Structural basis for the conformational protection of nitrogenase from O2

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Language: Английский

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Evaluation of Structure Prediction and Molecular Docking Tools for Therapeutic Peptides in Clinical Use and Trials Targeting Coronary Artery Disease

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(2), P. 462 - 462

Published: Jan. 8, 2025

This study evaluates the performance of various structure prediction tools and molecular docking platforms for therapeutic peptides targeting coronary artery disease (CAD). Structure tools, including AlphaFold 3, I-TASSER 5.1, PEP-FOLD 4, were employed to generate accurate peptide conformations. These methods, ranging from deep-learning-based (AlphaFold) template-based (I-TASSER 5.1) fragment-based (PEP-FOLD), selected their proven capabilities in predicting reliable structures. Molecular was conducted using four (HADDOCK 2.4, HPEPDOCK 2.0, ClusPro HawDock 2.0) assess binding affinities interactions. A 100 ns dynamics (MD) simulation performed evaluate stability peptide–receptor complexes, along with Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) calculations determine free energies. The results demonstrated that Apelin, a peptide, exhibited superior across all platforms, making it promising candidate CAD therapy. Apelin’s interactions key receptors involved cardiovascular health notably stronger more stable compared other tested. findings underscore importance integrating advanced computational design evaluation, offering valuable insights future applications CAD. Future work should focus on vivo validation combination therapies fully explore clinical potential these peptides.

Language: Английский

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Toward the Prediction of Binding Events in Very Flexible, Allosteric, Multidomain Proteins

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 5, 2025

Knowledge of the structures formed by proteins and small molecules is key to understand molecular principles chemotherapy for designing new more effective drugs. During early stage a drug discovery program, it customary predict ligand-protein complexes in silico, particularly when screening large compound databases. While virtual based on docking widely used this purpose, generally fails mimicking binding events associated with conformational changes protein, latter involve multiple domains. In work, we describe methodology generate bound-like conformations very flexible allosteric bearing sites exploiting only information unbound structure putative sites. The protocol validated paradigm enzyme adenylate kinase, which generated significant fraction structures. A these conformations, employed ensemble-docking calculations, allowed find native-like poses substrates inhibitors (binding active form enzyme), as well catalytically incompetent analogs inactive form). Our provides general framework generation challenging targets that are suitable host different ligands, demonstrating high sensitivity fine chemical details regulate protein's activity. We foresee applications screening, prediction impact amino acid mutations dynamics, protein engineering.

Language: Английский

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In silico antiviral effect assessment of some venom gland peptides from Odontobuthus doriae scorpion against SARS-CoV-2

Toxicon, Journal Year: 2025, Volume and Issue: unknown, P. 108229 - 108229

Published: Jan. 1, 2025

Language: Английский

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Antidiabetic Effects of Quercetin and Silk Sericin in Attenuating Dysregulation of Hepatic Gluconeogenesis in Diabetic Rats Through Potential Modulation of PI3K/Akt/FOXO1 Signaling: In Vivo and In Silico Studies

Journal of Xenobiotics, Journal Year: 2025, Volume and Issue: 15(1), P. 16 - 16

Published: Jan. 19, 2025

Type 2 diabetes mellitus (T2DM) is an intricate disease correlated with many metabolic deregulations, including disordered glucose metabolism, oxidative stress, inflammation, and cellular apoptosis due to hepatic gluconeogenesis aberrations. However, there no radical therapy inhibit disturbances yet. We thus sought probe the effectiveness uncover potential mechanism of quercetin (QCT) silk sericin (SS) in mitigating hyperglycemia-induced disorder, which remains obscure. Administration QCT SS diabetic male albino rats markedly restored levels glucose, insulin, advanced glycation end-products (AGEs), liver function enzymes, alpha-fetoprotein (AFP), globulin, glycogen, addition carbohydrate metabolizing enzymes comparison rats. Furthermore, treatment modulated malondialdehyde (MD), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), peroxidase (GPx), nitric oxide, tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), serum interleukin-6 (IL-6) cyclooxygenase-2 (COX-2), implying their safeguarding cells against impairment inflammation. Remarkably, treatments led upregulation expression phosphatidylinositol 3-kinases (PI3K), phospho-Akt (p-Akt), forkhead box-O1 (FOXO1) genes tissues compared rats, orchestrating these singling pathways for curtailing hyperglycemia pernicious consequences tissues. Importantly, immunohistochemical investigations exhibited downregulation caspase-3 treated animals. Beyond that, histopathological results demonstrated notable correlations biochemical findings. Interestingly, silico supported vivo findings, showing binding affinities PI3K, GPx, TNF-α proteins. These imply that could mitigate stress inflammation regulate revealed greater molecular interactions studied proteins than SS. Overall, our emphasize have significant therapeutic effects on attenuating gluconeogenesis, superior effectiveness.

Language: Английский

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Aedes aegypti midgut chymotrypsin has no significant role in blood meal protein digestion or fecundity

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

The Aedes aegypti mosquito is a vector of dengue, Zika, and chikungunya. mosquito's reliance on blood facilitates the transmission these viral pathogens to humans. Digestion proteins depends biphasic expression serine proteases, with trypsin-like activity contributing most in midgut. Other proteases found (serine collagenase- chymotrypsin-like) are thought contribute digestion, but their roles largely understudied. Thus, elucidating specific all midgut will help understand complexity digestion process validate them as potential targets for development new control strategy. Herein, we focused characterizing profile role Ae. chymotrypsin (AaCHYMO). Knockdown studies resulted elimination significant reduction chymotrypsin-like fed extracts, while vitro fluorescent protein assays revealed important substrate specificity differences. Interestingly, knockdown AaCHYMO did not impact fecundity, indicating presence an intricate network working collectively degrade proteins. Further, ecdysone receptor (EcR) led decrease overall mosquito, which may play regulatory role.

Language: Английский

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DDX50 cooperates with STAU1 to effect stabilization of pro-differentiation RNAs

Cell Reports, Journal Year: 2025, Volume and Issue: 44(1), P. 115174 - 115174

Published: Jan. 1, 2025

Highlights•Glucose binds directly to the ATP-binding site of DDX50 and dissociates dimers•DDX50 monomers compete with UPF1 for binding STAU1•DDX50 STAU1 modulate RNA structure pro-differentiation genes•DDX50 cooperates stabilize RNAsSummaryGlucose can alter protein oligomerization enable differentiation. Here, we demonstrate that glucose is a general capacity DExD/H-box helicases, including DDX50, which was found be essential differentiation diverse cell types. Glucose conserved ATP sequences altered conformation dissociated dimers. bound redirect from an RNA-decay-promoting complex DDX50-STAU1 ribonuclear complex. stabilized common set RNAs, JUN, OVOL1, CEBPB, PRDM1, TINCR, whose structures they also modified. These findings uncover DDX50-mediated mechanism reprograming its canonical role in Staufen-mediated mRNA decay opposite stabilizing RNAs establish activity controlling stability.Graphical abstract

Language: Английский

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Plasticity of BioPhi-Driven Humanness Optimization in ScFv-CD99 Binding Affinity Validated Through AlphaFold, HADDOCK, and MD Simulations

Computational and Structural Biotechnology Journal, Journal Year: 2025, Volume and Issue: 27, P. 369 - 382

Published: Jan. 1, 2025

BioPhi-guided humanization was utilized to enhance the humanness of a humanized single-chain variable fragment targeting CD99, leading development two variants: HuScFvMT99/3BP and HuScFvMT99/3HY. The variant incorporated framework region modifications, modest improvements in humanness, particularly VH domain, although VL domain remained suboptimal. To address this limitation, HuScFvMT99/3HY designed by combining wild-type with HuScFvMT99/3BP. Molecular dynamics simulations employing AlphaFold2, AlphaFold3, HADDOCK were performed evaluate HuScFv-CD99 peptide complexes. AF2-based demonstrated enhanced binding free energy (ΔGbinding) for both variants compared HuScFvMT99/3WT. However, ΔGbinding values obtained from AF3 HD inconsistent, exhibiting weakest affinity. While patterns derived AlphaFold3 aligned, amino acid decomposition analysis revealed variations interaction coordinates predicted Root-mean-square deviation indicated improved structural stability (0.975 Å) (1.075 relative HuScFvMT99/3WT (1.225 Å). Biolayer interferometry further confirmed that exhibited highest affinity (KD = 1.35 × 10⁻⁷ M) 2.64 3.95 M). Supporting evidence provided ELISA flow cytometry experiments. PITHA high immunogenicity risk all variants, despite displaying larger complementarity-determining (CDR) cavity, more hydrophobic CDR-H3 loop. These findings highlight delicate balance between enhancing preserving functional integrity critical therapeutic antibody development.

Language: Английский

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Nuclear adenine activates hnRNPA2B1 to enhance antibacterial innate immunity

Cell Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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G-quadruplex-forming small RNA inhibits coronavirus and influenza A virus replication

Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)

Published: Jan. 15, 2025

Future pandemic threats may be caused by novel coronaviruses and influenza A viruses. Here we show that when directly added to a cell culture, 12mer guanine RNA (G12) its phosphorothioate-linked derivatives (G12(S)), rapidly entered cytoplasm suppressed the propagation of human viruses between 1/100 nearly 1/1000 normal virus infectivity without cellular toxicity induction innate immunity. Moreover, G12(S) alleviated weight loss coronavirus infection in mice. might exhibit stable G-tetrad with left-handed parallel-stranded G-quadruplex, inhibit replication process impeding interaction viral nucleoproteins cytoplasm. Unlike previous antiviral strategies target G-quadruplexes genome, now excess exogenous G-quadruplex-forming small displaces genomic from ribonucleoprotein, effectively inhibiting replication. The approach has potential facilitate creation versatile middle-molecule antivirals featuring lipid nanoparticle-free delivery. Phosphorothioate-linked guanosine inhibits nucleoprotein cytoplasm, suppressing proliferation have cause future pandemics.

Language: Английский

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