Gain-of-function (GOF) variants in human TLR7 have recently been reported in 11 cases, six of which were diagnosed with systemic lupus erythematosus (SLE). We have identified the X-linked L840R TLR7 variant in hemizygosity in a male patient with SLE and in heterozygosity in his clinically asymptomatic mother. The leucine 840 is located at the first amino acid of TLR7 transmembrane domain and is conserved across various species. The L840R substitution is predicted to be deleterious by various scoring algorithms and may therefore affect TLR7 function. Molecular dynamics simulations of TLR7-UNC93B1 interactions revealed that R840 alters nearby amino acids interactions, resulting in increased hydrogen bond between E834 of TLR7 with R157 of UNC93B1. Finally, the L840R TLR7 variant has increased activity compared with WT, as measured with a nuclear factor κB (NF-κB)-specific luciferase reporter upon stimulation with TLR7 agonist R848. Hence, hemizygosity for L840R confers GOF for NF-κB activation and underlies SLE by potentially increasing TLR7 binding to UNC93B1.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and complex, multi-factorial pathology. Current single-target drugs provide only limited benefits, and there is a need for more effective therapeutic strategies. β-asarone, a major volatile component of Acorus tatarinowii used in traditional Chinese medicine (TCM), has demonstrated neuroprotective effects, including anti-apoptotic, anti-inflammatory, and anti-amyloid β (Aβ) toxicity properties. However, the molecular targets and signaling mechanisms of β-asarone in AD remain underexplored. This study aims to explore the molecular targets and signaling mechanisms of β-asarone in AD by integrating network pharmacology, molecular docking, and molecular dynamics simulations. Network pharmacology was used to identify overlapping targets between β-asarone and AD. Protein-protein interaction networks were constructed using STRING, and key targets were analyzed for enrichment in the PI3K-AKT/MAPK pathways. Molecular docking was conducted to assess the binding affinity of β-asarone with multiple targets along the PI3K-AKT axis. Additionally, molecular dynamics (MD) simulations of the β-asarone-AKT1 complex were performed for 100 ns to assess the stability of the interaction. Seventy-four overlapping targets of β-asarone and AD were identified, with key hub genes enriched in the PI3K-AKT/MAPK pathways. Molecular docking revealed that β-asarone binds to critical nodes along the PI3K-AKT axis with binding free energies (ΔG) of approximately -6.2 kcal/mol and to HRAS/IGF1 with ΔG ≈ -5.2/-4.1 kcal/mol. MD simulations showed stable trajectories for the β-asarone-AKT1 complex (RMSD ~3.5-4.0 Å) with persistent hydrogen bonds, indicating a durable interaction in the ATP-binding pocket. β-asarone interacts with multiple interconnected signaling nodes, particularly the PI3K-AKT pathway, to modulate apoptosis, neuroinflammation, and cellular energetics. These findings support the potential of β-asarone as a TCM-derived candidate for the development of therapeutic strategies for AD.

Molecular mechanisms of aquaporin 1 inhibition by Bacopaside I and Bacopaside II: Insights from molecular dynamics simulations.

The barnacle Amphibalanus amphitrite is a major marine fouling organism that adheres strongly to submerged surfaces through proteinaceous cement. Among its adhesive proteins, CP19k plays a crucial role in stable underwater adhesion due to its amyloid-like β-sheet nanofibrils.Remarkably, AaCP19k has inspired biomimetic strategies to develop next-generation adhesives for biomedical applications despite immunogenicity challenges. Notably, a targeted computational strategy for the de-immunization of AaCP19k has not yet been reported; thus, this study addresses this significant research gap, presenting the first rational design of a de-immunized AaCP19k variant tailored for biocompatible underwater adhesion. Herein, we employed a computational workflow for protein engineering, combining epitope mapping, structural modeling, and molecular dynamics (MD) simulations to optimize stability and reduce immunogenicity of AaCP19k. Immunogenic regions were identified using IEDB MHC-II Binding Predictions and DiscoTope 2.0, followed by rational modifications through alanine scanning and β-hairpin redesign to minimize immunogenicity while preserving structural integrity. The engineered variants were modeled using AlphaFold2, then MD simulations in GROMACS were performed to evaluate the stability, flexibility, and conformational dynamics of the engineered variants compared to the native protein. Results revealed that targeted modifications to immunogenic regions significantly reduced predicted antigenicity. AlphaFold2 modeling confirmed preservation of the β-sandwich fold in the engineered protein with high confidence (average pLDDT = 94.6). MD simulations further validated these modifications, demonstrating enhanced structural stability with an average RMSD decrease of ~1.4 Å compared to the native protein. Additionally, RMSF analysis indicated reduced local flexibility, particularly in previously immunogenic regions within the β-hairpin between β6 and β7 (residues 143–166), as well as 110–112, 118–120. PCA and dynamic cross-correlation analysis supported overall structural stabilization. These findings demonstrate the effectiveness of our computational design strategy in optimizing AaCP19k as a promising bioadhesive candidate with reduced predicted immunogenicity, supporting its potential industrial and biomedical applications.

Human-pathogenic molds produce various natural products (xenobiotics) that interact with human host proteins. Here, a sequence- and structure-based virtual screening pipeline for protein-xenobiotic interactions was established. Verification tests run on Methylene Blue and Fumagillin identified the known top interaction targets in both cases. The pipeline was then applied to 1,8-dihydroxynaphthalene (DHN)-melanin, an Aspergillus fumigatus spore pigment and virulence determinant. Our sequence-structure aggregated scoring for DHN-melanin-interacting proteins included protein localization, evolution, and function. Experimental data validated our identified candidates and support ranking accuracy. Conserved targets were further assessed: for their possible participation in the macrophage response to A. fumigatus (using gene ontology terms). Lower-scoring targets, such as glucosidase alpha (GAA; experimental data in this paper) and sentrin-specific protease 8 (SENP8), were shown not to bind DHN-melanin by molecular dynamics (MD) simulations as well as experiments, supporting their lower pipeline scores. The best DHN-melanin interacting candidates were validated by docking and molecular dynamics simulations, resulting in the identification of the most likely DHN-melanin-interacting proteins in human immune and epithelial cells. The pipeline identified the following previously validated DHN-melanin interaction targets with top score: C-type lectin receptor MelLec (CLEC1A) and surfactant protein-D (SP-D). In addition, two novel targets share the same top score, the aromatic hydrocarbon receptor (AHR) and methionine aminopeptidase 2 (METAP2), the latter of which was experimentally validated.

Resveratrol ameliorates sepsis-induced immune dysfunction by targeting GADD45A to maintain hematopoietic stem cell homeostasis: A predictive study integrating ensemble machine learning, single-cell transcriptomics, and molecular dynamics simulation.

JianPi QingRe HuoXue Formula targets Cadherin-17 to induce apoptosis in chronic atrophic gastritis with intestinal metaplasia.

Pharmacophore-based virtual screening, molecular dynamics simulations, and bioactivity validation for JAK1/TYK2 dual inhibitors

A first-principles study of hydrogen storage on MXene Mo2C monolayer.

Molecular simulations of the tunable pore structure models elucidate the adsorption of sulfamethoxazole on biochar.

Excess synaptic glutamate is neurotoxic, and enhancing its clearance via the excitatory amino acid transporter 2 (EAAT2/GLT-1) represents a promising neuroprotective strategy. This study repurposes a series of β-lactam compounds as potential EAAT2 positive allosteric modulators using an integrated in silico workflow comprising ligand preparation, high-throughput docking (Glide SP/XP), induced-fit docking (IFD), MM-GBSA binding energy estimation, molecular dynamics (MD) simulations, and ADMET prediction (QikProp). Initial virtual screening of 113 analogues identified high-scoring candidates, and subsequent IFD refinement of the top 23 compounds revealed improved complementarity within the EAAT2 allosteric pocket. Six lead analogues were prioritized based on favorable docking scores (−5.36 to −6.83), IFD scores (−755.3 to −759.4), and MM-GBSA binding energies (≈ − 45 to −55 kcal/mol). 100 ns MD simulations confirmed protein–ligand complex stability (protein Cα RMSD ~2 Å; ligand RMSD ~1–3 Å) and persistent interactions, including hydrogen bonding and π–π stacking, mimicking the binding behavior of the known allosteric modulator GT-949. Predicted ADMET profiles indicated drug-likeness, CNS permeability, and low hERG toxicity risk. Overall, this multi-step computational study identifies β-lactam analogues with promising potential as EAAT2 allosteric enhancers, supporting their further experimental evaluation as candidate neuroprotective agents. • Discovery of β-lactam analogues targeting the EAAT2 allosteric site. • Docking and IFD revealed favorable binding of selected compounds. • MD simulations confirmed stable EAAT2–ligand complexes. • Hydrophobic and aromatic interactions drive binding stability. • ADMET profiling suggests promising drug-like properties.

Evaluation of CendR peptides mined from protein databases as potential inhibitors of neuropilin-1 using an in-silico molecular modeling approach.

Α-Hederin alleviates psoriasiform skin inflammation by inhibiting NF-κB p65/CXCL2 Axis.

Integrative computational and experimental approaches to Hydnocarpus wightianus phytochemicals: Targeting breast Cancer through systems biology, molecular dynamics simulations, and in vitro validation in MDA-MB-231 cells.

Discovery of a novel PI3Kα inhibitor for breast cancer therapy via virtual screening method, molecular dynamics simulation and biological evaluation.

Investigating the effect of membrane pore size on the permeability of carbon nanotubes in reverse electrodialysis using molecular dynamics simulation.

Cannabidiol attenuates methamphetamine-induced psychosis via anti-oxidative stress: σ1R-mediated mitochondrial dysfunction as a critical pathway.

Jujuboside B from Zizyphi spinosi semen inhibits hepatocellular carcinoma progression by targeting the PI3K/Akt signaling pathway in vitro and in vivo

In-silico design of a multi-epitope vaccine targeting conserved transmembrane proteins of Gardnerella vaginalis using immuno-informatics approach.

Modulation of the Keap1–Nrf2 pathway using a peptide derived from edible mushrooms: In silico and in vitro studies