Towards accurate, force field independent conformational ensembles of intrinsically disordered proteins DOI Creative Commons

Kaushik Borthakur,

Thomas R. Sisk, Francesco Paolo Panei

и другие.

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

Опубликована: Окт. 5, 2024

Abstract Determining accurate atomic resolution conformational ensembles of intrinsically disordered proteins (IDPs) is extremely challenging. Molecular dynamics (MD) simulations provide atomistic IDPs, but their accuracy highly dependent on the quality physical models, or force fields, used. Here, we demonstrate how to determine IDPs by integrating all-atom MD with experimental data from nuclear magnetic resonance (NMR) spectroscopy and small-angle x-ray scattering (SAXS) a simple, robust fully automated maximum entropy reweighting procedure. We that when this approach applied sufficient data, IDP derived different fields converge similar distributions. The procedure presented here facilitates integration extensive datasets enables calculation accurate, force-field independent IDPs.

Язык: Английский

Self-Assembly of Amyloid-Beta (Aβ) Peptides from Solution to Near In Vivo Conditions DOI
Phuong H. Nguyen, Fabio Sterpone, Philippe Derreumaux

и другие.

The Journal of Physical Chemistry B, Год журнала: 2022, Номер 126(49), С. 10317 - 10326

Опубликована: Дек. 5, 2022

Understanding the atomistic resolution changes during self-assembly of amyloid peptides or proteins is important to develop compounds conditions alter aggregation pathways and suppress toxicity potentially aid in development drugs. However, complexity protein transient order/disorder oligomers along fibril are very challenging. In this Perspective, we discuss computational studies polypeptides carried out under various conditions, including closely mimicking vivo point challenges obtaining physiologically relevant results, focusing mainly on amyloid-beta Aβ peptides.

Язык: Английский

Процитировано

15
Manifold learning in atomistic simulations: a conceptual review DOI Creative Commons
Jakub Rydzewski, Ming Chen, Ómar Valsson

и другие.

Machine Learning Science and Technology, Год журнала: 2023, Номер 4(3), С. 031001 - 031001

Опубликована: Июль 17, 2023

Abstract 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.

Язык: Английский

Процитировано

9
Atomistic molecular dynamics simulations of intrinsically disordered proteins DOI Creative Commons

Fidha Nazreen Kunnath Muhammedkutty,

Matthew MacAinsh,

Huan‐Xiang Zhou

и другие.

Current Opinion in Structural Biology, Год журнала: 2025, Номер 92, С. 103029 - 103029

Опубликована: Март 10, 2025

Язык: Английский

Процитировано

0
Evidence of α-Synuclein/Glucocerebrosidase Dual Targeting by Iminosugar Derivatives DOI Creative Commons

Giuseppe Tagliaferro,

Maria Giulia Davighi, Francesca Clemente

и другие.

ACS Chemical Neuroscience, Год журнала: 2025, Номер unknown

Опубликована: Март 13, 2025

Intrinsically disordered proteins (IDPs) are highly flexible molecules often linked to the onset of incurable diseases. Despite their great therapeutic potential, IDPs considered as undruggable because they lack defined binding pockets, which constitute basis drug discovery approaches. However, small that interact with intrinsically state α-synuclein, protein Parkinson's disease (PD), were recently identified and shown act chemical chaperones. Glucocerebrosidase (GCase) is an enzyme crucially involved in PD, since mutations code for GCase among most frequent genetic risk factors PD. Following "dual-target" approach, stating one carefully designed molecule can, principle, interfere more than target, we a pharmacological chaperone interacts monomeric form α-synuclein. This result opens novel avenues be explored search on dual targets, particular, challenging targets such IDPs.

Язык: Английский

Процитировано

0
The thermodynamic hypothesis of protein aggregation DOI Creative Commons
Michele Vendruscolo

Molecular Aspects of Medicine, Год журнала: 2025, Номер 103, С. 101364 - 101364

Опубликована: Май 3, 2025

Язык: Английский

Процитировано

0
Virus-like particles of retroviral origin in protein aggregation and neurodegenerative diseases DOI Creative Commons
Serena Carra, Balázs Fábián,

Hamed Taghavi

и другие.

Molecular Aspects of Medicine, Год журнала: 2025, Номер 103, С. 101369 - 101369

Опубликована: Май 20, 2025

Язык: Английский

Процитировано

0
Covalent Adducts Formed by the Androgen Receptor Transactivation Domain and Small Molecule Drugs Remain Disordered DOI Creative Commons
Jiaqi Zhu, Paul Robustelli

Journal of Chemical Information and Modeling, Год журнала: 2025, Номер unknown

Опубликована: Май 30, 2025

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 simulations, 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.

Язык: Английский

Процитировано

0
N-terminal domain of androgen receptor is a major therapeutic barrier and potential pharmacological target for treating castration resistant prostate cancer: a comprehensive review DOI Creative Commons
Ye Chen, Tian Lan

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Сен. 18, 2024

The incidence rate of prostate cancer (PCa) has risen by 3% per year from 2014 through 2019 in the United States. An estimated 34,700 people will die PCa 2023, corresponding to 95 deaths day. Castration resistant (CRPC) is leading cause among men with PCa. Androgen receptor (AR) plays a critical role development CRPC. N-terminal domain (NTD) essential functional for AR transcriptional activation, which modular activation function-1 (AF-1) important gene regulation and protein interactions. Over last 2 decades drug discovery against NTD attracted interest CRPC treatment. However, an intrinsically disordered without stable three-dimensional structure, so far hampered drugs targeting this highly dynamic structure. Employing high throughput cell-based assays, small-molecule inhibitors exhibit variety unexpected properties, ranging specific binding NTD, blocking transactivation, suppressing oncogenic proliferation, prompts its evaluation clinical trials. Furthermore, molecular dynamics simulations reveal that compounds can induce formation collapsed helical states. Nevertheless, our knowledge structure been limited primary sequence amino acid chain few secondary motif, acting as barrier computational pharmaceutical analysis decipher conformation drug-target interaction. In review, we provide overview on sequence-structure-function relationships including polymorphism mono-amino repeats, elements transcription regulation, modeled tertiary NTD. Moreover, summarize activities therapeutic potential current NTD-targeting outline different experimental methods contributing screening novel compounds. Finally, discuss directions structure-based design breakthroughs exploring pharmacological motifs pockets could contribute new inhibitors.

Язык: Английский

Процитировано

3
Big dynorphin is a neuroprotector scaffold against amyloid β-peptide aggregation and cell toxicity DOI Creative Commons
Lucia Gallego Villarejo,

Cecilia Wallin,

Sylwia Król

и другие.

Computational and Structural Biotechnology Journal, Год журнала: 2022, Номер 20, С. 5672 - 5679

Опубликована: Янв. 1, 2022

Amyloid β-peptide (Aβ) misfolding into β-sheet structures triggers neurotoxicity inducing Alzheimer's disease (AD). Molecules able to reduce or impair Aβ aggregation are highly relevant as possible AD treatments since they should protect against neurotoxicity. We have studied the effects of interaction dynorphins, a family opioid neuropeptides, with Aβ40 most abundant species Aβ. Biophysical measurements indicate that interacts Big Dynorphin (BigDyn), lowering amount hydrophobic aggregates, and slowing down kinetics. As expected, we found BigDyn protects aggregates when in human neuroblastoma cells by cell survival assays. The cross-interaction between provides insight mechanism amyloid pathophysiology may open up new therapy possibilities.

Язык: Английский

Процитировано

11
Strategies for Conditional Regulation of Proteins DOI Creative Commons
Karthik Nadendla, Grant G. Simpson, Julie Becher

и другие.

JACS Au, Год журнала: 2023, Номер 3(2), С. 344 - 357

Опубликована: Янв. 26, 2023

Design of the next-generation therapeutics, biosensors, and molecular tools for basic research requires that we bring protein activity under control. Each has unique properties, therefore, it is critical to tailor current techniques develop new regulatory methods regulate proteins interest (POIs). This perspective gives an overview widely used stimuli synthetic natural conditional regulation proteins.

Язык: Английский

Процитировано

6