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PubMed2025

Unveiling novel antimicrobial peptides from the ruminant gastrointestinal microbiomes: A deep learning-driven approach yields an anti-MRSA candidate.

INTRODUCTION: Antimicrobial peptides (AMPs) present a promising avenue to combat the growing threat of antibiotic resistance. The ruminant gastrointestinal microbiome serves as a unique ecosystem that offers untapped potential for AMP discovery. OBJECTIVES: The aims of this study are to develop an effective methodology for the identification of novel AMPs from ruminant gastrointestinal microbiomes, followed by evaluating their antimicrobial efficacy and elucidating the mechanisms underlying their activity. METHODS: We developed a deep learning-based model to identify AMP candidates from a dataset comprising 120 metagenomes and 10,373 metagenome-assembled genomes derived from the ruminant gastrointestinal tract. Both in vivo and in vitro experiments were performed to examine and validate the antimicrobial activities of the AMP candidates that were selected through bioinformatic analysis and subsequently synthesized chemically. Additionally, molecular dynamics simulations were conducted to explore the action mechanism of the most potent AMP candidate. RESULTS: The deep learning model identified 27,192 potential secretory AMP candidates. Following bioinformatic analysis, 39 candidates were synthesized and tested. Remarkably, all synthesized peptides demonstrated antimicrobial activity against Staphylococcus aureus, with 79.5% showing effectiveness against multiple pathogens. Notably, Peptide 4, which exhibited the highest antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), confirmed this effect in a mouse model with wound infection, exhibiting a low propensity for resistance development and minimal cytotoxicity and hemolysis towards mammalian cells. Molecular dynamics simulations provided insights into the mechanism of Peptide 4, primarily its ability to disrupt bacterial cell membranes, leading to cell death. CONCLUSION: This study highlights the power of combining deep learning with microbiome research to uncover novel therapeutic candidates, paving the way for the development of next-generation antimicrobials like Peptide 4 to combat the growing threat of MRSA would infections. It also underscores the value of utilizing ruminant microbial resources.

Animals↗

PubMed2026

Activity of natural single nucleotide variants of human alkyladenine DNA glycosylase AAG R145H, G163S and R197C involved in DNA binding.

Alkyladenine DNA glycosylase (AAG) is a critical enzyme in the base excision repair (BER) pathway that safeguards genome integrity by removing structurally diverse alkylated and deaminated purine lesions from DNA. It serves as a primary defense against alkylation-induced mutations, which are linked to cancer development, chronic inflammation, and neurodegenerative diseases. Single nucleotide variants (SNVs) in the gene coding region have the potential to alter the enzyme's functionality, potentially modulating the repair capacity and affecting response and prognosis following chemoradiotherapy. In our study, we investigated three SNVs that lead to amino acid class changes in regions involved in DNA substrate coordination: R145H, G163S, and R197C using an in vitro approach. Using biochemical assays and molecular dynamics simulations, we evaluated the thermal stability, DNA binding affinity, and glycosylase activity of AAG variants toward hypoxanthine (Hx) and 1,N6-ethenoadenosine (εA) containing substrates. The G163S variant showed reduced thermal stability due to the conformational strain in the β-hairpin loop that intercalates in DNA, but retained εA excision activity comparable to that of wild-type AAG, while losing activity against Hx-containing DNA. The R197C variant had a four-fold reduction in DNA binding affinity for both substrates, and was catalytically inactive, unable to excise either damaged bases. This loss of function correlated with the rearrangement of the 201-210 loop and the reorientation of Arg-201 and Arg-207, which disrupts critical DNA contacts. However, the R145H variant retained near-wild-type thermal stability and activity on both substrates, despite bioinformatic predictions of deleterious effect. Molecular dynamics simulations revealed variant-specific structural disruptions. The data obtained underscore the importance of experimental validation in assessing the functional impact SNVs.

DNA Glycosylases↗

PubMed2026

Targeting EGFR in cancer using Terminalia arjuna: An integrated In Silico, molecular dynamics, experimental validation, and network pharmacology study.

The Epidermal Growth Factor Receptor (EGFR) plays a pivotal role in 20-60% of cancer cases, including glioblastoma, lung adenocarcinoma, and head and neck squamous cell carcinoma, as reported in The Cancer Genome Atlas (TCGA) dataset. The present study employed an integrated in silico and experimental workflow to evaluate EGFR-targeted compounds from Terminalia arjuna. Drug-likeness and ADMET screening were performed, followed by molecular docking and 1000 ns molecular dynamics simulations. In vitro validation was conducted using cancer cell-based assays and network pharmacology to explore the molecular mechanisms associated with the identified compound. Screening shortlisted eight compounds from T. arjuna. Molecular docking identified Arjunaside C (-8.2 kcal/mol), Arjunapthanoloside (-7.7 kcal/mol), and Beta-sitosterol (-7.4 kcal/mol) as potential EGFR inhibitors compared to Erlotinib (-6.6 kcal/mol). Arjunapthanoloside formed more H-bonds and exhibited most stable interactions with EGFR. MD simulations at 1000 ns revealed lower RMSD, RMSF, SASA, and Rg values for the Arjunapthanoloside-EGFR complex, indicating enhanced stability. Direct binding validation was limited by the unavailability of purified Arjunapthanoloside; therefore, Arjuna extract was evaluated, which demonstrated potent cytotoxicity with an IC₅₀ of 9 µg/mL in H357 oral cancer cells. Flow cytometry confirmed apoptosis-mediated cell death by increased early- and late-apoptotic cell populations. Network pharmacology analysis further identified additional targets (MMP3, MMP7, MMP9, and HRAS) that are directly involved in various cancers. Overall, the findings provide new insights into the therapeutic potential of Arjunapthanoloside as a stable compound that interacts with EGFR from T. arjuna, highlighting its significance in EGFR-targeted anticancer research.

ErbB Receptors↗

PubMed2026

Matrine Alleviates Sepsis-Induced Acute Lung Injury by Reinforcing NQO1/SLC7A11/GPX4-Associated Anti-Ferroptotic Defenses and Attenuating NF-κB-Driven Inflammation.

BACKGROUND: Sepsis triggers dysregulated systemic inflammation and multiple-organ dysfunction, with the lungs being particularly susceptible to injury. Sepsis-induced acute respiratory distress syndrome (ARDS) is mainly driven by TLR4/NF-κB-mediated hyperinflammation and alveolar macrophage activation. Matrine, a bioactive alkaloid derived from Sophora flavescens, has been reported to modulate redox homeostasis and ferroptosis-associated lipid peroxidation. However, the target-specific mechanisms underlying its effects on ferroptosis and inflammatory signaling in sepsis-induced acute lung injury (SALI) remain incompletely understood. PURPOSE: This study aimed to evaluate the therapeutic effects of matrine in a cecal ligation and puncture (CLP)-induced SALI model and to determine whether its protective effects involve reinforcement of NQO1/SLC7A11/GPX4-associated anti-ferroptotic defenses and suppression of NF-κB-driven inflammation. METHODS: We analyzed the single-cell RNA-sequencing (scRNA-seq) dataset GSE273924 to characterize CD45-enriched pulmonary immune-cell subsets in sham mice and mice with intratracheal Escherichia coli-induced pneumonia. Network pharmacology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to predict Kushen (KS)-related targets and pathways associated with SALI. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) of GSE245013 were used to identify candidate targets. Matrine-NQO1 binding and intracellular target engagement were evaluated using molecular docking, molecular dynamics simulations, surface plasmon resonance (SPR), and the cellular thermal shift assay (CETSA). The therapeutic effects of matrine were assessed in mice with CLP-induced SALI and in lipopolysaccharide (LPS)-stimulated MH-S cells. Lung histopathology, inflammatory cytokine production, target protein expression, ferroptosis-associated indicators, and NF-κB activation were evaluated using molecular, biochemical, and histological assays. The functional contribution of NQO1 was further examined using the NQO1 inhibitor ES936. RESULTS: scRNA-seq analysis of GSE273924 revealed substantial remodeling of the CD45-enriched pulmonary immune-cell landscape in mice with intratracheal E. coli-induced pneumonia, including macrophage transcriptional programs associated with ferroptosis and inflammatory signaling. Integrated network pharmacology and bioinformatics analyses prioritized NQO1 as a candidate target of matrine and identified NF-κB signaling as a potentially relevant pathway. Molecular docking, molecular dynamics simulations, SPR, and CETSA supported matrine-NQO1 binding and intracellular target engagement. Functionally, matrine improved survival, attenuated lung injury, reinforced NQO1/SLC7A11/GPX4-associated anti-ferroptotic defenses, and suppressed NF-κB activation in CLP mice. Similar protective effects were observed in LPS-stimulated MH-S cells. ES936 partially attenuated the matrine-mediated improvements in cell viability, redox homeostasis, ferroptosis-associated indicators, and NF-κB p65 phosphorylation, supporting a functional contribution of NQO1 to the protective effects of matrine. CONCLUSION: Matrine alleviates SALI by reinforcing NQO1/SLC7A11/GPX4-associated anti-ferroptotic defenses and attenuating NF-κB-driven inflammation.

Animals↗

PubMed2026

Integrative computational analysis combining network pharmacology, regulatory network modeling, and molecular dynamics reveals the mechanisms of Quanshen compound in ITP.

UNLABELLED: Immune thrombocytopenia (ITP) is a hemorrhagic disorder caused by immune dysfunction. Quanshen Compound (QSC) is an in-house preparation developed by the Uyghur Hospital in Hotan Prefecture. This study primarily investigates and validates the potential pharmacological basis and mechanism of action of QSC in modulating immune thrombopoiesis. Based on the multi-database screening of the QSC and the related targets of ITP, the intersection was obtained to construct a protein-protein interaction (PPI) network and screen the core targets; the intersection targets were analyzed for gene ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using R packages; a component-target-pathway network was constructed to screen the key active components and their mechanisms of action. At the same time, the TF-mRNA-miRNA regulatory network of the core targets was constructed, and chromosome localization and subcellular localization analysis were performed; further, the binding stability of key components and core targets was verified through molecular docking and molecular dynamics simulation. A total of 227 potential target sites were screened out, among which TNF, IL6, AKT1, TP53 and IL1B were the core targets. The enrichment results indicated that these intersecting target sites mainly participated in inflammatory responses, immune regulation and hemostasis-related biological processes, and were significantly enriched in the PI3K-Akt signaling pathway, Toll-like receptor signaling pathway, Th17 cell differentiation and PD-1/PD-L1 signaling pathway. The core target TF-mRNA-miRNA regulatory network contained 184 nodes and 200 edges, suggesting that the core targets were subject to multi-level regulation. Molecular docking results showed that the main active components had good binding activity with the core targets, and molecular dynamics simulation further verified the stability of the complex. QSC may improve ITP through a multi-component, multi-target, and multi-pathway synergistic mechanism involving key targets such as TNF, IL6, AKT1, TP53, and IL1B, as well as the PI3K-Akt signaling pathway. These findings provide new insights into the potential therapeutic mechanisms of QSC against ITP and warrant further experimental validation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00718-0.

Immune thrombocytopenia↗

PubMed2026

Integrated dual transcriptome sequencing and experimental validation reveal potential mechanisms of baicalin against pneumocystis pneumonia in immunosuppressed rats.

BACKGROUND: Pneumocystis pneumonia (PCP) remains a major cause of morbidity and mortality in immunocompromised individuals. Although baicalin (Ba), a natural bioactive flavonoid, has demonstrated protective and therapeutic effects against PCP, its molecular mechanisms remain undefined. We employed dual RNA sequencing (dual RNA-seq) to characterize host and pathogen transcriptional responses to Ba treatment in an immunosuppressed rat model of PCP. METHODS: Comparative transcriptomic analyses identified differentially expressed genes in both the host and Pneumocystis, followed by Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment analyses. Candidate targets were further investigated using network pharmacology, protein-protein interaction analysis, molecular docking, and molecular dynamics simulations. Key findings were validated by immunohistochemistry, enzyme-linked immunosorbent assay, and quantitative PCR. RESULTS: Ba markedly remodeled host and pathogen transcriptomes. Host transcriptomic analyses showed that Ba attenuated inflammatory and oxidative stress responses by modulating immune-related pathways, including Toll-like receptor, NF-κB, cytokine-cytokine receptor interaction, chemokine signaling, Th17 cell differentiation, and antigen processing and presentation. Experimental validation demonstrated that Ba reduced pulmonary expression of indoleamine 2,3-dioxygenase 1 (IDO1), Toll-like receptor 2 (TLR2), and TLR4 while increasing nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant enzyme heme oxygenase-1 (HO-1). Pathogen transcriptomic analysis identified Pneumocystis Rtt109 (PcRtt109), a fungal histone acetyltransferase, as a potential pathogen-specific target that was significantly downregulated after Ba treatment. Molecular docking and molecular dynamics simulations supported stable interactions between Ba and IDO1, Nrf2, TLR2, TLR4, and PcRtt109, with the strongest predicted binding observed for PcRtt109. CONCLUSION: Dual RNA-seq revealed that Ba exerts anti-PCP activity through coordinated modulation of host and pathogen molecular networks. Its therapeutic effects are associated with suppression of inflammatory signaling, enhancement of antioxidant defenses, and inhibition of a fungal virulence-associated target. These findings provide mechanistic insights into host-pathogen interactions during PCP and support Ba as a potential therapeutic candidate for PCP.

Nrf2↗

PubMed2026

Integrated computational and experimental benchmarking of Bacillus phage endolysins reveals the relationship between peptidoglycan-fragment recognition descriptors and antibacterial performance.

Protein-based antibacterials such as bacteriophage endolysins offer a targeted therapeutic strategy against Gram-positive pathogens. However, prioritizing the most effective candidates from the large sequence diversity available remains a significant challenge. Here we present a standardized computational-experimental benchmarking framework that evaluates seven phage-derived endolysin variants (E1, E2, E3, E7, E10, E12, and E15) identified from Bacillus genomes. We combined molecular docking and residue-level interaction mapping against muramyl dipeptide (MDP), a minimal conserved peptidoglycan motif, with 1000-ns molecular dynamics simulations, MM/PBSA binding free-energy estimation, and matched functional inhibition assays against Staphylococcus aureus and Micrococcus luteus. Computational analyses revealed generally favorable MDP recognition across variants, albeit with notable differences in contact patterns and complex stability profiles. Experimental screening identified E2 as the most potent antibacterial agent against both species, while E7 and E1 performed strongly in selected computational metrics. Integrated analysis showed only modest correlations between computational descriptors of fragment recognition/stability and observed antibacterial performance. This study establishes a practical comparative benchmarking platform for endolysin candidate prioritization, nominates E2 and E7 as promising candidates for further development, and highlights E1 as a potential structural scaffold for rational engineering, while explicitly demonstrating both the utility and the current limitations of using minimal peptidoglycan fragments as proxies for full cell-wall recognition in lysin benchmarking.

Endopeptidases↗

PubMed2024

Regulating IL-2 Immune Signaling Function Via A Core Allosteric Structural Network.

Human interleukin-2 (IL-2) is a crucial cytokine for T cell regulation, with therapeutic potential in cancer and autoimmune diseases. However, IL-2's pleiotropic effects across different immune cell types often lead to toxicity and limited efficacy. Previous efforts to enhance IL-2's therapeutic profile have focused on modifying its receptor binding sites. Yet, the underlying dynamics and intramolecular networks contributing to IL-2 receptor recognition remain unexplored. This study presents a detailed characterization of IL-2 dynamics compared to two engineered IL-2 mutants, "superkines" S15 and S1, which exhibit biased signaling towards effector T cells. Using NMR spectroscopy and molecular dynamics simulations, we demonstrate significant variations in core dynamic pathways and conformational exchange rates across these three IL-2 variants. We identify distinct allosteric networks and minor state conformations in the superkines, despite their structural similarity to wild-type IL-2. Furthermore, we rationally design a mutation (L56A) in the S1 superkine's core network, which partially reverts its dynamics, receptor binding affinity, and T cell signaling behavior towards that of wild-type IL-2. Our results reveal that IL-2 superkine core dynamics play a critical role in their enhanced receptor binding and function, suggesting that modulating IL-2 dynamics and core allostery represents an untapped approach for designing immunotherapies with improved immune cell selectivity profiles.

Interleukin-2↗

PubMed2026

Anti-inflammatory activity of an IL-6 missense variant against crystal-induced inflammatory response.

Interleukin-6 (IL-6) has an important modulator effect on inflammation and immunity and is involved in the progression of nephrolithiasis (kidney stone). However, whether IL-6 genetic variants affect the pathogenesis of kidney stones remains unclear. The present study conducted a combined investigation of candidate gene-driven screening and systematic screening on whole exome sequencing data from 28 patients of calcium oxalate stones, identifying a non-synonymous single nucleotide polymorphism (SNP) rs13306435 in IL-6 as a candidate research locus, which was further validated using HRM genotyping in an expanded cohort comprising 241 cases and 229 healthy subjects. Western blotting and qRT-PCR were used to assess the effects of this variant on crystal-induced inflammation, while molecular dynamics simulation was employed to analyze structural alterations in the receptor binding complex. In individuals aged ≤40 years, the A allele of rs13306435 was nominally associated with a reduced risk of stone formation, but no association was observed for the whole population. This missense variant causes an aspartate-to-glutamate substitution (D/E), inhibiting calcium oxalate monohydrate (COM)-triggered JAK2/STAT3 activation and inflammatory responses. However, it decreased the binding energy of IL-6/IL-6R/gp130 complex by increasing hydrogen bonds and salt brigdge at remote interfaces, suggesting that enhanced receptor binding does not necessarily translate to increased downstream signaling. Although this variant is not associated with general stone susceptibility, it exhibits notable anti-inflammatory activity by attenuating COM-induced JAK2/STAT3 activation and may influence the progression of stones through this pathway. These findings provide new insights into the role of anti-inflammatory mechanisms in nephrolithiasis.

Humans↗

PubMed2025

Structure-activity relationships study on inhibition of CRISPR-Cas9 by glycosaminoglycans.

The CRISPR-Cas9 system is a revolutionary genome editing system known for its precision, simplicity and efficiency, playing a crucial role in gene-editing. It has enabled applications ranging from biomedicine to agriculture. However, the uncontrollable activity of Cas9 has raised significant safety concerns in clinical settings, limiting its broader application. Consequently, regulating CRISPR-Cas9 activity holds substantial promise for enhancing the safety and efficacy of gene-editing technologies. In this study, we demonstrated that sulfated glycosaminoglycans (GAGs) exhibit inhibitory effects of Cas9. Specifically, both chondroitin sulfate (CS) and heparin (HP) can inhibit CRISPR/Cas9 activity, with heparin showing a stronger inhibitory effect that correlates positively with its concentration. Molecular dynamics simulations indicate that sulfated heparin residues might inhibit Cas9 function by binding to essential DNA-binding sites, which are crucial for functional interactions, potentially impairing activity. Additionally, higher molecular weight GAGs exhibit enhanced inhibitory effects under the same sulphation. Notably, the sulfation site also influenced activity. C6-sulfation of chondroitin sulfate is more favorable for Cas9 inhibition, and N-sulfation of heparin enhances its inhibitory effect on Cas9 activity. These findings provide valuable insights into the development of carbohydrate-based inhibitors for CRISPR-Cas9, offering a foundation for further exploration in this field.

CRISPR-Cas Systems↗

PubMed2026

Quantifying the peripheral surface information entropy from conformational ensembles of globular protein-peptide complexes.

Predicting favorable protein-peptide binding events remains a central challenge in biophysics, with continued uncertainty surrounding how nonlocal effects shape the global energy landscape. Here, we introduce peripheral surface information entropy, SΨ, a quantitative measure of the statistical variability in apolar and charged non-interacting surface (NIS) proportions across conformational ensembles. Within the Gibbs free-energy relation ΔG = ΔH - TΔS, SΨ is proposed as a computationally tractable entropic proxy rather than a direct thermodynamic observable or stand-alone estimator of binding affinity. Using energy-directed molecular docking via HADDOCK3 and explicit-solvent molecular dynamics simulations, it is demonstrated that favorable binding partners exhibit emergent, low-entropy N-states (discrete macrostates in NIS state space) indicative of preferential apolar/charged surface configurations. Across dozens of peptides and multiple receptor systems (WW, PDZ, and MDM2 domains), dominant N-states persisted under varied docking parameters and initial conditions. A meta-ensemble of 657 complexes from 36 experiments over 15 years confirmed the presence of dominant NIS modes independent of in silico methodology, suggesting an evolutionary selection pressure toward specific NIS fingerprints. These findings establish SΨ as a thermoinformatic descriptor that encodes favorable binding constraints into unique statistical signatures of the NIS.

Entropy↗

PubMed2025

TENT5C functions as a corepressor in the ligand-bound glucocorticoid receptor and estrogen receptor α complexes.

Terminal nucleotidyltransferase 5C (TENT5C) is a noncanonical poly(A) polymerase that promotes cancer suppression. TENT5C has been proposed to mediate the susceptibility of multiple myeloma to treatment with dexamethasone, a steroid hormone analog that binds to the glucocorticoid receptor (GR). However, the relationship between TENT5C and nuclear receptor (NR) signaling remains unclear. In this study, we investigate the regulatory role of TENT5C in the GR and estrogen receptor α (ERα) ligand complexes. We find that TENT5C acts as a corepressor of both GR and ERα. Molecular dynamics simulations indicate that the third TENT5C LXXLL motif directly interacts with ERα, but not GR. The physical interaction of TENT5C and ERα is supported by co-immunoprecipitation assays. Reporter assays show that mutations to the third TENT5C LXXLL motif disrupt TENT5C-mediated repression of ERα but do not affect the repression of the GR complex. In addition, the disruption of TENT5C poly(A) polymerase activity does not appear to affect TENT5C repression of ERα in the cell lines studied. Taken together, our findings highlight a role of TENT5C as an NR corepressor, differentially modulating GR- and ERα-induced transcriptional activity.

Receptors, Glucocorticoid↗

PubMed2026

How advances in chromosome conformation capture (3C) methods are reshaping our understanding of gene regulation in hematopoiesis.

The three-dimensional organization of the DNA within the nucleus plays a key role in regulating gene expression. Over the past two decades, advances in chromosome conformation capture (3C) technologies, in tandem with other methods, have shown that the genome forms a complex structure at multiple scales. Early studies identified large-scale structures such as chromosome territories, compartments and topologically associating domains (TADs). As the resolution of 3C techniques has improved, it has become possible to identify contacts between regulatory elements in detail and more recently, it has become possible to define intricate structures within cis-regulatory elements. In this chapter, we review the development of 3C-based methodologies and discuss the strengths and limitations of the different approaches. We examine how these technologies have refined our understanding of genome organization and gene regulation. Recent high-resolution studies reveal that chromatin architecture extends beyond classical domain structures to include nanoscale organization. Integration of 3C data with super-resolution imaging and molecular dynamics simulations supports a model in which genome folding is governed by the biophysical properties of chromatin.

Animals↗

PubMed2026

Structural and tissue-specific organisation of endocrine Fgf19 and Fgf21 signalling in rainbow trout.

Endocrine fibroblast growth factors (FGF19 subfamily) play a key role in regulating metabolic homeostasis in vertebrates. However, their functional diversification in salmonids remains poorly understood. In this study, we conducted an integrative characterisation of Fgf19 and Fgf21 signalling in rainbow trout (Oncorhynchus mykiss) by combining phylogenetic, structural and expression analyses. Phylogenetic analyses revealed the conservation of single fgf19 and fgf21 genes, despite the extensive expansion of receptors post-Ss4R (salmonid-specific fourth-round whole genome duplication). Structural modelling and molecular dynamics simulations demonstrated the stable interactions of both ligands to multiple Fgfr isoforms, with receptor-specific energetic profiles and conserved core interaction residues. Tissue expression profiling revealed clear differences from mammalian models, such as predominant hepatic fgf19 expression and the absence of hepatic fgf21 under basal conditions. In addition, there were complex and tissue-dependent distributions of fgfr and klotho transcripts. These findings support a receptor-driven diversification model of endocrine Fgf signalling in salmonids, suggesting enhanced endocrine plasticity associated with the retention of receptors following post-genomic duplication. Taken together, our findings provide new insights into the structural and regulatory organisation of endocrine Fgf signalling, as well as its potential role in metabolic regulation in rainbow trout.

Animals↗

PubMed2026

Cell-body curvature reduces stall frequency to enhance Vibrio cholerae swimming and chemotaxis through hydrogels.

The swimming motility of the bacterial pathogen Vibrio cholerae is a virulence factor that aids in breaching the mucus layer. V. cholerae has a curved cell shape, and previous work demonstrated that loss of curvature decreases infectivity. Here, we investigate the mechanism by which curvature affects single-cell motility. We compared the chemotactic performance of wild-type curved cells and straight mutants. The two exhibit similar swimming properties in liquid and viscous solutions but differ significantly in mucus-mimicking hydrogels, where curved cells demonstrate an 86% increase in chemotactic drift. Trajectory analysis indicates comparable swimming speeds, but straight mutants experience more frequent stalls, reducing total swimming time. Stalls further reduce chemotactic performance by imposing an average reorientation down the chemical gradient, regardless of cell shape. Coarse-grained molecular dynamics simulations corroborate these results across intestinal mucus hydrogel stiffnesses and identify an optimal curvature for movement through hydrogel-like meshes, close to the pathogen's median curvature. These findings highlight cell shape's role in pathogenicity and the need to study bacterial behaviors under conditions more closely mimicking the host environment.

Vibrio cholerae↗

PubMed2025

Design of nanobody targeting SARS-CoV-2 spike glycoprotein using CDR-grafting assisted by molecular simulation and machine learning.

The design of proteins capable effectively binding to specific protein targets is crucial for developing therapies, diagnostics, and vaccine candidates for viral infections. Here, we introduce a complementarity-determining region (CDR) grafting approach for designing nanobodies (Nbs) that target specific epitopes, with the aid of computer simulation and machine learning. As a proof-of-concept, we designed, evaluated, and characterized a high-affinity Nb against the spike protein of SARS-CoV-2, the causative agent of the COVID-19 pandemic. The designed Nb, referred to as Nb Ab.2, was synthesized and displayed high-affinity for both the purified receptor-binding domain protein and to the virus-like particle, demonstrating affinities of 9 nM and 60 nM, respectively, as measured with microscale thermophoresis. Circular dichroism showed the designed protein's structural integrity and its proper folding, whereas molecular dynamics simulations provided insights into the internal dynamics of Nb Ab.2. This study shows that our computational pipeline can be used to efficiently design high-affinity Nbs with diagnostic and prophylactic potential, which can be tailored to tackle different viral targets.

Spike Glycoprotein, Coronavirus↗

PubMed2026

Glycemic and bodyweight effects of GIPR coding variation reflect differences in surface expression and intrinsic functional impairment.

The glucose-dependent insulinotropic polypeptide receptor (GIPR) is a major therapeutic target in type 2 diabetes and obesity. Missense variation in GIPR could confer phenotypic effects through alterations to constitutive activity or functional responses to GIP or pharmacological agonists. In this study, we aimed to provide a deep understanding of the molecular mechanisms that underpin the cellular and physiological impacts of GIPR coding variation by studying 30 GIPR coding variants in cellular models and pancreatic islets. Many variants showed impaired GIP-induced cyclic adenosine monophosphate responses, and population-based association analysis highlighted that these loss-of-function variants decrease body mass index but increase glycemia. In many cases, reduced function was partly driven by reduced expression at the cell surface due to impaired stability and redirection toward proteasomal degradation. Molecular dynamics simulations suggest distinct variant-induced perturbations in inter- and intrahelical interactions, which interfere with receptor stability. This study highlights the mechanisms and consequences of GIPR coding variation, which may have implications for the therapeutic targeting of this receptor.

Humans↗

PubMed2025

Structural and thermodynamic impact of oncogenic mutations on the nucleosome core particle.

The nucleosome core particle is essential for chromatin structure and function, serving as the fundamental unit of eukaryotic chromatin. Oncogenic mutations in core histones disrupt chromatin dynamics, altering DNA repair and transcription processes. Here, we investigate the molecular consequences of two mutations-H2BE76K and H4R92T-using 36 μs of all-atom molecular dynamics simulations and experimental biophysical assays. These mutations destabilize the H2B-H4 interface by disrupting critical salt bridges and hydrogen bonds, reducing binding free energy at this interface. Principal-component analysis reveals altered helix conformations and increased interhelical distances in mutant systems. Thermal stability assays and differential scanning calorimetry confirm that these mutations lower the dimer dissociation temperature and reduce enthalpy compared with the wild-type. Taken together, our results elucidate how these mutations compromise nucleosome stability and propose mechanisms through which they could modulate chromatin accessibility and gene dysregulation in cancer.

Nucleosomes↗