Recent Advances and Future Challenges in Predictive Modelling of Metalloproteins by Artificial Intelligence

Molecules and Cells, Год журнала: 2025, Номер unknown, С. 100191 - 100191

Опубликована: Фев. 1, 2025

Metal coordination is essential for structural/catalytic functions of metalloproteins that mediate a wide range biological processes in living organisms. Advances bioinformatics have significantly enhanced our understanding metal-binding sites and their functional roles metalloproteins. State-of-the-art computational models developed seamlessly integrate protein sequence structural data to unravel the complexities metal environments. Our goal this mini-review give an overview these tools highlight current challenges (predicting dynamic sites, determining metalation states, designing intricate networks) remaining predictive sites. Addressing will not only deepen knowledge natural but also accelerate development artificial with novel precisely engineered functionalities.

Язык: Английский

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Zn(II) Affinity and Structural Conformations of 2His‐2Cys Zinc Finger‐Like Motif Peptide Determined by Ion Mobility–Mass Spectrometry and PM6 Molecular Modeling

Journal of Mass Spectrometry, Год журнала: 2025, Номер 60(3)

Опубликована: Фев. 14, 2025

ABSTRACT This study focuses on investigating the conformational structure and zinc(II) affinity of a zinc finger‐like motif (ZFM) peptide with sequence acetyl‐ His 1 ‐Cys 2 ‐Gly 3 ‐Pro 4 5 ‐ 6 7 , where bold highlights potential binding sites. Zinc fingers are crucial protein motifs known for their high specificity ions. The ZFM peptide's contains 2His‐2Cys zinc‐binding sites similar to those in natural finger proteins but without hydrophobic core, making it valuable model studying zinc(II)–peptide interactions. Previous research related peptides showed that collision cross sections B3LYP modeling predicted His‐2Cys‐carboxyl terminus coordination was more stable than 2His‐2Cys. Employing comprehensive approach integrating ion mobility–mass spectrometry theoretical techniques, various modes have been thoroughly compared ascertain influence competitive threshold collision‐induced dissociation method measuring relative gas‐phase Zn(II) peptide. measured is greater recently two primary structures, Cys Asp indicating preference ‐His side groups coordinating over or Asp‐His‐Cys‐carboxyl these heptapeptides.

Язык: Английский

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PinMyMetal: a hybrid learning system to accurately model transition metal binding sites in macromolecules

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 28, 2025

Metal ions are vital components in many proteins for the inference and engineering of protein function, with coordination complexity linked to structural, catalytic, or regulatory roles. Modeling transition metal ions, especially transient, reversible, concentration-dependent sites, remains challenging. We present PinMyMetal (PMM), a hybrid machine learning system designed accurately predict localization environment macromolecules, tailored tetrahedral octahedral geometries. PMM outperforms other predictors, achieving high accuracy ligand coordinate predictions. It excels predicting sites (median deviation 0.36 Å), demonstrating superior locating catalytic (0.33 Å) structural (0.19 Å). Each predicted site is assigned certainty score based on local physicochemical features, independent homologs. Interactive validation through our server, CheckMyMetal, expands PMM's scope, enabling it pinpoint validate diverse functional from different structure sources (predicted structures, cryo-EM, crystallography). This facilitates residue-wise assessment robust binding design. The lightweight demands minimal computing resources available at https://PMM.biocloud.top . workflow can interrogate sequence characterize most probable metals, which often interchangeable hard differentiate by nature.

Язык: Английский

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Brief analysis of Nav1.7 inhibitors: Mechanism of action and new research trends

Bioorganic & Medicinal Chemistry, Год журнала: 2025, Номер unknown, С. 118180 - 118180

Опубликована: Апрель 1, 2025

Язык: Английский

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Polysulfido Chain in Binuclear Zinc(II) Complexes

Inorganic Chemistry, Год журнала: 2022, Номер 61(16), С. 6295 - 6310

Опубликована: Апрель 13, 2022

The synthesis and a detailed reactivity study of binuclear zinc(II) bis(benzenethiolate) complex, [Zn2(BPMP)(SPh)2]+ (4), an unprecedented pentasulfido [Zn2(BPMP)(μ2-S5)]+ (6), are presented. While one-electron oxidation the coordinated benzenethiolate ligands in 4 by Cp2Fe+ produces diphenyl disulfide [Zn2(BPMP)(μ2-OH)]2+ (5), two-electron redox reaction between elemental S (S8) generated complex 6. Complex 6 features chelating, dianionic, (S52-) chain can consume up to maximum 3 equiv PPh3 generate Ph3PS 5, while with 1 diphenylphosphinoethane allowed isolation [Zn2(BPMP)(μ2-S4)]+ (7). A proteolysis S52- fluoroboric acid (HBF4), benzoic (PhCOOH), thioacetic (MeCOSH) generates complexes [Zn2(BPMP)(MeCN)2]3+ (1), [Zn2(BPMP)(μ2-PhCOO)2]+ (8), [Zn2(BPMP)(μ2-SCOMe)2]+ (9), respectively, protonated liberates S8 hydrogen sulfide (H2S). Finally, transfer selected organic compounds, namely, PhCH2Br PhC(O)Cl, for generation various organosulfur compounds is demonstrated.

Язык: Английский

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The zinc proteome of SARS-CoV-2

Metallomics, Год журнала: 2022, Номер 14(7)

Опубликована: Янв. 1, 2022

Abstract Zinc is an essential element for human health. Among its many functions, zinc(II) modulates the immune response to infections and, at high concentrations or in presence of ionophores, inhibits replication various RNA viruses. Structural biology studies on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) revealed that most common metal ion binds viral proteins. However, number zinc(II)-binding sites identified by experimental methods far from exhaustive, as ions may be lost during protein purification protocols. To better define proteome coronavirus, we leveraged wealth deposited structural data and state-of-the-art bioinformatics methods. Through this silico approach, 15 were a further 22 predicted Spike, open reading frame (ORF)3a/d, ORF8, several nonstructural proteins, highlighting role replication. Furthermore, relationships between eukaryotic (typically zinc fingers) indicate SARS-CoV-2 can compete with proteins binding. Given double-edged effect ions, both toxic only complete elucidation regulatory guide selective antiviral strategies based supplementation.

Язык: Английский

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Mining proteomes for zinc finger persulfidation

RSC Chemical Biology, Год журнала: 2024, Номер 5(6), С. 572 - 585

Опубликована: Янв. 1, 2024

A meta-analysis of 22 persulfide-specific proteomics datasets reveals widespread persulfidation zinc finger proteins across various species, highlighting the role as an important post-translational modification.

Язык: Английский

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Formation of highly stable multinuclear Ag_nS_nclusters in zinc fingers disrupts their structure and function

Chemical Communications, Год журнала: 2020, Номер 56(9), С. 1329 - 1332

Опубликована: Янв. 1, 2020

Silver (Ag(i)) binding to consensus zinc fingers (ZFs) causes Zn(ii) release inducing a gradual disruption of the hydrophobic core, followed by an overall conformational change and formation highly stable Ag_nS_nclusters.

Язык: Английский

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From methodological limitations to the function of metallothioneins - a guide to approaches for determining weak, moderate, and tight affinity zinc sites

Metallomics, Год журнала: 2023, Номер 15(5)

Опубликована: Апрель 27, 2023

Abstract Mammalian metallothioneins (MTs) are small cysteine-rich proteins whose primary role is participation in zinc and copper homeostasis. Ever since their discovery, MTs have been investigated terms of metal-binding affinity. The initial concept seven Zn(II) ions (Zn7MT) bound with the same, undifferentiated low-picomolar affinity α β domains prevailed for many years derived from spectroscopic studies. application fluorescent probes has changed perception MTs, showing that they function nanomolar to subnanomolar free concentrations due presence tight, moderate, weak binding sites. discovery Zn(II)-depleted tissues determination cellular differentiated sites revealed critical importance partially saturated Zn4–6MTs species buffering a wide picomolar range concentrations. Until today, there was no clear agreement on or only tight Here, we present series spectroscopic, mass spectrometry-based, enzymatic competition experiments reveal how weak, high-affinity ligands interact human MT2, special attention affinities. results show simplification stability model major reason determining significantly different data obscured actual function. Therefore, emphasize metal affinities single most important presumed function, which over and, thus, storage one highly dynamic.

Язык: Английский

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Differentiated Zn(II) binding affinities in animal, plant, and bacterial metallothioneins define their zinc buffering capacity at physiological pZn

Metallomics, Год журнала: 2023, Номер 15(10)

Опубликована: Окт. 1, 2023

Abstract Metallothioneins (MTs) are small, Cys-rich proteins present in various but not all organisms, from bacteria to humans. They participate zinc and copper metabolism, toxic metals detoxification, protection against reactive species. Structurally, they contain one or multiple domains, capable of binding a variable number metal ions. For experimental convenience, biochemical characterization MTs is mainly performed on Cd(II)-loaded proteins, frequently omitting limiting Zn(II) features related functions. Here, by choosing 10 with relatively well-characterized structures animals, plants, bacteria, we focused poorly investigated Zn(II)-to-protein affinities, stability–structure relations, the speciation individual complexes. that purpose, were characterized terms stoichiometry, pH-dependent binding, competition chromogenic fluorescent probes. To shed more light protein folding its relation affinity, reactivity variously Zn(II)-loaded was studied (5,5ʹ-dithiobis(2-nitrobenzoic acid) oxidation presence mild chelators. The results show animal plant MTs, despite their architectural differences, demonstrate same affinities Zn(II), varying nano- low picomolar range. Bacterial bind tightly but, importantly, different femtomolar weak, moderate, tight sites mechanisms internal electrostatic interactions. Differentiated define buffering capacity required for donation acceptance at free concentrations (pZn levels). data critical roles Zn(II)-depleted MT species processes.

Язык: Английский

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