024, Volume and Issue: 128(27), P. 5225 - 5228

Published: July 11, 2024

Language: Английский

Citations

Virtual Special Issue on Machine Learning in Physical Chemistry Volume 2 DOI

Andrew L. Ferguson, Jim Pfaendtner

The Journal of Physical Chemistry C, Journal Year: 2024, Volume and Issue: 128(27), P. 11079 - 11082

Published: July 11, 2024

Language: Английский

Citations