Results Of Molecular Dynamics Simulations Research Articles

Adsorption behaviors of dibutyl dithiophosphate and sodium-diisobutyl dithiophosphinate (3418A) on chalcopyrite: A combined experimental and theoretical study

Sodium-diisobutyl dithiophosphinate (3418A) is a new collector with good selectivity for lead and copper ore, even better than dibutyl dithiophosphate (DTP). However, there still exists a lack of research on a mechanism for the interaction between chalcopyrite and 3418A. In this study, micflotation, microcalorimetric, cyclic voltammetry, adsorption measurement, density functional theory (DFT) calculations, and molecular dynamics (MD) were carried out to investigate the adsorption behaviors and differences of DTP and 3418A on the chalcopyrite surface. The flotation results show that 3418A has higher chalcopyrite recoveries than DTP, and microcalorimetric and adsorption measurements indicate that the adsorption quantity and adsorption heat of 3418A on the chalcopyrite surface is higher than that of DTP. In addition, DFT calculations suggest that the chemical adsorption of 3418A on the chalcopyrite surface is stronger than that of DTP. MD simulation results suggest that the hydrophobicity of the chalcopyrite surface after 3418A adsorption is stronger than that of DTP. Hence, our results presented that the 3418A is more favorable to the flotation of chalcopyrite than DTP. Based on coordination chemistry theory, the orbital interaction between chalcopyrite and reagent molecules is analyzed. It is suggested that the interaction between DTP and chalcopyrite is positive σ action, as well as 3418A, while the π back-bonding has not occurred. In addition, the energy of the highest occupied molecular orbital (HOMO) of 3418A is higher than that of DTP. Therefore, the interaction of chalcopyrite with 3418A is stronger than with DTP.

Enantioselective effects of paclobutrazol and its enantiomers on glycolipid metabolism in zebrafish (Danio rerio)

Paclobutrazol is a plant growth inhibitor widely used in agricultural production. However, toxicology studies of paclobutrazol enantiomers towards aquatic organisms are limited. Herein, effects of paclobutrazol and its two enantiomers (2R, 3R; 2S, 3S) on glycolipid metabolism of zebrafish have been systemically explored at the concentration of 10 mg/L through biochemical analyses, LC-MS/MS, molecular dynamics simulation, and gene expression. In all treatments, the contents of glucose, citric acid and lactate significantly were increased while the glycogen and pyruvate contents were decreased, in which (2R, 3R)-paclobutrazol exhibited a greater effect than the (2S, 3S)-enantiomer (P < 0.05). Then, activities of hexokinase and lactate dehydrogenase in (2R, 3R)-paclobutrazol treatment were 0.74- and 1.18-fold higher than (2S, 3S)-enantiomer treatment, respectively (P < 0.001), and the results of molecular dynamics simulation revealed that the binding free energy of hexokinase 1 to (2R, 3R)-paclobutrazol was higher than that to the antipode. Moreover, lipids including triglycerides, total cholesterol, fatty acids, bile acids and glycerophospholipids in zebrafish were strikingly affected after paclobutrazol exposure. The (2R, 3R)-paclobutrazol-treated group showed the most obvious changes, indicating that it possessed much stronger disruption ability on the lipid metabolism of zebrafish. Furthermore, qRT-PCR analysis results revealed that (2R, 3R)-enantiomer significantly impacted expressions of glycolipid metabolism-related genes (hk1, g6pc, pck1, pk, aco, cebpa, cyp51, fasn and ppara) in zebrafish than (2S, 3S)-enantiomer (P < 0.05). Briefly, this study provides new evidences for the toxicity of paclobutrazol to aquatic organisms and the potential risk to human health at the chiral level.

Myricetin: A Potent Anti-Amyloidogenic Polyphenol against Superoxide Dismutase 1 Aggregation.

Amyotrophic lateral sclerosis (ALS) is believed to be caused by the aggregation of misfolded or mutated superoxide dismutase 1 (SOD1). As there is currently no treatment, research into aggregation inhibitors continues. Based on docking, molecular dynamics (MD) simulations, and experimental observations, we propose that myricetin, a plant flavonoid, can act as a potent anti-amyloidogenic polyphenol against SOD1 aggregation. Our MD simulation results showed that myricetin stabilizes the protein interface, destabilizes the preformed fibril, and decreases the rate of fibril elongation. Myricetin inhibits the aggregation of SOD1 in a dose-dependent manner as shown by the ThT aggregation kinetics curves. Our transmission electron microscopy, dynamic light scattering, and circular dichroism experiments indicate that fewer shorter fibrils have formed. Fluorescence spectroscopy results predict the involvement of a static quenching mechanism characterized by a strong binding between protein and myricetin. Importantly, size exclusion chromatography revealed the potential of myricetin for fibril destabilization and depolymerization. These experimental observations complement the MD results. Thus, myricetin is a potent SOD1 aggregation inhibitor that can reduce the fibril load. Using the structure of myricetin as a reference, it is possible to design more effective therapeutic inhibitors against ALS that prevent the disease and reverse its effects.

Acetylcholinesterase inhibitory activities of some flavonoids from the root bark of Pinus krempfii Lecomte: in vitro and in silico study

From the root bark of Pinus krempfii Lecomte, four flavonoids were isolated and evaluated for their inhibitory activities against AChE and BChE enzymes in vitro and in silico. Tectochrysin (1) was found to inhibit AChE with an IC50 value of 33.69 ± 2.80 μM. The docking study results also showed agreement with the in vitro test results. All four compounds also showed the best binding affinity for the AChE enzyme, characterised by binding energy (ΔG) values as low as −8.1 to −9.3 kcal/mol, in which, the compound tectochrysin had the best binding affinity for the AChE protein with a ΔG value of −9.329 kcal/mol. Tectochrysin (1) was also bound to the amino acid Phe295 of AChE with a bond length of 2.8 Å, similar to the control dihydrotanshinone-I. Galangin (2) also showed its in vitro inhibitory activity against BChE with an IC50 value of 82.21 ± 2.70 μM. In silico, it also had the best binding energy value of −9.072 kcal/mol with BChE and formed hydrogen bonds with the His438 (2.85 Å) residues of BChE like the positive control (tacrine). The steered molecular dynamics (SMD) simulation results of these two complexes revealed a mechanistic insight that the protein-ligand complexes showed stable trajectories throughout the 20 and 150 ns simulations. Moreover, the drug likeliness suggested that both flavonoids (1 and 2) were expected to be drug-like and have an LD50 toxicity level of 5. This study has contributed new results for drug discovery and the development of substances with neuroprotective effects, especially for the treatment of Alzheimer’s disease. Communicated by Ramaswamy H. Sarma

Effect of Cross-Linking Density on Non-Linear Viscoelasticity of Vulcanized SBR: A MD Simulation and Experimental Study.

In recent years, there has been a growing interest in changes in dynamic mechanical properties of mixed rubber during dynamic shear, yet the influence of vulcanized characteristics on the dynamic shear behavior of vulcanized rubber, particularly the effect of cross-linking density, has received little attention. This study focuses on styrene-butadiene rubber (SBR) and aims to investigate the impact of different cross-linking densities (Dc) on dynamic shear behavior using molecular dynamics (MD) simulations. The results reveal a remarkable Payne effect, where the storage modulus experiences a significant drop when the strain amplitude (γ0) exceeds 0.1, which can be attributed to the fracture of the polymer bond and the decrease in the molecular chain's flexibility. The influence of various Dc values mainly resides at the level of molecular aggregation in the system, where higher Dc values impede molecular chain motion and lead to an increase in the storage modulus of SBR. The MD simulation results are verified through comparisons with existing literature.

Screening and Evaluation of Novel α-Glucosidase Inhibitory Peptides from Ginkgo biloba Seed Cake Based on Molecular Docking Combined with Molecular Dynamics Simulation.

Food-derived α-glucosidase inhibitory peptides have gained significant interest in treating type 2 diabetes mellitus (T2DM) owing to their favorable safety profiles. Molecular docking combined with molecular dynamics simulation was performed to screen α-glucosidase inhibitory peptides from Ginkgo biloba seed cake (GBSC), and two novel peptides (Met-Pro-Gly-Pro-Pro (MPGPP) and Phe-Ala-Pro-Ser-Trp (FAPSW)) were acquired. The results of molecular docking and molecular dynamics simulation suggested that FAPSW and MPGPP could generate stable complexes with 3wy1, and the electrostatic and van der Waals forces played contributory roles in FAPSW and MPGPP binding to 3wy1. The α-glucosidase inhibition assay corroborated that FAPSW and MPGPP had good α-glucosidase inhibition capacity, with IC50 values of 445.34 ± 49.48 and 1025.68 ± 140.78 μM, respectively. In vitro simulated digestion results demonstrated that FAPSW and MPGPP strongly resisted digestion. These findings lay a theoretical foundation for FAPSW and MPGPP in treating T2DM.

Molecular dynamics simulation of the transformation of Fe-Co alloy by machine learning force field based on atomic cluster expansion

The force field describing the calculated interaction between atoms or molecules is the key to the accuracy of many molecular dynamics (MD) simulation results. Compared with traditional or semi-empirical force fields, machine learning force fields have the advantages of faster speed and higher precision. We have employed the method of atomic cluster expansion (ACE) combined with first-principles density functional theory (DFT) calculations for machine learning, and successfully obtained the force field of the binary Fe-Co alloy. Molecular dynamics simulations of Fe-Co alloy carried out using this ACE force field predicted the correct phase transition range of Fe-Co alloy.

Analysis of Fe2+ and Mn2+ ions in DES and water: A theoretical study using molecular dynamic simulations, QTAIM and NCI-RDG

This work was essential to analyze the behavior of Fe2+ and Mn2+ ions in water and deep eutectic solvent (DES) based on choline chloride and ethylene glycol (1ChCl:2EG (choline chloride and ethylene glycol, DES)) to evaluate the electrodeposition of metallic ions. Due to their low toxicity, high solubility, biodegradability and thermal stability, DES have shown promise as alternatives to traditional solvents such as water in various applications, including biological studies. They also dissolve insoluble substances in other types of solvents, working from the purification of chemicals to the manufacture of semiconductor devices. Water, choline and ethylene glycol molecules were optimized by Density Functional Theory (DFT) through B3LYP/6–311 +G(d,p) model implemented with the Gaussian 09 W software. Molecular Dynamics (MD) simulations were performed by GROMACS software 2020.04 in a cubic box of dimensions 8 nm × 8 nm × 8 nm. Quantum Theory of Atoms in Molecules (QTAIM) and analysis of Non-covalent Interactions (NCI) used Multiwfn 3.8 software. The preliminary results of MD simulations showed that gradually adding water increased the interaction between the metal center and water. Fe2+ and Mn2+ ions were placed in water (OW) and 1ClCh:2EG, indicating that the interaction between the cations and the chloride anion in DES was strong, followed by the ethylene glycol molecules (O1, O2). In the presence of water, however, Fe-OW and Mn-OW interactions were more substantial in all systems, either with the ions alone or in a mixture. Electrostatic forces acting on the electrons in the last filled layer of the iron atom provided the formation of shorter and stronger bonds than the Mn2+ ions. When placed in a 1:1 equimolar mixture, they showed little difference from when they were isolated. Thus, the Mn-Cl interaction was more significant in the presence of a eutectic solvent than the Fe-Cl interaction. QTAIM analysis showed for the FeDES and MnDES systems that the Electron Localization Function (ELF) values increased for the Fe-(O1, O2) and Mn-(O1, O2) interactions but decreased for the Fe-Cl and Mn-Cl interactions in the metal mixture. It revealed strong hydrogen bonding interactions between the water molecules, Fe2+ and Mn2+, which may affect their chemical reactivity, as the Fe-Cl interaction in DES was stronger than Fe-Cl in any water. The Laplacians of the electronic densities were positive, and so were the ELF values, indicating a predominance of non-covalent interactions of the van der Waals forces type. Considering the two metal ions alone, in the presence of DES, the interaction strength followed Fe-Cl > Mn-Cl > Fe-(O1, O2) > Mn-(O1, O2). In the mixture, Fe-Mn followed the pattern Mn-Cl > Fe-Cl > Fe-(O1, O2) > Mn-(O1, O2). Thus, comparing the 3 systems, the interaction strength was Fe-Cl > Mn-Cl > Mn-Clmixture > Fe-Cl mixture e Fe-(O1, O2) mixture > Fe-(O1, O2) > Mn-(O1, O2)mixture > Mn-(O1, O2). The interaction strength for the systems with water was Fe-Clmixture > Fe-Cl > Mn-Cl > Mn-Clmixture. However, for the interaction with OW, the observed behaviors were: W300, Mn-OW > Fe-OWmixture > Mn-OWmixture > Fe-OWmixture; W600, Mn-OWmixture > Fe-OWmixture > Mn-OW > Fe-OW; W900, Mn-OW > Fe-OW > Mn-OWmixture > Fe-OWmixture; W1200, Mn-OW > Mn-OWmixture > Fe-OWmixture > Fe-OWmixture; W5580, Mn-OW > Fe-OW > Mn-OWmixture > Fe-OWmixture. The mixtures in the 1:1 molar ratio of the cations presented a little discrepant from their isolated ions, suggesting a new approach to observing the behavior of these systems and the coordination possibilities. One of the prospects for expanding the study will be temperature variation, modification of metal ions and molar proportions, and the effects of these changes.

Influence of inorganic and organic salts on the hydration mechanism of montmorillonite based on molecular simulation

The molecular dynamics method is used to further reveal, from the molecular point of view, the mechanisms of salt inhibiting the hydration of Na-MMT. The interaction between water molecules, salt molecules, and montmorillonite are calculated by establishing the adsorption models. According to the simulation results, the adsorption conformation, interlayer concentration distribution, self-diffusion coefficient, ion hydration parameters, and other data are compared and analyzed. The simulation results show that the volume and basal spacing increase in a stepwise manner with the increase of water content, and water molecules have different hydration mechanisms. The addition of salt will enhance the hydration properties of compensating cations of montmorillonite and affect the mobility of particles. The addition of inorganic salts mainly reduces the adsorption tightness between water molecules and crystal surfaces, thereby reducing the thickness of water molecules layer, while the organic salts can better inhibit migration by controlling interlayer water molecules. The results of molecular dynamics simulations reveal the microscopic distribution of particles and the influence mechanism when the swelling properties of montmorillonite are modified by chemical reagents.

Experimental and molecular dynamics simulation study of toluene absorption by nanofluids

It is well known that the emission of volatile organic compounds (VOCs) is a significant threat to human health and the ecological environment, and toluene is a typical representative of aromatic VOCs, whose elimination makes an important contribution to the prevention and control of air pollution. Absorption is the classical process to eliminate air pollutants, but the application of absorption is often constrained by absorbent and gas-liquid mass transfer. In recent years, process intensification has become an important development in the chemical industry, and nanotechnology can effectively reduce mass transfer resistance and improve gas-liquid mass transfer effectiveness. This work aims to evaluate the effect of adding nanoparticles on the gas-liquid mass transfer process. The effects of TiO2, Al2O3, and SiO2 nanoparticles on the removal of toluene by green solvent low transition temperature mixtures (LTTM) were investigated experimentally and theoretically. The mass transfer enhancement factors of the toluene absorption process were measured at different concentrations and sizes of TiO2, Al2O3, and SiO2 nanoparticles, absorption temperatures and number of cycles. Molecular dynamics (MD) simulations of the microscopic properties of LTTM and toluene were performed. Based on the MD simulation results, the toluene density distribution, interaction energy, radial distribution function, spatial distribution function, and self-diffusion coefficient were calculated, which helped to explain the absorption mechanism of toluene gas. The findings demonstrated that nanoparticles can alter the gas-liquid mass transfer process, and provided a method and theoretical reference for enhancing the toluene absorption process.

Interaction of C-terminal Truncated Beta-amyloid Peptides with Human Serum Albumin

Background: The formation of plaque from protein fibrils is the major source of diseases, such as Alzheimer's and Prion diseases. Amyloid beta (Aβ) is a peptide with different lengths, which is one of the main components of the plaque in the brain of people with Alzheimer's. Of the amyloid beta of various lengths in the brain cells plaque, beta-amyloid with 40 amino acids (Aβ1- 40) is more abundant than the rest. Aβ monomers are in a dynamic equilibrium of various conformations with beta sheets that aggregate as oligomers or larger structures. The misfolding of betaamyloid peptide is involved in its accumulation. On the other hand, various species that exist in the cell environment can affect the structure of beta-amyloid peptides. Aims: This study aimed to study the interaction of truncated forms of beta-amyloid peptide with human albumin serum protein. Objective: Interaction of beta-amyloid peptide with other proteins is effective in causing Alzheimer's disease. These include interactions between beta-amyloid and cell surface proteins, such as prions and extracellular proteins, such as clusterins and human serum albumin (HSA). As HSA concentrations are higher than other proteins, more than half of the interaction of beta-amyloid with proteins is related to interaction with this protein. Interaction of HSA with beta-amyloid reduces the aggregation of beta-amyloid. However, due to the diversity of beta-amyloid peptides with different lengths, the mechanism of their interaction with HSA has not been well understood. In this work, the interaction of C-terminal truncated beta-amyloid peptides with HSA has been investigated. Method: The C-terminal truncated forms of beta-amyloid peptides, Aβ1 − 26, Aβ1 − 30, and Aβ1 − 36 and Aβ1 − 40, were designed in silico. Docking between these truncated peptides was performed with serum albumin. A molecular dynamics simulation of the interaction of designed peptides with serum albumin was also performed. Results and Discussion: The results showed that Aβ1 − 26 and Aβ1 − 30 peptides interact with the interfacial region of the chains A and B of HSA and the surface of the HSA. While the interaction of Aβ1 − 36 and Aβ1 − 40 peptides occurs only with the HSA surface. On the other hand, the interaction of peptides with chain A of HSA is more favorable than their interaction with chain B of HSA. Also, as the length of the peptide increases, the number of residues involved in the hydrophobic interaction increases. The results of molecular dynamics simulation confirm the results obtained from docking. Conclusion: The results of molecular dynamics and docking simulations show that the binding affinity of peptides to serum albumin decreases with peptide shortening. Also, by changing the structure of beta-amyloid peptides, serum albumin reduces their tendency to aggregate.

Mechanisms of resistance to tyrosine kinase inhibitor treatments in patients with ROS1 fusion-positive non-small cell lung cancer.

9062 Background: ROS1 rearrangement was found in about 1% non-small cell lung cancer (NSCLC), and the fusion proteins created during this process will result in the successive activation of the ROS1 kinase domain. NSCLC patients with ROS1 gene fusions were considered a unique subtype highly sensitive to related tyrosine kinase inhibitor (TKI) treatments. However, the acquired TKI resistance was the major hurdle preventing patients from getting prolonged treatment benefits. Methods: 107 patients diagnosed with advanced or metastatic NSCLC harboring ROS1 fusion were retrospectively recruited. All patients were treated with crizotinib as first-line treatment, and 21 patients received lorlatinib after crizotinib progression. Samples were collected at baseline, after crizotinib progression, and after lorlatinib progression, which all underwent targeted DNA sequencing. TKIs binding to mutated ROS1 fusion proteins was simulated using molecular dynamics simulations. Results: The most witnessed fusion partner of ROS1 was CD74 (58%), followed by SDC4 (14%), EZR (11%), and SLC34A2 (9%). The median progression-free survival was 12.9 months for crizotinib and 6.4 months for lorlatinib. Patients with CD74-ROS1 and SLC34A2-ROS1 had significantly longer PFS than those with other ROS1 fusion types when treated with crizotinib. Patients with baseline TP53 mutations showed worse PFS compared to TP53 wild-type (WT) patients (P &lt; 0.001, HR: 0.19, 95%CI: 0.09-0.39) under crizotinib treatment. An accumulation of both on-target (baseline vs. post-crizotinib vs. post-lorlatinib: 0% vs. 43% vs. 62%) and off-target resistant mutations (baseline vs. post-crizotinib vs. post-lorlatinib: 22% vs. 26% vs. 43%) after multiple TKI treatments was observed. A total of ten on-target resistance mutations were detected after TKI therapies, with 4 first-reported mutations (ROS1 L2010M, G1957A, D1988N, L1982V). According to the molecular dynamics simulation results, ROS1 L2010M mutations (happening in the ROS1 kinase ATP binding cassette) maybe resistant to lorlatinib, entrectinib, cabozantinib, and crizotinib. ROS1 G1957A may lead to resistance to cabozantinib. Moreover, all four novel on-target mutations may lead to resistance to crizotinib. Conclusions: In summary, CD74- and SLC34A2-ROS1 patients showed better crizotinib efficacy with different resistance mutation patterns. Patients of these subtypes are potential beneficiaries of molecular testing after crizotinib progression, directing future treatment strategies. Multiple TKI treatments may lead to the accumulation of both on-target and off-target resistance mutations. In addition, 4 novel ROS1 on-target mutations identified underwent molecular dynamics simulations, unveiling potential resistance to different TKIs, which can provide vital information for future ROS1 fusion-positive NSCLC patient treatment selections.

Neuromorphic nanocluster networks: Critical role of the substrate in nano-link formation

Atomic cluster-based networks represent a promising architecture for the realization of neuromorphic computing systems, which may overcome some of the limitations of the current computing paradigm. The formation and breakage of links between the clusters are of utmost importance for the functioning of these computing systems. This paper reports the results of molecular dynamics simulations of synapse (bridge) formation at elevated temperature and thermal breaking processes between 2.8 nm-sized Au1415 clusters deposited on a carbon substrate, a model system. Crucially, we find that the bridge formation process is driven by the diffusion of gold atoms along the substrate, no matter how small the gap between the clusters themselves. The complementary simulations of the bridge breaking process reveal the existence of a threshold bias voltage to activate bridge rupture via Joule heating. These results provide an atomistic-level understanding of the fundamental dynamical processes occurring in neuromorphic cluster arrays.

Leaflet Tensions Control the Spatio-Temporal Remodeling of Lipid Bilayers and Nanovesicles.

Biological and biomimetic membranes are based on lipid bilayers, which consist of two monolayers or leaflets. To avoid bilayer edges, which form when the hydrophobic core of such a bilayer is exposed to the surrounding aqueous solution, a single bilayer closes up into a unilamellar vesicle, thereby separating an interior from an exterior aqueous compartment. Synthetic nanovesicles with a size below 100 nanometers, traditionally called small unilamellar vesicles, have emerged as potent platforms for the delivery of drugs and vaccines. Cellular nanovesicles of a similar size are released from almost every type of living cell. The nanovesicle morphology has been studied by electron microscopy methods but these methods are limited to a single snapshot of each vesicle. Here, we review recent results of molecular dynamics simulations, by which one can monitor and elucidate the spatio-temporal remodeling of individual bilayers and nanovesicles. We emphasize the new concept of leaflet tensions, which control the bilayers' stability and instability, the transition rates of lipid flip-flops between the two leaflets, the shape transformations of nanovesicles, the engulfment and endocytosis of condensate droplets and rigid nanoparticles, as well as nanovesicle adhesion and fusion. To actually compute the leaflet tensions, one has to determine the bilayer's midsurface, which represents the average position of the interface between the two leaflets. Two particularly useful methods to determine this midsurface are based on the density profile of the hydrophobic lipid chains and on the molecular volumes.

Wettability of Tetrahexcarbon: MD, DFT, and AIMD Approaches.

Graphene and its allotropes have attracted attention due to their special electronic, mechanical, and thermal properties. Numerous studies investigate their wetting behavior. Tetrahexcarbon (THC) is a new carbon allotrope and is obtained from pentagraphene. This research, examines THC's wettability properties using reactive molecular dynamics (MD) and density functional theory (DFT) simulations. The results of molecular dynamics simulation reveal that THC is a hydrophobic substrate with a contact angle of 113.4° ± 2.8°. Using molecular dynamics, this research also evaluates quantities such as contact diameter, dipole moment, and density profile of water droplet. In addition, hydrogen and oxygen atoms' distribution functions, hydrogen bonds, path of the droplet's center of mass, and potential energy surface are presented. According to the simulation results, the droplet's structure on THC is slightly layered. Also, the water molecules' orientations in the interface are such that they do not allow the hydrogen bonds to form between water molecules and the THC substrate. The results of MD show that there are two different behavioral patterns for the hydrogen bonds between and within the water droplet's layers. Furthermore, this research utilizes DFT and AIMD in order to show how a water molecule interacts with THC. DFT exhibits that the water molecule's hydrogen atoms are toward the substrate. But an opposite configuration happens in the droplet-THC interface. The results of the atoms-in-molecules (AIM) theory indicate that there is a weak interaction between the water molecules and the THC substrate. The thermochemical results reveal that water molecules' adsorption is within the range of physical adsorption. Finally, NBO analysis shows that the THC's carbon atoms have a permanent partial charge. These results confirm that the THC is a hydrophobic material.

Anisotropic orientation dependent shock wave responses of monocrystalline molybdenum

Molybdenum (Mo) demonstrates excellent industrial application potentials in micro-nano devices, which are inevitably subjected to shock loads during their application under harsh service environments. This study employs molecular dynamics (MD) simulations to investigate the shock responses of Mo under high-strain loading conditions with respect to the effects of crystal orientations. The findings reveal that monocrystalline Mo, along the shock direction of [111], exhibits inhomogeneous microstructure features characterized by significantly high-density and high-temperature localized regions. Once the rarefaction wave is produced, the physical parameters, including density and lateral pressure, will gradually decrease while normal pressure retains a residual value. The us-up, Pzz-up, and Pzz-V/V0 relations along the shock loading direction of [111] show deviations from those of [001] and [110] directions, with this difference being more pronounced for Pzz-V/V0. The formation of dislocations and the magnitude of shear stress experienced within the post-shock region are strongly dependent on crystal orientations. Specifically, an elevated probability of dislocation formation was observed along the [110] direction. Moreover, the magnitude of shear stress induced by shock loading along the [001] and [110] directions can exceed that of the [111] direction when the shock velocity is 1.5 km/s. The MD simulation results can serve as a valuable supplement to the investigations of mechanical properties pertaining to Mo.

DSF inactivator RpfB homologous FadD upregulated in Bradyrhizobium japonicum under iron limiting conditions

Phytopathogenic bacteria Xanthomonas campestris pv. campestris (Xcc) causes black rot and other plant diseases. Xcc senses diffusible signal factor (DSF) as a quorum-sensing (QS) signal that mediates mainly iron uptake and virulence. RpfB deactivates DSF in this DSF–QS circuit. We examined differential gene expression profiles of Bradyrhizobium japonicum under low versus high iron conditions and found that fadD and irr were upregulated under low iron (log2 fold change 0.825 and 1.716, respectively). In addition to having similar protein folding patterns and functional domain similarities, FadD shared 58% sequence similarity with RpfB of Xcc. The RpfB–DSF and FadD–DSF complexes had SWISSDock molecular docking scores of − 8.88 kcal/mol and − 9.85 kcal/mol, respectively, and the 100 ns molecular dynamics simulation results were in accord with the docking results. However, significant differences were found between the binding energies of FadD–DSF and RpfB–DSF, indicating possible FadD-dependent DSF turnover. The protein–protein interaction network showed that FadD connected indirectly with ABC transporter permease (ABCtp), which was also upregulated (log2 fold change 5.485). We speculate that the low iron condition may be a mimetic environmental stimulus for fadD upregulation in B. japonicum to deactivate DSF, inhibit iron uptake and virulence of DSF-producing neighbors. This finding provides a new option of using B. japonicum or a genetically improved B. japonicum as a potential biocontrol agent against Xcc, with the added benefit of plant growth-promoting properties.

Spectroscopic, voltammetric and computational approaches shed light on the combination characteristics of an anticancer agent, bexarotene with human serum albumin

The combination process of bexarotene (BEX) with the primary transporter protein in blood plasma, human serum albumin (HSA) was explored to comprehend the anticancer agent’s transport in the circulatory system. The HSA fluorescence spectrum was discovered to be successively quenched by BEX. Involvement of static quenching process as well as the BEX–HSA complexation were suggested by the bimolecular quenching rate constant (kq) values. This finding was further corroborated by ultraviolet absorption spectral analysis. The binding affinity of BEX–HSA interaction was found as moderate on the basis of Ka values (Ka = 3.19–8.72 × 104 M−1) for the system. Thermodynamic particulars (ΔS = 175.93 J mol−1 K−1; ΔH = 25.85 kJ mol−1) revealed that the stabilizing intermolecular forces associated in the reaction were hydrophobic interactions and hydrogen bonds. BEX binding altered the microenvironment near Trp and Tyr residues of HSA, but it improved the protein’s resistance to heat stress. Both site-specific ligand displacement and computational docking outcomes indicated that Sudlow’s Site II was detected as the position for BEX binding to HSA with higher priority. The BEX–HSA complex constancy was demonstrated by the complex maintaining equilibrium during the course of the simulations, according to analysis of the molecular dynamics simulation results.

Training Neural Network Models Using Molecular Dynamics Simulation Results to Efficiently Predict Cyclic Hexapeptide Structural Ensembles.

Cyclic peptides have emerged as a promising class of therapeutics. However, their de novo design remains challenging, and many cyclic peptide drugs are simply natural products or their derivatives. Most cyclic peptides, including the current cyclic peptide drugs, adopt multiple conformations in water. The ability to characterize cyclic peptide structural ensembles would greatly aid their rational design. In a previous pioneering study, our group demonstrated that using molecular dynamics results to train machine learning models can efficiently predict structural ensembles of cyclic pentapeptides. Using this method, which was termed StrEAMM (Structural Ensembles Achieved by Molecular Dynamics and Machine Learning), linear regression models were able to predict the structural ensembles for an independent test set with R2 = 0.94 between the predicted populations for specific structures and the observed populations in molecular dynamics simulations for cyclic pentapeptides. An underlying assumption in these StrEAMM models is that cyclic peptide structural preferences are predominantly influenced by neighboring interactions, namely, interactions between (1,2) and (1,3) residues. Here we demonstrate that for larger cyclic peptides such as cyclic hexapeptides, linear regression models including only (1,2) and (1,3) interactions fail to produce satisfactory predictions (R2 = 0.47); further inclusion of (1,4) interactions leads to moderate improvements (R2 = 0.75). We show that when using convolutional neural networks and graph neural networks to incorporate complex nonlinear interaction patterns, we can achieve R2 = 0.97 and R2 = 0.91 for cyclic pentapeptides and hexapeptides, respectively.

Virtual screening-based discovery of AI-2 quorum sensing inhibitors that interact with an allosteric hydrophobic site of LsrK and their functional evaluation.

Introduction: Quorum sensing (QS) is a bacterial intracellular and intercellular communication system that regulates virulence factor production, biofilm formation, and antibiotic sensitivity. Quorum-sensing inhibitors (QSIs) are a novel class of antibiotics that can effectively combat antibiotic resistance. Autoinducer-2 (AI-2) is a universal signaling molecule that mediates inter- and intraspecies QS systems among different bacteria. Furthermore, LsrK plays an important role in regulating the activity and stability of the intracellular AI-2 signaling pathway. Thus, LsrK is considered an important target for the development of QSIs. Methods: We designed a workflow integrating molecular dynamic (MD) simulations, virtual screening, LsrK inhibition assays, cell-based AI-2-mediated QS interference assays, and surface plasmon resonance (SPR)-based protein affinity assays to screen for potential LsrK kinase inhibitors. Results: MD simulation results of the LsrK/ATP complex revealed hydrogen bonds and salt bridge formation among four key residues, namely, Lys 431, Tyr 341, Arg 319, and Arg 322, which are critical for the binding of ATP to LsrK. Furthermore, MD simulation results indicated that the ATP-binding site has an allosteric pocket that can become larger and be occupied by small molecule compounds. Based on these MD simulation results, a constraint of forming at least one hydrogen bond with Arg 319, Arg 322, Lys 431, or Tyr 341 residues was introduced when performing virtual screening using Glide's virtual screening workflow (VSW). In the meantime, compounds with hydrophobic group likely to interact with the allosteric hydrophobic pocket are preferred when performing visual inspection. Seventy-four compounds were selected for the wet laboratory assays based on virtual screening and the absorption, distribution, metabolism, and excretion (ADME) properties of these compounds. LsrK inhibition assays revealed 12 compounds inhibiting LsrK by more than 60% at a 200μM concentration; four of these (Y205-6768, D135-0149, 3284-1358, and N025-0038) had IC50 values below 50μM and were confirmed as ATP-competitive inhibitors. Six of these 12 LsrK inhibitors exhibited high AI-2 QS inhibition, of which, Y205-6768 had the highest activity with IC50 = 11.28 ± 0.70μM. The SPR assay verified that compounds Y205-6768 and N025-0038 specifically bound to LsrK. MD simulation analysis of the docking complexes of the four active compounds with LsrK further confirmed the importance of forming hydrogen bonds and salt bridges with key basic amino acid residues including Lys 431, Tyr 341, Arg 319, and Arg 322 and filling the allosteric hydrophobic pocket next to the purine-binding site of LsrK. Discussion: Our study clarified for the first time that there is an allosteric site near the ATP-binding site of Lsrk and that it enriches the structure-activity relationship information of Lsrk inhibitors. The four identified compounds showed novel structures, low molecular weights, high activities, and novel LsrK binding modes, rendering them suitable for further optimization for effective AI-2 QSIs. Our work provides a valuable reference for the discovery of QSIs that do not inhibit bacterial growth, thereby avoiding the emergence of drug resistance.