Molecular Dynamics Research Articles

Indomethacin forms elusive nanoparticles with calcium in situ causing enhanced permeation across a biomimetic barrier.

Clinical and epidemiological studies suggest similarities in dysregulation of pathways in type 2 diabetes (T2DM) and Parkinson's disease (PD). Efficacy of several antidiabetic drugs has been tested in PD. Exenatide, a synthetic version of exendin-4, an incretin-mimetic drug, is an agonist of glucagon-like peptide 1 receptor (GLP1R) and is approved for the treatment of T2DM. Exenatide can cross the blood-brain barrier and exerts neuroprotective and neurorestorative effects via GLP1R at doses similar to those used in T2DM, resulting in improved motor performance, behaviour, learning and memory in different rodent PD models. Reports in human PD patients have also shown promise. In this work, we carried out substitution at the fourteenth position of exenatide (M14) with basic, acidic and nonpolar residues and investigated their effect on aggregation of recombinant human α-synuclein in vitro and in SH-SY5Y cells. Molecular dynamic (MD) simulation studies showed altered stability of α-synuclein upon substitution at M14 in exenatide. Exenatide had no effect on aggregation of α-synuclein in vitro. The M14K mutant, which stabilized α-synuclein, prolonged lag time and caused significant reduction in aggregation. On the contrary, aggregation of α-synuclein was significantly attenuated in SH-SY5Y cells in the presence of exenatide for all mutants tested, with a concomitant increase in cell survival. Flow cytometric analysis suggested induction of autophagy in the presence of the peptides, explaining the reduction in protein aggregation. Thus, mutants of exenatide could be investigated further as inhibitors of aggregation of α-synuclein.

Biomolecules rely on water and ions for stable folding, but these interactions are often transient, dynamic, or disordered and thus hidden from experiments and evaluation challenges that represent biomolecules as single, ordered structures. Here, we compare blindly predicted ensembles of water and ion structure to the cryo-EM densities observed around the Tetrahymena ribozyme at 2.2-2.3 Å resolution, collected through target R1260 in the CASP16 competition. Twenty-six groups participated in this solvation "cryo-ensemble" prediction challenge, submitting over 350 million atoms in total, offering the first opportunity to compare blind predictions of dynamic solvent shell ensembles to cryo-EM density. Predicted atomic ensembles were converted to density through local alignment and these densities were compared to the cryo-EM densities using Pearson correlation, Spearman correlation, mutual information, and precision-recall curves. These predictions show that an ensemble representation is able to capture information of transient or dynamic water and ions better than traditional atomic models, but there remains a large accuracy gap to the performance ceiling set by experimental uncertainty. Overall, molecular dynamics approaches best matched the cryo-EM density, with blind predictions from bussilab_plain_md, SoutheRNA, bussilab_replex, coogs2, and coogs3 outperforming the baseline molecular dynamics prediction. This study indicates that simulations of water and ions can be quantitatively evaluated with cryo-EM maps. We propose that further community-wide blind challenges can drive and evaluate progress in modeling water, ions, and other previously hidden components of biomolecular systems.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and cholinergic dysfunction. This study evaluated the neuroprotective potential of Ficus microcarpa leaf extract via a multidisciplinary approach that integrates phytochemical profiling, in silico analysis, and in vivo validation. LC‒MS analysis revealed key bioactive compounds, including fortunellin, thalsimine, and vocalristine, which are flavonoids, alkaloids, and terpenoids, that are known for their neuroprotective effects. Drug-likeness and toxicity evaluations via SwissADME and ProTox-II revealed favorable pharmacokinetic properties. Network pharmacology and KEGG enrichment analyses identified AChE, APP, and GSK3β as central AD-related targets. Molecular docking (AutoDock 4.2) revealed strong binding affinities of fortunellin (-9.2kcal/mol) and donepezil (-9.0kcal/mol) with AChE, which was supported by active site interactions. Molecular dynamics (200ns, GROMACS) confirmed the complex stability via RMSD, RMSF, SASA, and hydrogen bond analyses. The MM-PBSA calculations further validated the binding stability. In vivo studies revealed that F. microcarpa (100 and 200mg/kg, po) and donepezil (3mg/kg, po) administered for 21 days significantly reversed scopolamine-induced (2mg/kg, ip) memory deficits in Wistar rats, as assessed by the Morris water maze, elevated plus maze, and novel object recognition tests. Biochemical analysis revealed reduced oxidative stress, increased antioxidant enzyme levels, and the restoration of cholinergic function. Histopathological studies revealed that the integrity of the hippocampus was preserved. Overall, these findings support F. microcarpa, particularly fortunellin, as a promising multitarget candidate for AD therapy, meriting further pharmacological investigation.

Chagas disease is a neglected tropical condition with limited treatment options, emphasizing the need for new antichagasic agents. Cruzipain (CZP), the main cysteine protease of Trypanosoma cruzi, is a validated target; however, achieving strong trypanocidal activity through CZP inhibition remains challenging. In this work, we report a series of novel triazole-based noncovalent CZP inhibitors designed by applying state-of-the-art molecular modeling techniques, showing good potency against isolated CZP combined with effective trypanocidal activity. Structure-activity relationships that define key pharmacodynamic features were elucidated, enabling analogues to translate enzymatic inhibition into cellular effects. The computer-aided design workflow combining molecular docking, molecular dynamics simulations, and binding free-energy calculations was key to reveal conserved interaction patterns within the oxyanion hole and the S1/S1' subsites (Gln19, His162, Trp184) of CZP for the most effective inhibitors. Overall, our findings introduce new 1,2,3-triazole-based antichagasic candidates and clarify molecular determinants influencing the translational gap between enzymatic and cellular activity, contributing with a predictive framework for the rational design of CZP-targeted inhibitors for Chagas disease therapy.

Compound (E)-1-(((4-chloro-2-hydroxyphenyl)imino)methyl)naphthalen-2-ol (HNC) was prepared by the reaction between 2-hydroxynaphthyl-1-carboxaldehyde and 2-amino-5-chlorophenol in an equimolar ratio and obtained in moderate yield. HNC was characterized using physicochemical and various spectroscopic techniques. The slow evaporation of a hot methanolic solution of HNC resulted in the formation of the zwitterionic ketoenamine form of HNC, and denoted as HNC'. Structurally, HNC' comprises one naphthoxide ring bridged with one chlorophenol ring by the azomethine group, and the torsion angle between the naphthoxide and the chlorophenol ring is 11.78°, speculating a nonplanar geometry. The density functional theory (DFT) at M06-2X/def2-TZVP level of theory described the facile enolimine-ketoenamine tautomerism and the highest occupied molecular orbital-lowest unoccupied molecular orbital gap of 5.757eV for HNC, consistent with a moderately reactive scaffold. The inhibitory potential of HNC against cyclin-dependent kinases 2 (CDK2) was evaluated using molecular docking, molecular dynamics simulations, and molecular mechanics generalized Born surface area (MM-GBSA) free energy calculations. Docking results showed that HNC achieved a binding score of -8.75kcal/mol, slightly lower than the reference inhibitor Roscovitine (RVT), which scored -9.41kcal/mol. MM-GBSA calculations yielded ΔGtotal values of -40.95kcal/mol for HNC and -41.14kcal/mol for RVT, suggesting comparable binding affinities. Generally, our findings pose HNC as a credible CDK2 inhibitor and tractable starting point for optimization toward selective antiproliferative agents.

Low-field nuclear magnetic resonance (NMR) is a powerful technique for characterizing fluid behavior in shale oil reservoirs. However, the abundant nanopores in shale and the limitations of experimental echo time hinder its further application in characterizing oil occurrence. This study integrates the ratio of longitudinal to transverse relaxation times (T1/T2) with molecular dynamics simulations to determine the distributions of dissolved, adsorbed, and free n-decane in kerogen nanoslits and further develops quantitative models to characterize the occurrence characteristics of n-decane in these confined systems. The results indicate that alkane molecules in the same state exhibit identical T1/T2 values, with the T1/T2 values of dissolved, adsorbed, and free molecules being 25.27, 18.61, and 14.86, respectively. For each occurrence state, both the self-diffusion coefficient of n-decane and its interaction energy with the kerogen nanoslit walls exhibit distinct linear correlations with T1/T2. Furthermore, three mathematical models are developed to quantify the relationships between T1/T2 and the slit width, the adsorption layer thickness (H), and the free-to-adsorbed mass ratio (mf/ma). When T1/T2 ranges from 75.21 to 53.25, mf/ma = 0, indicating the absence of a free state. This state corresponds to slit widths of 1-3 nm, within which H varies linearly with T1/T2. As T1/T2 decreases further from 53.25 to 1.00, mf/ma increases exponentially while H stabilizes at ∼2.86 nm, suggesting three-state coexistence within 3-50 nm slits. Free-state dominance occurs when T1/T2 approaches 1, corresponding to a slit width of approximately 50 nm. Additionally, with increasing kerogen maturity, the kerogen matrix exhibits reduced solubility but enhanced adsorption capacity for n-decane. For kerogen types I-A, II-D, and III-A, T1/T2 shows exponential correlations with both slit width and mf/ma, indicating free-state dominance at slit widths of 45, 50, and 58 nm, respectively. This work is expected to provide novel insights into shale reservoir evaluation and enhanced oil recovery.

Zika virus (ZIKV) remains a global health threat, for which no licensed antiviral treatment has been available. In this study, we employed in silico approaches to optimize monoclonal antibodies targeting the Zika virus envelope protein (ZIKV E) in the Domain III (DIII) region, which is crucial for receptor binding and virus entry. A high-resolution crystal structure of ZIKV E in complex with the neutralizing antibody ZV-64 was used as a template for designing a library of antibody variants through targeted double-point mutations. The variants were systematically evaluated for stability, binding affinity, solubility, and protein-protein interaction potential using FoldX, DeepPurpose, SoluProt, and molecular docking. Among all the mutants, Variants-213 and -206 were identified as the top candidates, exhibiting the most favorable predicted binding affinity and solubility compared to the control antibody. The molecular dynamics simulations further revealed the structural stability of the two mutant variants, in which Variant-206 showed a predicted binding energy (-76.90kcal/mol) along with higher conformational flexibilities. The findings demonstrate the use of computational antibody engineering to identify potentially high-affinity therapeutics against ZIKV, providing a foundation for future experimental validation and therapeutic development against ZIKV.

The overexpression or activation of C-terminal Src kinase (CSK) has been recognized as a pivotal factor in the progression of hepatocellular carcinoma (HCC), positioning CSK as a promising therapeutic target. Despite this potential, no CSK-specific inhibitors have been developed for HCC treatment to date. Addressing this gap, our study established a robust virtual screening protocol that integrates energy-based screening techniques with machine learning methodologies. Through this systematic approach, we identified a novel compound, 6, exhibiting potent CSK inhibitory activity, as evidenced by an IC50 value of 675 nM in a homogeneous time-resolved fluorescence (HTRF) bioassay. Notably, this compound demonstrated significant growth inhibition in Huh-7 and Huh-6 cell lines, along with the suppression of clone formation. To elucidate the underlying mechanism, we conducted molecular dynamics simulations, which revealed critical binding interactions between compound 6 and CSK. Specifically, residues Phe333 and Met269 were found to play essential roles in mediating these interactions, providing valuable insights into the compound's mode of action.

In silico screening of flavonoid-based inhibitors targeting UDP-galactopyranose mutase of Brugia malayi for lymphatic filariasis drug design.

This study aims to identify the phytochemical components of Weiweisu (WWS) decoction, evaluate its therapeutic potential for chronic atrophic gastritis (CAG), and elucidate the underlying mechanisms with a focus on antiferroptotic effects. Liquid chromatography-mass spectrometry was used to characterize the phytochemical constituents of WWS. Network pharmacology was applied to predict potential therapeutic targets and signaling pathways. Core compounds and targets were verified through molecular docking and molecular dynamics simulations. Subsequently, a CAG rat model was established. Enzyme-linked immunosorbent assay was used to measure levels of prostaglandins (pepsinogen I/II) and tumor necrosis factor-α in gastric tissue, while Fe2+, glutathione, and malondialdehyde concentrations were assessed. Gene and protein expression levels of key targets were analyzed using quantitative real-time polymerase chain reaction and western blotting. A total of 1017 chemical constituents were identified via liquid chromatography-mass spectrometry. Network pharmacology revealed 20 ferroptosis-related genes associated with WWS and CAG, primarily involving cancer-related signaling pathways. In vivo experiments showed that WWS ameliorated gastric ulcers and mucosal atrophy, downregulated pepsinogen I/II and tumor necrosis factor-α levels, reduced Fe2+ and malondialdehyde concentrations, and increased glutathione levels. WWS treatment also elevated HSP90AA1, MAPK, and mTOR expression while inhibiting GPX4 expression. Molecular docking indicated strong binding affinities between key active compounds and core targets. Molecular dynamics simulations confirmed the stability of these interactions. In summary, WWS decoction can treat CAG through antiferroptosis, and its main mechanism may be related to the regulation of tumor signaling pathways.

Herein, the conformation of planar polymer brushes of varying chain length and grafting density is investigated, comparing experiments with molecular dynamics (MD) simulations. The grafting densities investigated cover a wide range: from the mushroom regime to a dense brush. Experimentally, poly(ethylene glycol)methylethermethacrylate (MN = 300) based polymer brushes were synthesized by atom transfer radical polymerization. The conformation was characterized by neutron reflectometry. At room temperature, below the lower critical solution temperature, the extracted polymer density profiles reveal a stretched conformation that becomes more pronounced with increasing grafting density. The presented MD simulations employ a new approach to "synthesize" polymer chains from the grafting surface. Chains can only grow when a free monomer approaches an active chain-end, analogous to the experimental synthesis. The resulting polymer brushes exhibit a more stretched polymer conformation, differing significantly from the usual monodisperse case. The thereby induced intrinsic polydispersity increases with increasing grafting density due to chain crowding during growth. For the first time, experimentally acquired polymer volume fraction profiles, in a good solvent, are matched to those of MD-simulated brushes by comparing grafting density lengths. Normalized profiles show very good agreement between experiments and simulations, even reproducing the extent of stretching.

Sorting Nexins (SNXs) are a large group of diverse cellular trafficking proteins that play essential roles in membrane remodeling and cargo sorting between organelles. SNX proteins comprise a banana-shaped BAR domain that acts as a curvature-inducing scaffold and a phosphoinositide lipids sensitive Phox-Homology Domain (PXD) that interacts with the membrane to ensure specific and efficient organelle binding. In concert with the larger retromer machinery, these proteins traffic and recycle cargo between the endosomal membrane, trans-Golgi network, and plasma membrane. Interestingly, the SNX1-SNX5 heterodimeric construct forms a part of the newly discovered pathway where cargo sorting and membrane remodeling can take place in a retromer-independent fashion. In this work, we use molecular dynamics and continuum mechanics simulations to understand the features of SNX1-SNX5 heterodimer, especially the molecular determinants at PXDs, which impart organelle membrane specificity and retromer-independent cargo recognition ability to these proteins. Our all-atom molecular dynamics simulations with isolated PXDs and full-length SNX1-SNX5 on bilayers show that SNX1-PXD has robust membrane-binding features that are largely insensitive to single or double mutation of the basic residues on its surface. Comparing the simulation-based binding poses against the recently solved cryo-EM structures of tubular membrane-bound SNX1 homodimer and SNX1-SNX5 heterodimer also provided interesting insights into the association profile of isolated PXDs when they have the freedom to explore different membrane-binding poses. Our protein-protein simulations of SNX5-PXD with the tail region of the CI-MPR transmembrane cargo protein using metadynamics simulations reveal aromatic residue-rich π-π interactions between the two proteins, and a favorable and kinetically accessible binding free energy profile for SNX5. To model the emergent behavior of cargo sequestration and endosomal tube formation by SNX1-SNX5 heterodimer, we also performed Dynamically Triangulated Surface (DTS) based mesoscopic simulations by developing an augmented Helfrich-like continuum-mechanics Hamiltonian to incorporate transmembrane proteins in DTS models.

BackgroundSystemic lupus erythematosus (SLE) is a complex autoimmune disease with a scarcity of effective treatment options and considerable side effects linked to current therapies. Withania somnifera, is rich in phytochemicals that have demonstrated immunomodulatory and anti-inflammatory effects, suggesting its promise as a natural therapeutic candidate for SLE.MethodsAn in silico methodology explored the therapeutic potential of W. somnifera phytocompounds for SLE. Phytochemicals were obtained from Indian Medicinal Plants, Phytochemistry, and Therapeutics (IMPPAT) and KNApSAcK databases, followed by virtual screening using SwissADME, MOLSOFT, and ProTox 3.0 to identify drug-like and non-toxic candidates. Target genes were predicted using SwissTargetPrediction and STITCH, while SLE-associated genes were compiled from GeneCards and Online Mendelian Inheritance in Man (OMIM). The intersection of these genes was analyzed to construct a protein-protein interaction network, with hub genes identified through Cytoscape. Molecular docking and 100 ns Molecular Dynamic simulations, with Molecular Mechanics, General Born Surface Area (MM-GBSA) free energy calculations, were conducted for lead compounds against top hub proteins.ResultsThe study identified three phytocompounds-vanillic acid, (+)-catechin, and withanolide K-that show favorable pharmacokinetic and toxicity characteristics. Network analysis identified 161 common target genes, with Caspase 3 (CASP3), HIF1A (Hypoxia-inducible factor 1-alpha subunit), Interleukin 1 beta (IL1B), and Interleukin 6 (IL6) as significant hub proteins. Docking studies revealed (+)-catechin and withanolide K have strong binding affinities with IL6 and CASP3. Molecular dynamics simulations confirmed complex stability, and MM-GBSA calculations showed favorable binding free energies, especially in (+)-catechin-protein interactions.Conclusions(+)-Catechin and withanolide K are promising biomolecules for SLE, demonstrating a strong binding affinity with key proteins linked to the disease. These results offer a computational basis for experimental validation and the potential development of safer, plant-based therapies for SLE.

Glucagon-like peptide-1 receptor (GLP-1R) is overexpressed in >90% of insulinomas, making it an optimal target for imaging. However, current GLP-1R agonist tracers may induce side effects including hypoglycemia and nausea, particularly in pediatric patients. In this study, we employed a rational design approach combining molecular dynamics (MD) simulations with experimental validation to develop three 68Ga-labeled NOTA-conjugated exendin(9-39) derivatives featuring antagonist activity for safer imaging. MD simulations predicted differential binding affinities based on conjugation sites at Asp09 (E09), Lys12 (E12), and Lys27 (E27), with MM/GBSA calculations ranking E09 (-216.06 kcal/mol) > E12 (-200.01 kcal/mol) > E27 (-117.08 kcal/mol). Experimental validation through surface plasmon resonance confirmed these computational predictions, showing binding affinities consistent with the computational predictions. All radiotracers achieved radiochemical yields (>95%) and plasma stability (>91% intact after 120 min). In vivo PET imaging validated the computational hierarchy, with [68Ga]Ga-E09 demonstrating superior tumor uptake (SUVmax: 3.99 at 60 min) compared with E12 (SUVmax: 0.75 at 60 min) or E27 (undetectable). These findings highlight the power of combining computational screening with systematic experimental validation. In conclusion, [68Ga]Ga-E09 demonstrates superior binding affinity, cellular uptake, and imaging performance, suggesting its potential as a promising agent warranting further studies.

Pterygium, a common ocular surface disorder, is associated with environmental factors such as ultraviolet exposure and air pollution. Tris(1,3-dichloro-2-propyl) phosphate (TDCPP), a widely used organophosphate flame retardant, has been detected in environmental and biological samples, yet its role in pterygium pathogenesis remains unclear. This study employed an integrative approach combining network toxicology, transcriptome sequencing, and in vitro cytotoxicity assays to elucidate the molecular mechanisms linking TDCPP exposure to pterygium development. Bioinformatics analysis identified 273 TDCPP-related targets and 1,078 pterygium-associated genes, with 43 overlapping candidates. Weighted gene co-expression network analysis (WGCNA) revealed two key modules correlated with pterygium phenotypes, highlighting MMP3 as a central regulator. Molecular docking and dynamics simulations confirmed stable interactions between TDCPP and MMP3 (binding energy: -5.9kcal/mol), supported by RMSD, RMSF, and hydrogen bonding analyses. In vitro experiments demonstrated that low-dose TDCPP (0.5 µM) upregulated MMP3 expression in immortalized human conjunctival fibroblasts, enhancing cell proliferation, while higher concentrations (50 µM) induced cytotoxicity. These findings suggest that TDCPP promotes pterygium pathogenesis via MMP3-mediated extracellular matrix remodeling and fibroblast proliferation. This study provides novel insights into the environmental etiology of pterygium and identifies MMP3 as a potential therapeutic target for TDCPP-associated ocular surface disorders.

Streptococcus pneumoniae (S. pneumoniae) has developed resistance to β-lactam antibiotics, largely due to mutations in penicillin-binding protein 2x (PBP2x), particularly within conserved motifs such as STMK and KSG. PBP2x mutations are frequently reported in multidrug-resistant pneumococcal strains associated with pneumonia, meningitis, and septicaemia. especially in serotypes 19A, 19F, and 23F, showing reduced susceptibility to β-lactam antibiotics. These mutations in the PBP2x disrupt antibiotic binding and enzymatic functions, highlighting the need for alternative therapeutic strategies. This study focused on five clinically relevant PBP2x mutations (T338A/G/P and K547G/T) within its active site. A library of phytocompounds was screened using a machine learning model trained to identify antibacterial compounds. Top candidates were filtered based on ADMET properties, and their electronic characteristics were assessed using HOMO-LUMO analysis and electrostatic potential mapping, through density functional theory (DFT). Glucozaluzanin C, a phytochemical derived from Elephantopus scaber, emerged as a potential candidate. Molecular docking and dynamics simulations revealed strong binding affinity and structural integrity with all PBP2x mutants, over a 100-ns timescale. RMSD, RMSF, and hydrogen bonding analysis confirmed stable interactions, suggesting Glucozaluzanin C may effectively interact with PBP2x mutants. Overall, the study highlights an effective strategy for identifying plant-derived inhibitors against β-lactam-resistant S. pneumoniae.

Chemoresistance remains a major challenge in addressing T-cell lymphoblastic lymphoma/leukemia (T-LBL/ALL), underscoring the necessity for novel strategies to unravel the molecular factors driving resistance. Through transcriptomic profiling, circBPTF was found to be markedly overexpressed in chemoresistant samples. Further functional experiments demonstrated that BPTF-665aa, the protein product of circBPTF, plays a pivotal role in mediating resistance. Notably, BPTF-665aa prevents the ubiquitination degradation of full-length BPTF, and promotes chromatin accessibility at key promoter sites, such as that of c-Myc promter 2 (P2), facilitating transcriptional activation crucial for cellular survival and proliferation under therapeutic stress. Structural studies confirmed the motifs of BPTF-665aa, including the Plant Homeodomain (PHD) finger and Bromodomain, essential for its chromatin remodeling function. HY-B0509 was identified as a small-molecule inhibitor of BPTF-665aa, with molecular docking and dynamics simulations showing stable binding to critical residues within the protein's active site. Overall, this study introduces a new mechanism where circBPTF affects chromatin accessibility, causing chemoresistance, making BPTF-665aa as a potential therapeutic target for treating T-LBL/ALLs.

Thyroid dysfunction is a disease closely associated with autoinflammatory responses and immune imbalances. Derived from the traditional Chinese medicine Sinomenium acutum, sinomenine is an alkaloid that possesses immunomodulatory and anti-inflammatory activities. However, the exact molecular mechanism underlying its therapeutic effects on thyroid dysfunction has not been clarified. This study integrates network pharmacology, molecular docking and molecular dynamics simulation techniques to explore the mechanism of sinomenine on thyroid dysfunction. Databases such as GeneCards, PharmMapper, SwissTargetPrediction, and OMIM were used to screen the targets of sinomenine and thyroid dysfunction. Subsequent GO and KEGG enrichment analyses, PPI network construction, and drug-target-pathway network analysis were conducted. Molecular docking and molecular dynamics simulations were further employed for validation. The results of GO and KEGG enrichment analyses revealed that sinomenine's mechanism of action involves cellular responses to oxidative stress caused by inflammation, the role of nuclear transcription factors in gene expression, as well as processes of cell proliferation and apoptosis. Its targets are distributed across various pathways, suggesting a complex synergistic effect of multiple pathways in its potential mechanism; Molecular docking experiments showed that sinomenine and 14-episinomenine exhibit good binding affinity with the key targets, including TNF, STAT3, NFKB1, IL6, SRC, ESR1, and MAPK8; Molecular dynamics simulations were carried out on the two most stable binding complexes. RMSD, RMSF, Rg, and SASA curves showed that both proteins, ESR1 (PDB ID:4pxm) and MAPK8 (PDB ID:4yr8), were stabilized with sinomenine. Our study implies that via the synergistic action of multiple targets and pathways, sinomenine has the potential to impact cellular proliferation and apoptosis processes in thyroid dysfunction. The findings provide a theoretical basis for investigating the molecular mechanisms of sinomenine in treating thyroid dysfunction.

The interplay of specific surface interactions as well as ion and hydration structuring takes on a pivotal role in dictating the intermolecular, intersurface, and colloidal behavior at solid-liquid interfaces. The detailed atomic and molecular structure consequently influences a wide array of surface-mediated functions in technological and biological systems. Ion and hydration structuring at the interface is susceptible to various surface parameters, including surface potential, structural modifications including molecular adsorbents, the charge of specific functional groups, and electrolyte composition. Here, we disclose an electromechanical adhesion switch mechanism and demonstrate, in operation, the impact of molecular surface modification and potential modulation on adhesive and repulsive forces between surfaces. We exemplify these fundamental interactions by measuring the acting intermolecular forces between mica and metal surfaces modified with self-assembled monolayers including mercaptobenzimidazole and cysteamine films, showcasing the potential for tailoring surface interactions via ion adsorption manipulation. Employing an electrochemical surface forces apparatus complemented with molecular dynamics simulation, we present a comprehensive analysis of the specific forces involved in film-mica interactions and the impact of ion ordering under electrochemical modulation on such forces. Our results offer a novel perspective on how hydration and ion adsorption shape solid-solid interactions involving organic thin films and how these interactions provide a flexible route for electromechanical adhesion switches.