Search Results (2,717)

CO₂-enhanced oil recovery (CO₂-EOR) can be an effective method for recovering shale oil and for the sequestration of CO₂, but the influence of water on the microscopic CO₂ displacement behavior of shale nanopores is not well understood. Molecular dynamics (MD) simulations were conducted to analyze the microscopic CO₂ displacement behavior of hydrophilic quartz nanopores at a fixed NaCl salinity of 40,000 ppm with a range of molar ratios of water and oil. The distribution of carbon dioxide and petroleum molecules in the pores can be described by introducing two parameters, the directional residence coefficient in pore space (DRCPS) and relative local fluctuation (RLF), which can clearly define the migration dynamics of the two liquid phases in various water saturation conditions. CO₂ preferentially accumulates near pore walls, occupies adsorption sites originally occupied by oil molecules, weakens oil–wall interactions, and promotes oil desorption. Meanwhile, dissolved CO₂ enhances oil mobility by reducing intermolecular interactions. Pore size significantly affected displacement performance, with 7.5 nm pores exhibiting higher recovery than 4.5 nm pores. For the 2:3 water–oil molar system, CO₂ exhibited consistently high DRCPS values, and a moderate water content reduced the transport resistance and enhanced the nanopore displacement efficiency. The RLF of water has a smaller impact on CO₂ transport in small pores. However, in large pores, and even at higher MWORs, the presence of water molecules may form a “barrier” to CO₂ migration, thus affecting the displacement effect. Adsorbed water layers can weaken oil–wall interactions, while excessive water forms water bridges that hinder CO₂ migration and reduce displacement efficiency. These findings demonstrate that an appropriate MWOR can improve CO₂-EOR performance in shale nanopores and provide microscopic insights for optimizing CO₂ flooding in shale reservoirs. Full article

Conformational sampling remains a major challenge in molecular dynamics (MD) simulations of proteins with large-scale functional motions. Here, we use apo Escherichia coli adenylate kinase (AdK) as a benchmark for the open–closed transition and compare nine sampling protocols under a uniform explicit-solvent budget of 300 ns per method. The methods include unbiased MD, metadynamics, targeted MD (TMD), accelerated MD, simulated tempering, interpolation-based MD, and BioEmu. Closed-state sampling was evaluated relative to a reference-closed basin defined from ligand-stripped PDB 1AKE. TMD was the only method that both reached and maintained the closed reference, whereas unbiased MD did not enter this basin within 300 ns. Metadynamics increased sampling along the domain-distance coordinate but also promoted excessive LID opening, while simulated tempering showed a similar tendency. BioEmu generated closed-like conformations, but these states were not maintained during subsequent short MD simulations. Overall, the results show that collective-variable coverage does not necessarily correspond to stable target state occupancy and that different sampling methods provide different types of conformational information. These findings highlight the importance of selecting sampling strategies according to the specific scientific objective. Full article

Molecular dynamics (MD) simulations were used to study the deposition and growth of Fe-Co-Ni-M-Al multi-component alloy films on a Si(100) substrate. By comparing the surface topography at incident energies of 0.1~0.5 eV, it was observed that an increase in incident energy enhances local impact perturbations and induces surface roughening, with the film’s root-mean-square (RMS) roughness increasing from 0.3393 nm to 0.4870 nm. The selection of input data was consistent with the preparation conditions of the electron beam evaporation deposition process. The 0.1 eV condition, which yielded the best surface quality, was selected to study the deposition and growth process. The results indicate that deposited atoms first form a continuous covering layer on the substrate surface, followed by localized accumulation and island-like thickening, exhibiting characteristics of a mixed layer–island growth pattern. The radial distribution function (RDF) exhibits a stable first-neighbor peak at approximately 2.5 Å, with higher-order peaks and shoulders gradually appearing during the deposition process, indicating that short-range order formed within the film and gradually evolved into medium-range order. Polyhedral template matching (PTM) results show that the film exhibits a non-equilibrium structure characterized by a predominance of FCC structure, accompanied by the coexistence of HCP, BCC, and amorphous structures. Based on the solute formation rules derived from the atomic size difference δ and Ω parameter, as well as the empirical criteria of VEC, this composition exhibits the potential to form a solid solution and a structure with a tendency toward FCC. Meanwhile, both Debye-simulated XRD results and experimental data show a broadened main peak near 44°, cross-sectional SEM characterization confirms that the film surface is not completely flat but exhibits some local topographical variations, and TEM characterization reveals the presence of nanocrystalline/polycrystalline structures within the film; together, these findings demonstrate the ability of the MD model to predict the average atomic spacing and primary local order characteristics of the experimental film. Full article

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin (ID), may produce gastrointestinal adverse effects associated with cyclooxygenase-1 (COX-1) inhibition, motivating the investigation of microencapsulation strategies for modulating drug release. However, protein-based encapsulating materials remain comparatively underexplored using molecular simulation relative to synthetic polymers. In this study, the interaction tendencies of ID with cottonseed flour protein (CFP) and maltodextrin (MD) as potential encapsulating matrices were explored in silico using molecular dynamics simulations under NPT and NVT ensembles, cohesive energy density and Hildebrand solubility parameter (δ) calculations, the Flory–Huggins interaction parameter (χ), and mixing energy (E_mix). The protein cohesive properties exhibited substantial force-field dependence, while the absolute χ values obtained for the binary systems were considerably higher than those reported for comparable drug–excipient systems, limiting their quantitative interpretation as predictors of miscibility. Nevertheless, within the same computational framework, CFP–ID exhibited lower χ and E_mix values than MD–ID, indicating comparatively less unfavorable calculated interactions. As a complementary analysis independent of the formulation assessment, molecular docking of free ID against COX-1 and COX-2 showed a relative computational trend qualitatively consistent with published enzyme-inhibition data. Overall, the results support the use of the present workflow as an exploratory computational pre-screening approach and identify CFP as the candidate warranting further investigation among the two encapsulating materials evaluated, subject to experimental validation. Full article

Excessive activation of PI3Kα is prevalent in breast cancer, aberrantly activating the PI3K/Akt/mTOR pathway to drive tumor progression, thus rendering PI3Kα a vital therapeutic target. Two PI3Kα inhibitors (alpelisib and inavolisib) have been approved for clinical application. Inavolisib exerts a mutation-selective degradation mechanism and functions by directly eliminating aberrant proteins. To develop novel PI3Kα inhibitors, we employed multiple computational strategies including scaffold hopping based on the structure of inavolisib, -CDOCKER docking, Lipinski’s rule of five, ADMET prediction, molecular dynamics (MD) simulation and GLORYx metabolic prediction. These tools were used to assess candidate compounds for their predicted binding modes and binding affinity with PI3Kα, physicochemical profiles, pharmacokinetic properties, metabolic pathways and generated metabolites. Ultimately, M-288, a computationally prioritized candidate compound and imidazole derivative with favorable predicted properties, was identified. Its alanine moiety formed a H-bond with the key residue Gln859 in the binding pocket, and the oxygen atom on its carboxyl group established a salt bridge with non-conserved Arg770 to enhance binding affinity. M-288 also formed H-bonds with Asp933, Tyr836 and Val851, facilitating its stable binding to PI3Kα. This compound was predicted to occupy the ATP-binding pocket. Compared with other screened candidates, it exhibited low predicted toxicity and no inhibitory activity against major hepatic CYP450 isoforms, while satisfying drug-likeness criteria and possessing favorable hepatic metabolic clearance. Molecular dynamics simulations verified its stable binding profile. This study indicates that M-288 serves as a potential PI3Kα inhibitor and provides valuable references for subsequent discovery of PI3Kα inhibitors. Full article

Enzymatic depolymerization of poly(ethylene terephthalate) (PET) is a promising route toward closed-loop plastic recycling, yet the catalytic factors that become limiting once an enzyme already samples reaction-ready geometries remain unclear. Here, we compare two parent-variant pairs, FAST-PETase/FAST-Y61Q and LCC-ICCG/LCC-A2 (H218Y/N248D), using replicated molecular dynamics (MD) simulations, pre-reaction-state (PRS) analysis, noncovalent-interaction characterization, quantum-mechanical cluster calculations, and distortion/interaction activation-strain (DIAS) analysis. Y61Q remodels the second-shell environment and the conformational ensemble of the PET ethylene-glycol linker, thereby increasing the population of Bürgi–Dunitz compatible attack geometries. By contrast, LCC-A2 and LCC-ICCG exhibit similar populations of the two-coordinate geometric PRS, whereas LCC-A2 shows more favorable oxyanion-hole organization, Ser-His proton-transfer readiness, substrate polarization, and transition-state interactions, together with a lower calculated acylation barrier. These results support a bottleneck-guided view of PET-hydrolase engineering: when reaction-ready geometries are sparsely populated, mutations can act primarily by improving geometric preorganization; once such geometries are already abundant, further gains can arise from improving the chemical quality of the PRS ensemble. This framework distinguishes PRS quantity from PRS quality and provides a mechanistic basis for selecting stage-appropriate descriptors in PET-hydrolase design. Full article

The classical nuclear import pathway in eukaryotic cells is mediated by the importin (IMP) α and β1 heterodimer, where IMPα acts as an adaptor protein that recognises and binds to nuclear localisation signals (NLSs) on nuclear protein cargoes. IMPα from Toxoplasma gondii (TgIMPα), the causative agent of toxoplasmosis, is an essential gene and validated druggable target, but its NLS binding properties remain largely uncharacterised. To investigate the NLS binding properties of purified TgIMPα we designed NLS peptides and compared its properties with those of mammalian (mouse) IMPα by AlphaScreen binding assays. The well-characterised viral NLS from simian virus SV40 large tumour-antigen (T-ag NLS) was recognised by TgIMPα with low-nM binding affinity comparable to Mus musculus IMPα (MmIMPα), whereas a T. gondii-specific NLS from the GCN5 gene product (TgGCN5) exhibited high affinity binding to TgIMPα but not MmIMPα. Mutational analysis of basic residues within the NLSs indicated pronounced binding selectivity. To elucidate the structural basis of these interactions, molecular dynamics (MD) simulations of an ab initio TgIMPα model bound to each NLS was performed. Key polar, salt-bridge, and cation-π interactions driving NLS recognition were identified. Critically, the lysine at position 2 (Lys128 in T-ag and Lys95 in TgGCN5) of each NLS engages conserved threonine and aspartate residues at the major binding site, playing an essential role in binding stability. Strikingly, TgIMPα displayed a more extensive and distinct cation-π interaction network than MmIMPα, revealing that, while the overall NLS binding architecture is conserved, specific pocket variations underlie differential high affinity recognition. Collectively, this study provides insights for the first time into the molecular distinctions in NLS binding between parasite and mammalian IMPα, potentially representing the foundation for future selective targeted drug design or peptidomimetic strategies against T. gondii. Full article

Endpoint structure–activity relationships (SARs) for irreversible inhibitors can integrate reversible binding, covalent chemistry, conformational behavior, and cellular factors, making it difficult to assign a potency change to a single molecular event. We reanalyzed a previously reported series of irreversible inhibitors of wild-type (WT) HER2 and HER2 A775_G776insYVMA (HER2^YVMA) as six matched analogue pairs. Three complementary analyses were kept physically distinct. Pre-reaction molecular dynamics (MD) trajectories were used to quantify the fraction of frames satisfying a predefined near-attack-conformation (NAC)-like distance–angle criterion; continuous structural descriptors calculated from OpenComplex2 (OC2)-generated covalently linked HER2–inhibitor structures were used to characterize structural differences after covalent linkage; and covalent-adduct MD trajectories were used to characterize post-bond-formation dynamics. The Michael addition step itself was neither simulated nor measured. Cyclization of compound 3 to compound 9c increased the NAC-like frame fraction in HER2^WT from 0.0217% to 0.358% but decreased it in HER2^YVMA from 0.745% to 0.333%, with the overall direction preserved across all six sensitivity definitions. In HER2^YVMA, the modification distinguishing compounds 4a and 5a increased the NAC-like fraction from 2.620% to 6.244% despite a loss of cellular potency. The analogous tail modification increased this fraction in the 8c/10e series, whereas the HER2^YVMA 9c/11f response was starting conformation sensitive. The distribution of OC2-generated covalently linked structures across the predefined structural coordinate and the final-adduct MD readouts likewise varied with HER2 context and scaffold, although some differential effects were sensitive to the coordinate reference. These analyses complement experimental SARs but do not provide a measure of reaction kinetics or thermodynamic populations. Full article

In solid rocket motors, the liner serves as a critical interfacial material between the propellant and insulation, and its resistance to plasticizer migration directly affects the long-term structural stability of the propellant grain. In this study, hydroxyl-terminated polybutadiene (HTPB) was used as the matrix and isophorone diisocyanate (IPDI) as the curing agent to prepare composite liners with varying graphene oxide (GO) contents (0, 0.1, 0.3, and 0.5 wt%). The ability of the liners to suppress the migration of dioctyl sebacate (DOS) was systematically investigated. Molecular dynamics (MD) simulations were also conducted by constructing two amorphous cell models, namely DOS/HTPB/IPDI and GO/DOS/HTPB/IPDI, to calculate binding energy and migration coefficient and elucidate the role of GO at the molecular level. Immersion experiments revealed that the incorporation of GO significantly lowered the migration rate of DOS in the liner, with the optimal anti-migration performance achieved at a GO content of 0.3 wt%, which exhibited the lowest equilibrium migration concentration. MD showed that the incorporation of GO reduced the binding energy between DOS and the matrix from 290.998 to 229.264 kcal/mol, while the migration coefficient of DOS decreased from 6.52 × 10⁻¹¹ m²/s to 5.52 × 10⁻¹¹ m²/s, corresponding to a reduction of approximately 15.3%. The combined experimental and simulation results indicate that an appropriate amount of GO forms a two-dimensional physical barrier within the HTPB/IPDI matrix, effectively extending the diffusion pathway of DOS molecules and weakening their affinity with the matrix, thereby significantly enhancing the anti-migration performance of the liner. This work provides both experimental and molecular-level insights for the development of high-performance liner materials with enhanced resistance to plasticizer migration. Full article

RA-XII, a unique natural cyclopeptide, is a potential anti-colorectal cancer candidate by mainly inhibiting protective autophagy, SREBP-1-dependent lipid biogenesis and suppressing activation of the Akt-mTOR pathway in HCT-116 cells. However, there have been no investigations into its solid forms, and its poor solubility restricts its application in the development of clinical anticancer agents. Background/Objectives: To investigate and develop advantageous medicinal solid forms of RA-XII and further improve its solubility characteristics. Methods: Various recrystallization methods were used to screen crystal forms of RA-XII, and single crystals (Forms I, II and V) were obtained by the vapor diffusion method. The forms were characterized by powder X-ray diffraction (PXRD), spectroscopy (FTIR, Raman), thermal analyses (DSC, TGA) and scanning electron microscopy (SEM). Structural parameters were determined by single crystal X-ray diffraction (SCXRD). The solubility and intrinsic dissolution rate were determined in a pH 7.4 pharmaceutical buffer solution with water. Hirshfeld surface analyses, molecular electrostatic potential surface (MEPs) analyses and molecular dynamics (MD) simulations were employed to reveal differences in hydrogen bond interactions of the crystal structure. Results: Five solvatomorphs and an amorphous form of RA-XII were successfully obtained. Then, three single crystals of Forms I, II and V were obtained, and their conformations were investigated. Hirshfeld surface analyses and crystal structures revealed significant differences in hydrogen bonding interactions and molecular packing. Moreover, MEPs analyses and MD suggested the formation mechanisms of RA-XII solvatomorphs, in which the hydrogen bonding strengths increase between RA-XII and solvent molecules. Conclusions: Form I is physically more stable and exhibits great solubility in water. Form I possesses significant medicinal advantages. These findings provide valuable insights into understanding the solvatomorph mechanisms and the quality control of RA-XII. Full article

The safe and efficient removal of hydrogen sulfide (H₂S) from natural gas is essential to prevent environmental hazards and equipment corrosion. This study investigates the influence of crosslinker concentration on the H₂S adsorption performance of tetraethylenepentamine (TEPA) impregnated polyacrylic acid (PAA) hydrogels through a combination of experimental analysis and molecular dynamics (MD) simulations. The synthesized hydrogel samples were experimentally characterized using Fourier-Transform Infrared Spectroscopy (FTIR) to identify the functional groups. MD simulations were performed to optimize and equilibrate the molecular structures. Simulated X-ray diffraction (XRD) patterns were generated to analyze the structural characteristics of the models. Grand Canonical Monte Carlo (GCMC) simulations were used to investigate H₂S adsorption under different temperatures and pressures. The results reveal that increasing the crosslinker concentration reduces the hydrogel’s H₂S adsorption capacity (down to 1.5 mmol/g) by limiting available adsorption sites, restricting swelling, and negatively affecting TEPA distribution. Conversely, lower crosslinker concentrations enhance H₂S uptake (up to 3 mmol/g) by promoting polymer chain flexibility and enabling more effective TEPA–H₂S interactions. This integrated experimental and simulation study provides insight into the adsorption mechanisms of H₂S, offering valuable guidance for the development of high-performance amine-impregnated polymer hydrogels for industrial gas purification applications. Full article

Medicinal plants are valuable sources of structurally diverse bioactive compounds with potential antiviral properties, although their chemical complexity complicates candidate prioritization. This study developed a hierarchical computational framework to prioritize metabolites from Uvaria chamae against Ebola virus glycoprotein GP1–GP2 (PDB ID: 5F1B) and SARS-CoV-2 papain-like protease PLpro (PDB ID: 7CMD). A library of 105 phytochemicals was evaluated using statistical analyses, molecular docking, Prime MM-GBSA, ADMET and medicinal chemistry assessments, induced-fit docking, 100 ns molecular dynamics simulations, and conceptual DFT. Although overall docking-score distributions did not differ significantly among plant organs, top-ranked candidates were predominantly associated with roots and stems, while flavonoids, acetogenins, and phenolics showed the most favorable profiles. Proanthocyanidin emerged as the leading Ebola GP candidate (Prime MM-GBSA ΔGbind = −45.66 kcal/mol), whereas uvangoletin showed the most balanced PLpro profile (−41.69 kcal/mol). MD simulations with toremifene and GRL0617 as references supported structural persistence of the prioritized complexes. DFT analysis yielded HOMO–LUMO gaps of 5.37 eV for proanthocyanidin and 4.81 eV for uvangoletin. This framework enables reproducible prioritization of plant organs, phytochemical classes, and metabolites before experimental validation. Full article

Understanding the molecular organization of surfactants at the sc-CO₂/water interface is essential for the rational design of CO₂-philic interfacial formulations with reduced fluorine content. In this work, three low-fluorinated anionic surfactants (LF1–LF3) with different hydrophobic-tail architectures were investigated together with a fluorine-free branched co-surfactant (ZBJ) using density functional theory (DFT) calculations and molecular dynamics (MD) simulations. DFT calculations revealed a clear amphiphilic segregation of solvent affinity: the fluorinated tails preferentially interacted with CO₂, whereas the sulfonate headgroups exhibited stronger affinity for water. MD simulations showed that the surfactants, initially positioned at the sc-CO₂/water interface, underwent interfacial reorganization and orientational ordering, with their fluorinated tails extending into the sc-CO₂ phase and their hydrophilic headgroups oriented toward the aqueous phase. Tail branching strongly affected interfacial packing and structural stability; the three-tailed, claw-like LF3 formed the thickest and most thermodynamically stable monolayer, with an interfacial formation energy of −330.30 kJ/mol. In the LF3/ZBJ mixed system, ZBJ occupied packing voids between LF3 molecules, further stabilizing the mixed monolayer and yielding an interfacial formation energy of −342.07 kJ/mol. These results clarify how tail architecture, CO₂-philic/hydrophilic partitioning, counterion coordination, and steric complementarity govern the interfacial organization and stabilization of low-fluorine surfactants, providing molecular-level guidance for the rational design of low-fluorine surfactant formulations for sc-CO₂/water systems. Full article

Introduction: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder for which single-target strategies may be insufficient. This study explored a host–microbial multitarget strategy using a CNS-oriented small molecule predicted to engage both human acetylcholinesterase (AChE) and Porphyromonas gingivalis lysine-specific gingipain K (Kgp). Methods: A CNS-focused library of 116,226 compounds was standardized and filtered to 1000 candidates for sequential AChE/Kgp docking. Refined docking, interaction-guided pose analysis, dual-target ranking, and SwissADME predictions were used for prioritization. ADKGP_0026671 was subsequently evaluated in single 100 ns molecular dynamics trajectories for AChE and Kgp, alongside donepezil and KYT-36 reference complexes, followed by MM/PBSA endpoint energy analysis. Results: ADKGP_0026671 showed docking scores of −11.804 kcal/mol for AChE and −7.345 kcal/mol for Kgp, was predicted to be BBB-permeant and not a P-glycoprotein substrate, and contained no PAINS or Brenk alerts. The single MD trajectories showed continued binding-site association and limited protein backbone deviation over the simulated period, although reproducibility cannot be established without independent replicas. MM/PBSA endpoint estimates were negative for AChE (−18.86 kcal/mol) and Kgp (−15.67 kcal/mol), but less favorable than donepezil and KYT-36, respectively. Conclusions: ADKGP_0026671 showed a balanced computational profile across two mechanistically distinct targets, supporting experimental evaluation of a host–microbial dual-target strategy in AD. These findings remain hypothesis-generating and require biochemical validation and replicated simulations. Full article

Xenon (Xe) is an inert noble gas receiving increasing attention in medical research due to its anesthetic properties, ability to regulate metabolic processes, and broad organoprotective effects. Due to its small size and non-covalent intermolecular interactions, Xe can be encapsulated within α-cyclodextrin (α-CD). In this study, we combine a theoretical study based on molecular mechanics (MM) and molecular dynamics (MD) simulations with the synthesis and characterization of the α-CD/Xe inclusion complex. During the MD simulations, surface interactions and the formation of inclusion complexes, with Xe atoms encapsulated within the α-CD cavity, were observed in aqueous solution. As the Xe concentration in water increased, α-CD/Xe inclusion complexes with 1:1, 1:2, and 1:3 stoichiometries were formed and remained stable over time, suggesting increasingly effective encapsulation at higher pressures. Following this computational investigation, experimental work was conducted to synthesize and characterize the α-CD/Xe inclusion complex using a liquid-phase encapsulation method. The complexes were prepared at Xe loading pressures of 2, 4, 6, and 8 bar. Thermogravimetric analysis (TGA) revealed weight loss between 100 and 200 °C. The effective encapsulation of Xe was also confirmed by solid-phase microextraction coupled with gas chromatography–mass spectrometry (SPME-GC-MS), which detected the characteristic m/z signals of Xe and allowed monitoring of its release over time upon contact with aqueous solution. Full article