Dynamics Simulation Analysis Research Articles

Evaluation of novel Anti-SARS-CoV-2 compounds by targeting nucleoprotein and envelope protein through homology modeling, docking simulations, ADMET, and molecular dynamic simulations with the MM/GBSA calculation

The current prominent virus that induces severe acute respiratory syndrome is SARS-CoV-2. The incidence of COVID-19 cases is increasing, necessitating the immediate development of effective treatments. Our objective was to employ an in-silico approach to evaluate the effectiveness of conventional compounds against COVID-19's nucleoprotein and envelope protein. A docking simulation was performed on 9 compounds as SARS-coronavirus inhibitors using AMDock software. Anti-covid-19 activities were further evaluated for the compounds. Based on docking results, the binding affinity of "N-(4-carbamoylphenyl)-8-cyclopropyl-7-(naphthalen-1-ylmethyl)-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxamide,” also called compound 36 in this research, was found to be −8.8 ​kcal/mol for the modeled envelope protein and −7.3 ​kcal/mol for the template envelope protein, while −10.1 ​kcal/mol for the modeled nucleocapsid proteins (NP) and −8.7 ​kcal/mol for the template nucleocapsid proteins (NP) of SARS-coronavirus, respectively. The ligand and control drug (ritonavir) with high docking scores were subjected to pharmacological screening, molecular dynamic simulations, and Molecular Mechanics-generalized Born Surface Area (MM/GBSA) calculations. Furthermore, the jobs of pharmacokinetics were assessed, and the outcomes acquired show that the proposed compound 36 includes great oral bioavailability and a capacity to diffuse through various organic boundaries. The protein-ligand complexes were subjected to dynamic simulation analyses with a re-enactment time of 10 ns, likewise, their free binding energy was inspected operating the MM/GBSA approach. The docking (MD simulation) results acquired emphasize the pivotal residues answerable for the protein-ligand interaction, giving an understanding of the method of association. The MD simulation analysis verifies the structural stability of the selected complexes during the MD trajectory, with minor changes detected. The MM/GBSA data show that compound 36 has the lowest free energy of −12.498 ​kcal/mol for EP and −57.5185 ​kcal/mol for NP proteins of SARS-coronavirus, confirming the molecular docking result. As a result, the identified chemical can be used to develop a new family of antiviral medications against SARS-coronavirus-2.

Optimizing and designing upper-stage separation spring of lifting-body rocket

Because the upper-stage separation of a lifting-body rocket is difficult under the low-altitude and high-speed flight environments, an upper-stage separation scheme based on the separation spring is proposed. The integration of ADAMS and MATLAB realizes the multi-body dynamics simulation analysis of upper-stage separation. The experimental design method is used to carry out the target simulation and calculation of the upper-stage separation process, with the separation condition deviation and the separation spring deviation considered at the same time, thus ensuring the reliability of the separation scheme. In order to further optimize the separation scheme, an upper-stage separation optimization model is established with the Isight software, and the mass of separation spring is optimized with the multi-island genetic algorithm and significantly reduced by 48.87% under the condition that the upper-stage separation process satisfies all constraints, thereby effectively improving the performance of the lifting-body rocket.

Dynamic simulation analysis of molten salt reactor-coupled air–steam combined cycle power generation system

Dynamic simulation analysis of molten salt reactor-coupled air–steam combined cycle power generation system

Molecular dynamics simulation analysis of the effects and mechanisms of lipid nanoparticles in drug delivery systems

Molecular dynamics simulation analysis of the effects and mechanisms of lipid nanoparticles in drug delivery systems

Percolating Network of Anionic Vacancies in Prussian Blue: Origin of Superior Ammonium-Ion Storage Performance.

Emerging aqueous ammonium-ion batteries (AIBs) are considered inexpensive, highly safe, ecofriendly, and sustainable energy storage systems. Although some high-performance electrode materials have been reported for AIBs, a comprehensive understanding of the origin of the high ammonium-ion storage performance is still lacking. Herein, the percolating network of anionic vacancies is determined to be the origin of the superior ammonium-ion storage properties of the Prussian blue analogues based on ab initio molecular dynamics simulation and electrochemical kinetic analyses. Fe[Fe(CN)6] with a percolating anionic vacancy network delivers an outstanding rate of 64.7 mAh g-1 at 2000 mA g-1 in addition to a capacity retention of 94.5% after 10 000 cycles. The low-strain intercalation ammonium-ion storage mechanism of highly deficient Fe Prussian blue with Fe as the redox center is revealed by in situ X-ray diffraction and ex situ X-ray absorption fine structure analysis. The results provide insights into the mechanism of ammonium-ion storage in Prussian blue analogues and guidance in the development of aqueous AIBs.

Discovery of thiazolidinedione-based pancreatic lipase inhibitors as anti-obesity agents: synthesis, in silico studies and pharmacological investigations

A series of new 2,5-disubstituted arylidene derivatives of thiazolidinedione (16a-e, 17a-d, 18a-c) designed using molecular hybridization approach were synthesized, structurally characterized, and explored for their anti-obesity potential via inhibition of Pancreatic Lipase (PL). Compound 18a presented the most potent PL inhibitory activity with IC50 = 2.71 ± 0.31 µM, as compared to the standard drug, Orlistat (IC50 = 0.99 µM). Kinetic study revealed reversible competitive mode of enzyme inhibition by compound 18a with an inhibitory constant value of 1.19 µM. The most promising compound 18a revealed satisfactory binding mode within the active site of the target protein (human PL, PDB ID: 1LPB). Also, MM/PBSA binding free energy and molecular dynamics (MD) simulation analysis were performed for the most promising compound 18a, which showed potent inhibition according to the results of in vitro studies. Furthermore, a stable conformation of the 1LPB-ligand suggested the stability of this compound in the dynamic environment. The ADME and toxicity analysis of the compounds were examined using web-based online platforms. Results of in vivo studies confirmed the anti-obesity efficacy of compound 18a, wherein oral treatment with compound 18a (30 mg/kg) resulted in a significant reduction in the body weight, BMI, Lee index, feed intake (in Kcal), body fat depots and serum triglycerides. Compound 18a significantly decreased the levels of serum total cholesterol (TC) to 128.6 ± 0.59 mg/dl and serum total triglycerides (TG) to 95.73 ± 0.67 mg/dl as compared to the HFD control group. The present study identified disubstituted TZD derivatives as a new promising class of anti-obesity agents. Communicated by Ramaswamy H. Sarma

Retracted: Dynamic Modeling and Simulation Analysis of Virtual Product Design and Creation Based on OSG Artificial Intelligence Platform

Retracted: Dynamic Modeling and Simulation Analysis of Virtual Product Design and Creation Based on OSG Artificial Intelligence Platform

The in vitro and in vivo antiviral effects of IGF1R inhibitors against respiratory syncytial virus infection

The insulin-like growth factor 1 receptor (IGF1R) was recognized as a pivotal receptor that facilitated the cellular entry of RSV. Small molecule inhibitors designed to target IGF1R exhibited potential as potent antiviral agents. Through virtual screening, we conducted a screening process involving small molecule compounds derived from natural products, aiming to target the IGF1R protein against respiratory syncytial virus infection. The molecular dynamics simulation analysis showed that tannic acid and daptomycin interacted with the IGF1R. The experimental results in vivo and in vitro showed that tannic acid and daptomycin had anti-RSV infection potential through reducing viral loads, inflammation, airway resistance and protecting alveolar integrity. The CC50 values of tannic acid and daptomycin were 6 nM and 0.45 μM, respectively. Novel small-molecule inhibitors targeting the IGF1R, tannic acid and daptomycin, may be effective anti-RSV therapy agents. This study may in future broaden the arsenal of therapeutics for use against RSV infection and lead to more effective care against the virus. Communicated by Ramaswamy H. Sarma

Inhibiting the oligomerization of mycobacterial DNA-directed RNA polymerase (RNAP) using natural compound via in-silico techniques

Mycobacterium tuberculosis (Mtb) is responsible for the spread of tuberculosis (TB). The current study employed virtual screening of 2569 natural compounds against the DNA-directed RNA polymerase (RNAP) of Mtb to identify the possible binders that can inhibit its function. The in-silico methodology included molecular docking to the compounds, further, the stability and flexibility of the best complexes were studied using molecular dynamics simulation, the MM/GBSA binding free energy technique with energy decomposition, PCA, FEL, steered MD simulation, and umbrella sampling. Individual virtual screenings were conducted for the five RNAP subunits (chains A, B, C, D, and E) to identify a compound capable of inhibiting RNAP oligomerization. A promising compound, isoestradiol 3-benzoate, exhibited a low binding score (−7.28 ​kcal/mol to −8.21 ​kcal/mol) and showed binding ability with all subunits of the protein. Thus, the five complexes with isoestradiol 3-benzoate were selected for molecular dynamics simulation analysis. Furthermore, RMSD showed that isoestradiol 3-benzoate bound with chain E showed the lowest RMSD of 0.49 ​nm, while with chains A and B it had the most stable and consistent conformations with RMSD of 1.75 ​nm and 1.2 ​nm, respectively. The H-bond between isoestradiol 3-benzoate and chains C and E showed the highest occupancy (58.27 ​%, 45.33 ​%, and 50.80 ​%, 42.25 ​%, 11.75 ​%). Moreover, the MMPBSA technique showed that isoestradiol 3-benzoate had a strong association with chains B and C (ΔGbind ​= ​−126.25 ​± ​2.03 and −129.27 ​± ​2.25). Additionally, free energy decomposition, PCA, FEL-steered MD simulation, and umbrella sampling were also performed to validate the association of the ligand with the protein. Isoestradiol 3-benzoate binds strongly to chains B and E; therefore, it should be considered as viable candidate for inhibiting the formation of RNAP protein complex, concluded in this study.

Ursolic acid acetate and iso-mukaadial acetate bind to Plasmodium falciparum Hsp90, abrogating its chaperone function in vitro

Plasmodium falciparum is the most lethal malaria parasite. Increasing incidences of drug resistance of P. falciparum have prompted the need for discovering new and effective antimalarial compounds with an alternative mode of action. Heat shock protein 90 (PfHsp90) facilitates protein folding and is a promising antimalarial drug target. We have previously reported that iso-mukaadial acetate (IMA) and ursolic acid acetate (UAA) exhibit antimalarial activity. We investigated the abilities of IMA and UAA to bind PfHsp90 by molecular docking and dynamics simulations. The in silico predictions were validated by biochemical assays conducted on recombinant PfHsp90. The interaction between the ligands and PfHsp90 was evaluated using ultraviolet-visible spectroscopy (UV-vis), Fourier transform infrared (FTIR), and surface plasmon resonance (SPR) analysis. The results obtained by docking calculations and MD dynamics simulation predicted that UAA and IMA preferentially bound to PfHsp90 via the N-terminal domain, with UAA binding more stable than IMA. UV-vis-based data suggest that PfHsp90 harbors buried aromatic amino acids, which were exposed in the presence of either IMA or UAA. In addition, data obtained using FTIR suggested that IMA and UAA destabilized the secondary structure of PfHsp90. Of the two compounds, UAA bound to PfHsp90 within the micromolar range based on surface plasmon resonance (SPR)-based binding assay. Furthermore, both compounds disrupted the holdase chaperone function of PfHsp90 as the chaperone failed to suppress heat-induced aggregation of the model proteins, malate dehydrogenase (MDH), luciferase, and citrate synthase in vitro. In addition, both compounds lowered the ATPase activity of PfHsp90. The molecular dynamics simulation analysis indicated that the docked complexes were mostly stable for 100 ns, validating the data obtained through the biochemical assays. Altogether, this study expands the repository of antiplasmodial compounds that have PfHsp90 among their possible targets.

Double enzymes coupled screening assisted molecular modification of α-Amino acid ester acyltransferase for L-Alanyl-l-Glutamine biosynthesis

L-Alanyl-l-Glutamine (Ala-Gln) is a kind of functional dipeptide, which is widely used in food and health care. Ala-Gln can be synthesized from l-glutamine and l-alanine methyl ester hydrochloride by α-Amino acid ester acyltransferase (AET). Still, the low catalytic efficiency and conversion rate of AET are key limiting factors in Ala-Gln production. In this study, the mutant library of AET were built based on structural model and semi-rational design. To facilitate the screening of AET mutants, the double enzymes coupled screening method was constructed and optimized. The amino acid residues I115, D203, F211, D300, A298, and R334 were selected as candidate mutation sites by alanine scanning and virtual saturation mutation and the catalytic activity of the optimal mutation A298C increased by 23.7%. Molecular dynamics simulation and molecular docking analysis suggested that the increased flexibility of the catalytic pocket in AET (A298C) and the formation of additional hydrogen bonds with substrate contributed to the improvement of enzyme activity.

Insights from in silico exploration of major curcumin analogs targeting human dipeptidyl peptidase IV

The goal of this work is to use a variety of in-silico techniques to identify anti-diabetic agents against DPP-IV enzyme from five main curcumin analogues. To produce the successful molecules, five main curcumin analogues were docked into the active site of DPP-IV enzyme. In comparison to the control molecule (Saxagliptin, −6.9 kcal/mol), all the compounds have the highest binding affinity (-7.6 to −7.7 kcal/mol) for the DPP-IV enzyme. These compounds underwent further testing for studies on drug-likeness, pharmacokinetics, and acute toxicity to see the efficacy and safety of compounds. To assess the stability of the docking complex and the binding posture identified during the docking experiment, our study got THC as the lead compound, which was then exposed to 200 ns of molecular dynamic simulation and PCA analysis. Additionally, DFT calculations were conducted to determine the thermodynamic, molecular orbital, and electrostatic potential characteristics of lead compound. Overall, the lead chemical has shown strong drug-like properties, is non-toxic, and has a sizable affinity for the DPP-IV enzyme. Communicated by Ramaswamy H. Sarma

In silico screening of phytoconstituents as potential anti-inflammatory agents targeting NF-κB p65: an approach to promote burn wound healing

Chronic burn wounds are frequently characterised by a prolonged and dysregulated inflammatory phase that is mediated by over-activation of NF-κB p65. Synthetic wound healing drugs used for treatment of inflammation are primarily associated with several shortcomings which reduce their therapeutic index. In this scenario, phytoconstituents that exhibit multifaceted biological activities including anti-inflammatory effects have emerged as a promising therapeutic alternative. However, identification and isolation of phytoconstituents from medicinal herbs is a cumbersome method that is linked to profound uncertainty. Hence, present study aimed to identify prospective phytoconstituents as inhibitors of RHD of NF-κB p65 by utilizing in silico approach. Virtual screening of 2821 phytoconstituents was performed against protein model. Out of 2821 phytoconstituents, 162 phytoconstituents displayed a higher binding affinity (≤ −8.0 kcal/mol). These 162 phytoconstituents were subjected to ADMET predictions, and 15 of them were found to satisfy Lipinski’s rule of five and showed favorable pharmacokinetic properties. Among these 15 phytoconstituents, 5 phytoconstituents with high docking scores i.e. silibinin, bismurrayaquinone A, withafastuosin B, yuccagenin, (+)-catechin 3-gallate were selected for molecular dynamics (MD) simulation analysis. Results of MD simulation indicated that withafastuosin B, (+)-catechin 3-gallate and yuccagenin produced a compact and stable complex with protein without significant variations in conformation. Relative binding energy analysis of best hit molecules indicate that withafastuosin B, and (+)-catechin 3-gallate exhibit high binding affinity with target protein among other lead molecules. Findings of study suggest that these phytoconstituents could serve as promising anti-inflammatory agents for treatment of burn wounds by inhibiting the RHD of NF-κB p65. Communicated by Ramaswamy H. Sarma

Multi‐Technique Approach to Identify Potent Antimicrobial Agents from Calotropis procera: Insight into Pharmacophore Modeling, Molecular docking, MD simulation, and DFT Approaches

AbstractIn this research, natural compounds from Calotropisprocera were screened according to their antimicrobial activity against the pathogenic microbes selected as E. coli, S. aureus, Traypanosomabrucei, Moraxella catarrhalis, and Leishmaniaamazonensis. A 3D‐QSAR study was performed that evaluated the correlation of the structural parameters for the antimicrobial activity of the natural compounds which were selected based on their antimicrobial in‐vivo and in‐vitro studies previously. The screened active compounds were further studied by molecular docking to analyze the various interactions between the ligands and target proteins. Molecular docking was also performed with the three FDA‐approved antibiotics Cephalexin, Dicloxacillin, and Levofloxacin, having antimicrobial potential, and their results were compared with the docking results of the hit compounds. Results of ADME/T study of the compounds revealed that the two compounds stigmasterol and caryophyllene oxide are the hit compounds having no toxicity, best values of TPSA and average molecular weight. Validation of the docking results was also carried out by re‐docking as well as by molecular dynamic simulation. DFT study was also carried out to explore the stability and chemical properties of active compounds. Results showed that caryophyllene oxide is the hit compound because of the highest Moldock score with 3VOB protein, better than standard drugs and according to dynamic simulation analysis. Therefore, the derived results in these studies provide crucial information for designing antimicrobial drugs by using natural compounds that have better antimicrobial activity.

Sequence and structure statistics of the nanobody database and molecular dynamics simulation analysis of the nanobody VHH

Antibodies are immunoglobulins produced in vivo by immune cells stimulated by exogenous molecules, and nano-antibodies are a class of molecules that are similar to conventional antibodies but smaller in size. Originally discovered as an antibody in camelidsand cartilaginous fishes, they are called heavy chain antibodies due to the lack of light and heavy chain constant regions in the CH1 region except for the retained heavy chain, and their binding region to the antigen consists of the heavy chain variable region only, making them the smallest antibodies available with complete antibody functional properties. In this experiment, we analyzed the commonalities and differences of the nanobodies by extracting all their amino acid sequences, performed protein modeling of the relevant nanobodies of coronaviruses among them, and then analyzed the data of RMSD and RMSF by using molecular dynamics simulation, and finally predicted and analyzed the protein conformation and the structures of VHH at all levels.

Effects of grain size and dislocation density on thermally-induced martensitic transformation of nanocrystalline NiTi alloys

Nanoscale grain and high dislocation density are the most common microstructures of nanocrystalline NiTi alloy. Although grain size and dislocation density influence the functional properties of NiTi alloy significantly, their effects on martensitic transformation have not been investigated quantitatively. In this work, the effects of grain size and dislocation density on thermally-induced martensitic transformation of nanocrystalline NiTi alloys are studied based on experiment, molecular dynamics simulation and theoretical analysis. Firstly, the drop of martensite-start-temperature and austenite-finish-temperature with decreasing grain size is determined, which is attributed to the increased fraction of grain boundary and the enhanced disordering of austenite near grain boundary via molecular dynamics simulation. Secondly, the positive correlation between dislocation density and transformation temperatures is verified by experiments and molecular dynamics simulations, which is ascribed to the enhanced stability of correspondence variant pair with habit plane of (−0.4138 0.8684 0.2688) and invariant shear direction of [−0.4432 −0.458 0.77706] under the dislocation-induced stress field. At last, a novel thermodynamic model of nanocrystalline NiTi considering grain size and dislocation density is proposed to predict martensite-start-temperature and austenite-finish-temperature. Prediction results accord to experimental data reasonably with the error generally less than 15 K. This study provides a basis for regulating the functional properties of nanocrystalline NiTi alloys through microstructural manipulation.

CT analysis of frontal recess air cell and fluid dynamics simulation of frontal sinus in people with different frontal sinus development after Draf1–3 surgery

ObjectiveTo explore the effects of Draf1–3 on frontal sinus airflow and frontal sinus irrigation in people with different frontal sinus developmentMethodsThe development of the frontal sinus and the distribution of the frontal recess cells were evaluated by CT scan in 150 adults (300 sides). The airflow changes into the frontal sinus and frontal recess after Draf were analyzed by Fluent software under a steady state and quiet inspiratory state. Nasal irrigation after Draf in adults with well-developed frontal sinus was simulated using 120 mL saline at a rate of 12 mL/s in a position at 45° to observe the changes in transient flow distribution.ResultsThe moderately developed type of the frontal sinus was the most common. The airflow patterns in the frontal sinus and frontal recess in the moderate development group were laminar, while several large vortexes were formed between the frontal sinus and frontal recess in the well-development group. The Draf exerted more significant effects on the patterns, pressure, and velocity of the airflow in the frontal sinus and frontal recess in the well development group than in the moderate development group. The volume fraction of saline in the frontal sinus increased significantly from Draf1 to Draf3, and the time required for a complete infiltration of saline in the frontal sinus mucosa was significantly reduced.ConclusionsDraf1–3 has different effects on the airflow field of the frontal sinus with different developmental types; and Draf1–3 can significantly improve the postoperative flushing of the frontal sinus.

Molecular dynamics simulation and experimental analysis of nucleation and growth mechanism of mixed inorganic salts in supercritical water

Supercritical water gasification (SCWG) technology is one of the more promising approaches for processing oily wastewater. However, there needs to be more research on the sedimentation of mixed inorganic salts in the supercritical water reactor while treating oily wastewater. In this study, the clustering process of mixed inorganic chlorides containing NaCl, KCl, and CaCl2 in supercritical water was simulated through molecular dynamics simulation. Molecular dynamics simulation was mainly conducted for mixed inorganic salts within the parameter range of 673 K-1073 K and 22 MPa-28 MPa. Combined with Yasuoka and Matsumoto's cluster theory, it can be concluded that the nucleation process of mixed inorganic salts in the supercritical water environment is mainly affected by density. Although the ion diffusion coefficient increases with temperature, the nucleation rate of inorganic salts gradually decreases due to the decrease in density. In the temperature range of 673 K-1073 K, the nucleation rate of mixed inorganic salts decreased from 34.96 to 1.65 1036 m−3·s−1. At the same pressure, the crystal growth rate parameter decreased gradually with increasing temperature, reaching about 168.25–60.09 m·s−1. Finally, the simulation results were verified experimentally, confirming that the crystal growth rate decreases with increasing temperature.

Genome-wide mapping and cryo-EM structural analyses of the overlapping tri-nucleosome composed of hexasome-hexasome-octasome moieties

The nucleosome is a fundamental unit of chromatin in which about 150 base pairs of DNA are wrapped around a histone octamer. The overlapping di-nucleosome has been proposed as a product of chromatin remodeling around the transcription start site, and previously found as a chromatin unit, in which about 250 base pairs of DNA continuously bind to the histone core composed of a hexamer and an octamer. In the present study, our genome-wide analysis of human cells suggests another higher nucleosome stacking structure, the overlapping tri-nucleosome, which wraps about 300-350 base-pairs of DNA in the region downstream of certain transcription start sites of actively transcribed genes. We determine the cryo-electron microscopy (cryo-EM) structure of the overlapping tri-nucleosome, in which three subnucleosome moieties, hexasome, hexasome, and octasome, are associated by short connecting DNA segments. Small angle X-ray scattering and coarse-grained molecular dynamics simulation analyses reveal that the cryo-EM structure of the overlapping tri-nucleosome may reflect its structure in solution. Our findings suggest that nucleosome stacking structures composed of hexasome and octasome moieties may be formed by nucleosome remodeling factors around transcription start sites for gene regulation.

Unraveling the function and structure impact of deleterious missense SNPs in the human OX1R receptor by computational analysis

The orexin/hypocretin receptor type 1 (OX1R) plays a crucial role in regulating various physiological functions, especially feeding behavior, addiction, and reward. Genetic variations in the OX1R have been associated with several neurological disorders. In this study, we utilized a combination of sequence and structure-based computational tools to identify the most deleterious missense single nucleotide polymorphisms (SNPs) in the OX1R gene. Our findings revealed four highly conserved and structurally destabilizing missense SNPs, namely R144C, I148N, S172W, and A297D, located in the GTP-binding domain. Molecular dynamics simulations analysis demonstrated that all four most detrimental mutant proteins altered the overall structural flexibility and dynamics of OX1R protein, resulting in significant changes in the structural organization and motion of the protein. These findings provide valuable insights into the impact of missense SNPs on OX1R function loss and their potential contribution to the development of neurological disorders, thereby guiding future research in this field.