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• The interaction mechanism of rice glutelin and soybean 11S globulin was revealed. • Multi-spectroscopy and molecular dynamics simulation were used in the interaction. • The secondary structure of complex was significantly correlated with particle size. Rice gluten, as the hydrophobic protein, exhibits restricted application value in hydrophilic food, which may be enhanced through interaction with soybean 11S globulin, characterized by favorable functional properties. This study aims at revealing their interaction mechanism via multi-spectroscopy and molecular dynamics simulation. The formation and structural change of rice glutelin-soybean 11S globulin complexes were detected using fluorescence, ultra–violet and circular dichroism spectra. The addition of 11S globulin increased the contents of α-helix, β-turn and random coil, but decreased β-sheet content, and the change in secondary structure was correlated with particle size. Moreover, exposure of hydrophobic groups and formation of disulfide bonds occurred in the complexes. Molecular dynamics simulation verified these experimental results through analyses of root mean square deviation and fluctuation, hydrogen bond, secondary structure, and binding free energy analysis. This study contributes to expounding the interaction mechanism of protein and protein from the molecular level. [ABSTRACT FROM AUTHOR]

[Display omitted] • This paper identifies natural inhibitors of Syk from traditional Chinese medicine. • Sophoraflavanone G (SFG) is confirmed as a novel natural Syk inhibitor with an IC 50 of 2.2 μM. • The binding kinetics and stability of SFG and Syk were analyzed by molecular dynamics simulation. • SFG binds to Syk stably and inhibits its downstream signaling pathways in mast cells. • SFG suppresses IgE-mediated mast cell degranulation and allergic response both in vitro and in vivo. Spleen tyrosine kinase (Syk) plays a crucial role as a target for allergy treatment due to its involvement in immunoreceptor signaling. The purpose of this study was to identify natural inhibitors of Syk and assess their effects on the IgE-mediated allergic response in mast cells and ICR mice. A list of eight compounds was selected based on pharmacophore and molecular docking, showing potential inhibitory effects through virtual screening. Among these compounds, sophoraflavanone G (SFG) was found to inhibit Syk activity in an enzymatic assay, with an IC 50 value of 2.2 μM. To investigate the conformational dynamics of the SYK-SFG system, we performed molecular dynamics simulations. The stability of the binding between SFG and Syk was evaluated using root mean square deviation (RMSD) and root mean square fluctuation (RMSF). In RBL-2H3 cells, SFG demonstrated a dose-dependent suppression of IgE/BSA-induced mast cell degranulation, with no significant cytotoxicity observed at concentrations below 10.0 μM within 24 h. Furthermore, SFG reduced the production of TNF-α and IL-4 in RBL-2H3 cells. Mechanistic investigations revealed that SFG inhibited downstream signaling proteins, including phospholipase Cγ1 (PLCγ1), as well as mitogen-activated protein kinases (AKT, Erk1/2, p38, and JNK), in mast cells in a dose-dependent manner. Passive cutaneous anaphylaxis (PCA) experiments demonstrated that SFG could reduce ear swelling, mast cell degranulation, and the expression of COX-2 and IL-4. Overall, our findings identify naturally occurring SFG as a direct inhibitor of Syk that effectively suppresses mast cell degranulation both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Filamentous fungi are the main industrial source of cellulases which are important in the process of converting cellulose to fermentable sugars. In this study, transcriptome analysis was conducted on Aspergillus terreus NEAU-7 cultivated using corn stover and glucose as carbon sources. Four putative endoglucanases (EG5A, EG7A, EG12A, and EG12C) from A. terreus NEAU-7 were efficiently expressed in Pichia pastoris. Among them, EG7A exhibited the highest enzyme activity (75.17 U/mg) with an optimal temperature of 40 °C and pH 5.0. EG5A and EG12A displayed specific activities of 19.92 U/mg and 14.62 U/mg, respectively, at 50 °C. EG12C showed acidophilic characteristics with an optimal pH of 3.0 and a specific activity of 12.21 U/mg at 40 °C. With CMC-Na as the substrate, the Km value of EG5A, EG7A, EG12A or, EG12C was, 11.08 ± 0.87 mg/mL, 6.82 ± 0.74 mg/mL, 7.26 ± 0.64 mg/mL, and 9.88 ± 0.86 mg/mL, with V max values of 1258.23 ± 51.62 μmol∙min−1∙mg−1, 842.65 ± 41.53 μmol∙min−1∙mg−1, 499.38 ± 20.42 μmol∙min−1∙mg−1, and 681.41 ± 30.08 μmol∙min−1∙mg−1, respectively. The co-treatment of EG7A with the commercial cellulase increased the yield of reducing sugar by 155.77 % (filter paper) and 130.49 % (corn stover). Molecular docking assay showed the interaction energy of EG7A with cellotetraose at −10.50 kcal/mol, surpassing EG12A (−10.43 kcal/mol), EG12C (−10.28 kcal/mol), and EG5A (−9.00 kcal/mol). Root Mean Square Deviation (RMSD) and Solvent Accessible Surface Area (SASA) values revealed that the presence of cellotetraose stabilized the molecular dynamics simulation of the cellotetraose-protein complex over a 100 ns time scale. This study provides valuable insights for developing recombinant enzymes and biomass degradation technologies. [Display omitted] [ABSTRACT FROM AUTHOR]

Copyright of Modern Food Science & Technology is the property of Editorial Office of Modern Food Science & Technology and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The stability of a protein is determined from its properties and surrounding solvent. In our previous study, the total energy as a sum of the conformational and solvation free energies was demonstrated to be an appropriate energy function for evaluating the stability of a protein in a protein folding system. We plotted the various energies against the root mean square deviation, required as a reference structure. Herein, we replotted the various energies against the end-to-end distance between the N- and C-termini, which is not a required reference and is experimentally measurable. The solvation free energies for all proteins tend to be low as the end-to-end distance increases, whereas the conformational energies tend to be low as the end-to-end distance decreases. The end-to-end distance is one of interesting measures to study the behavior of proteins. [ABSTRACT FROM AUTHOR]

Background: Humanization of mouse monoclonal antibodies (mAbs) is crucial for reducing their immunogenicity in humans. However, humanized mAbs often lose their binding affinities. Therefore, an in silico humanization method that can prevent the loss of the binding affinity of mAbs is needed. Methods: We developed an in silico V(D)J recombination platform in which we used V(D)J human germline gene sequences to design five humanized candidates of anti-tumor necrosis factor (TNF)-α mAbs (C1–C5) by using different human germline templates. The candidates were subjected to molecular dynamics simulation. In addition, the structural similarities of their complementarity-determining regions (CDRs) to those of original mouse mAbs were estimated to derive the weighted interatomic root mean squared deviation (wRMSDi) value. Subsequently, the correlation of the derived wRMSDi value with the half maximal effective concentration (EC50) and the binding affinity (KD) of the humanized anti-TNF-α candidates was examined. To confirm whether our in silico estimation method can be used for other humanized mAbs, we tested our method using the anti-epidermal growth factor receptor (EGFR) a4.6.1, anti-glypican-3 (GPC3) YP9.1 and anti-α4β1 integrin HP1/2L mAbs. Results: The R2 value for the correlation between the wRMSDi and log(EC50) of the recombinant Remicade and those of the humanized anti-TNF-α candidates was 0.901, and the R2 value for the correlation between wRMSDi and log(KD) was 0.9921. The results indicated that our in silico V(D)J recombination platform could predict the binding affinity of humanized candidates and successfully identify the high-affinity humanized anti-TNF-α antibody (Ab) C1 with a binding affinity similar to that of the parental chimeric mAb (5.13 × 10−10). For the anti-EGFR a4.6.1, anti-GPC3 YP9.1, and anti-α4β1 integrin HP1/2L mAbs, the wRMSDi and log(EC50) exhibited strong correlations (R2 = 0.9908, 0.9999, and 0.8907, respectively). Conclusions: Our in silico V(D)J recombination platform can facilitate the development of humanized mAbs with low immunogenicity and high binding affinities. This platform can directly transform numerous mAbs with therapeutic potential to humanized or even human therapeutic Abs for clinical use. [ABSTRACT FROM AUTHOR]

Copyright of Karaelmas Science & Engineering Journal / Karaelmas Fen ve Mühendislik Dergisi is the property of Karaelmas Science & Engineering Journal and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Farnesol, a self-secreted quorum-sensing molecule (QSM) of Candida albicans , has been known to limit yeast-to-hyphal transition by blocking the RAS1–cAMP–PKA pathway. In a similar fashion, certain bacterial QSMs have also been reported to be successful in attenuating C. albicans biofilm and hyphal formation at relatively high cell density. This prompted us to investigate the antihyphal efficacy of certain bacterial QSMs through virtual docking against seminal drug targets, viz., CYCc and RAS1, that have been reported to be the hallmark players in C. albicans dimorphic virulence cascade. Against this backdrop, 64 QSMs belonging to five different bacterial QS signaling systems were subjected to initial virtual screening with farnesol as reference. Data of the virtual screening unveiled QSMs belonging to diketopiperazines (DKPs), i.e., 3-benzyl-6-isobutylidene-2,5-piperazinedione (QSSM 1157) and cyclo(l-Pro-l-Leu) (QSSM 1112), as potential inhibitors of CYCc and RAS1 with binding energies of −8.2 and −7.3 kcal mol−1, respectively. Further, the molecular dynamics simulations (for 50 ns) of CYCc-QSSM 1157 and RAS1-QSSM 1112 complexes revealed the mean ligand root mean square deviation (RMSD) values of 0.35 and 0.27 Å, respectively, which endorsed the rigid nature, less fluctuation in binding stiffness, and conformation of binding complexes. Furthermore, the identified two QSMs were found to be good in solubility, absorption, and permeation and less toxic in nature, as revealed by pharmacokinetics and toxicity analyses. In addition, the in vitro antihyphal assays using liquid and solid media, germ-tube experiment, and microscopic analysis strongly validated DKP-QSSM 1112 as a promising inhibitor of hyphal transition. Taken together, the present study unequivocally proves that DKPs can be used as potent inhibitors of C. albicans virulence dimorphism. [ABSTRACT FROM AUTHOR]

Black cumin is commonly used as traditional medicine due to its wide range of pharmacological potential. Black cumin oil (BCO) was often prepared as nanoemulsion to improve its solubility, stability, and bioavailability. This study was conducted to investigate the molecular behavior as well as structural evolution of BCO-surfactant systems during selfassembly micellization using molecular dynamics (MD) simulations. Several BCO constituents and variations of surfactants were employed to model BCO-surfactant systems. 50 ns of MD simulations were performed to elucidate their evolution of structures and physicochemical properties during formation. Results showed that BCO-tween20 and BCO-lecithin were able to form spherical-shaped micelles with the effective radii of 10.20 and 8.67 nm at the end of the simulation. Also, from the root mean square deviation and radius of gyration profile, it is showed that BCO-tween20 system was able to maintain the stability of its structure throughout the simulation. Results also revealed that self-assembly of BCO-surfactant systems were exothermic processes, confirming spontaneous nature upon formation. [ABSTRACT FROM AUTHOR]

• Lupeol rich fraction was obtained from Crateva adansonii DC leave extract • Lupeol shown promising enzymes inhibition crucial for diabetes and inflammation • Lupeol exhibit promising in vitro anti-inflammatory and anti-diabetic potential • Lupeol shown least docking score with enzymes target than standard drugs • Molecular dynamic simulation of lupeol with targets shown good binding affinity Enzyme inhibitor from natural origin without any side effects and multi diseases target provide more advantageous over commercial drugs. In present study phytocompound lupeol was isolated from Indian traditional medicinal plant Crateva adansonii leave extracts and its possible applications for treating diabetes and inflammation diseases. Single major peak in HPLC profiling and FTIR functional group analysis of lupeol fraction (LF) confirmed the presence of phytocompound lupeol in LF. LF obtained from chloroform leave extract of Crateva adansonii had most prominent inhibitory activity on alpha-amylase and alpha glucosidase with IC50 values 16.31 µg/mL and 41.25 µg/mL respectively. LF exhibit superior COX-2 enzyme (91.36%) inhibition potential among all tested samples whereas LF exhibit equipotent (81.38%) MPO enzyme inhibitory potential compared with celecoxib standard drug (86.19%). In silico validation reveals that lupeol exhibit least docking score with excellent binding affinities of -9.2, -7.6, -10.0 -8.2 Kcal/mol with COX-2, myeloperoxidase, α-amylase and α-glucosidase inflammatory molecular target enzymes respectively than inflammatory (celecoxib) and diabetic (acarbose) reference standard drugs. Further in silico molecular dynamics simulation analysis revealed that Lupeol-COX-2 RMSD (root mean square deviation) plot showed that both COX-2 and Lupeol are stable after 20 NS at 9.0 Å for ligand and 3.2 Å for protein. Lupeol-α amylase complex showed good level of interaction throughout the simulation when compared with reference standard drug acarbose. Present study findings suggests that lupeol from Crateva adansonii plant could be incorporated in medicinal formulations intended for treatment of chronic inflammation and diabetic disorders. [ABSTRACT FROM AUTHOR]

Copyright of Shipin Kexue/ Food Science is the property of Food Science Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Karaelmas Science & Engineering Journal / Karaelmas Fen ve Mühendislik Dergisi is the property of Karaelmas Science & Engineering Journal and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

In the rural communities of sub-Saharan African (sSA) countries, malaria is being managed using phytocompounds. Artesunate is reported to inhibit Gephyrin E, a central, multi-domain scaffolding protein of inhibitory post-synapses. Neem plant and its metabolites like azadirachtin are being indicated for management of malaria by traditional healers. The present study was aimed to cheminformatically analyse the binding potential of artesunate and azadirachtin with various reactive moieties of Gephyrin E, to reduce malaria scourge. With molecular dynamics (MD), binding free energy estimation and binding affinity of artesunate and azadirachtin to Gephyrin E was done. GRIP docking was done to study the interactions of these test ligands with Gephyrin E (6FGC). MD simulation gave insights to structural changes upon binding of artesunate and azadirachtin in the ligand-binding pocket of Gephyrin E. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) were calculated. From the estimation, azadirachtin had a total binding energy of −36.97 kcal/mol; artesunate had a binding energy of −35.73 kcal/mol. The GRIP docking results provided a clearer evidence that artesunate has comparatively better binding affinity to Gephyrin E than azadirachtin, and the critical binding sites (in activity order) were cavity 3, 2, 8, and 6 for artesunate while for azadirachtin, it was cavity 6, 3, 8, and 2. The GRIP docking provided detailed interactions at the atomic levels, providing evidence; both compounds have chances to overcome the drug resistance problem, albeit higher for artesunate. Our findings added another piece of evidence that azadirachtin may be effective as an anti-malarial agent. The results herein may provide impetus for more studies into bioactive components of plant origin towards the effective management of malaria disease phenotype. [ABSTRACT FROM AUTHOR]

Most β-galactosidases reported are sensitive to the end product (galactose), making it the rate-limiting component for the efficient degradation of lactose through the enzymatic route. Therefore, there is ongoing interest in searching for galactose-tolerant β-galactosidases. In the present study, the predicted galactose-binding residues of β-galactosidase from Bacillus coagulans , which were determined by molecular docking, were selected for alanine substitution. The asparagine residue at position 148 (N148) is correlated with the reduction of galactose inhibition. Saturation mutations revealed that the N148C, N148D, N148S, and N148G mutants exhibited weaker galactose inhibition effects. The N148D mutant was used for lactose hydrolysis and exhibited a higher hydrolytic rate. Molecular dynamics revealed that the root mean square deviation and gyration radius of the N148D-galactose complex were higher than those of wild-type enzyme-galactose complex. In addition, the N148D mutant had a higher absolute binding free-energy value. All these factors may lead to a lower affinity between galactose and the mutant enzyme. The use of mutant enzyme may have potential value in lactose hydrolysis. [Display omitted] [ABSTRACT FROM AUTHOR]

Black fungus is the foremost life-threatening disease during the SARS-CoV-2 affected patients and spreading quickly in the region of the subcontinent of India although there was no prescribed proper medication. As the Dglucofuranose and its derivatives are reported to show strong antifungal activity, this study has been designed with them for their computational investigation. Firstly, the overallprediction of activity spectra for substances (PASS) value illustrates a goodprobability to be active(Pa) and probability to be inactive (Pi) value. Next, pharmacokinetics parameters including drug-likeness and Lipinski's rules, absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters, and overall quantum calculation of computational approaches by Density Functional Theory (DFT) have graduallybeen performed to analyze quantum calculations. After the analysis of docking score, it is found at -9.4 kcal/mol, -7.5 kcal/mol, -7.8 kcal/mol, -8.5 kcal/mol against the strain of black fungus protein strains Mycolicibacterium smegmatis, Mucor lusitanicus, Rhizomucor mieh, and white fungus protein Candida Auris, Aspergillus luchuensis and Candida albicans. Next, the molecular dynamics of docked complexes have been performed to check their stability in biological systems with water ranging 100 ns calculating the Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF)where the minimum RMSD and RMSF value indicated the higher stable configuration of docked complexes. These compounds have perfectly matched all the pharmacokinetics criteria to be a good drug candidate against both black and white fungus, and they are non-carcinogenic, low solubility, low toxic for both aquatic and non-aquatic. In addition, the quantum calculation using DFT conveys the strongest support and information about their chemical stability and biological significance. Finally, it could be concluded that the carboxylic group and methyl group inthe benzene ring causes higher binding affinity against black and white fungus protein strain through the formation of hydrogen and hydrophobic bonds. [ABSTRACT FROM AUTHOR]

Herbal plants are often used as alternative medicine because they contain active compounds for the treatment of diseases and disorders with minimal side effects, and are easily obtained from the surrounding environment. Some of them have antiviral activity. This study aimed to analyze the potential of phytochemical compounds in the leaf of "pangi" (Pangium edule Reinw) as anti- SARS-CoV-2 using molecular docking study. The drug- and lead-likeness properties of the selected compounds were obtained from the Swiss ADME and admetSAR online server tools. Molecular dynamics (MD) simulation of the selected ligand was carried out to validate the stability of the interaction. The results suggested that pangi leaves contain three compounds with remarkable binding affinities with Mpro (main protease) and RBD (receptor binding domain) were (5.beta.) pregnane-3,20.beta.-diol, 14.alpha.,18.alpha.-[4-methyl-3-oxo-(1-oxa-4-azabutane-1,4-diyl)]-, diacetate (PD), ethyl cholate (EC), and bis(3,5,5-trimethylhexyl) phthalate. Because EC will be metabolized in the body into cholic acid (Cho), this compound was then docked and validated using MD simulation. The compound has the best free binding energy (ΔG) with SARS-CoV-2 (-7.1 kcal/ mol with Mpro and -6.0 kcal/mol with RBD). Moreover, the compound is bound strongly to the active cavity of Mpro on Thr24, Thr26, His41, and Cys145 residues. The MM-GBSA calculation showed that the interaction of Cho with Mpro was higher than with RBD. According to the RMSD (root mean square deviation), RMSF (root mean square fluctuation), the radius of gyration (Rg), and intermolecular hydrogen bond (H-bond) analysis obtained from 50 ns MD simulations, Cho formed stable interactions with Mpro and RBD. The finding of this study indicated that Cho showed good anti-SARS-CoV-2 activity. The potential of the compound to inhibit the virus can serve as a starting point in the process of developing COVID-19 therapeutic natural medicine. [ABSTRACT FROM AUTHOR]

The high transmission and pathogenicity of SARS-CoV-2 has led to a pandemic that has halted the world's economy and health. The newly evolved strains and scarcity of vaccines has worsened the situation. The main protease (Mpro) of SARS-CoV-2 can act as a potential target due to its role in viral replication and conservation level. In this study, we have enlisted more than 1100 phytochemicals from Asian plants based on deep literature mining. The compounds library was screened against the Mpro of SARS-CoV-2. The selected three ligands, Flemichin, Delta-Oleanolic acid, and Emodin 1-O-beta-D-glucoside had a binding energy of −8.9, −8.9, −8.7 KJ/mol respectively. The compounds bind to the active groove of the main protease at; Cys145, Glu166, His41, Met49, Pro168, Met165, Gln189. The multiple descriptors from the simulation study; root mean square deviation, root mean square fluctuation, radius of gyration, hydrogen bond, solvent accessible surface area confirms the stable nature of the protein-ligand complexes. Furthermore, post-md analysis confirms the rigidness in the docked poses over the simulation trajectories. Our combinatorial drug design approaches may help researchers to identify suitable drug candidates against SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Osteoporosis is skeletal fragility caused by the excessive bone resorption due to osteoclastogenesis. But current drugs are less bioavailable and possess higher toxicity. Our study was conducted to identify safe oral bioavailable drugs from Fenugreek steroidal saponins and to delineate underlying mechanism of them to lower the osteoclastogenic bone resorption. We observed higher molecular docked binding affinities in finally selected eight hit compounds within the range of −11.0 to −10.1 kcal/mol which was greater than currently used drugs. Molecular Dynamics simulation with Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Solvent Accessible Surface Area (SASA) and Gyration trajectory projection reinforced the stability of the protein-ligand complexes. Pharmacokinetics analysis confirmed bioavailability of seven compounds out of eight, and drug likeliness and bioavailability profile evaluation indicated that they all are eligible to be developed as a potent oral inhibitor of CSF-1R. By literature mining knowledge-driven analysis, RNAseq data and Molecular Dynamics Simulation, we proposed that, the hit derivatives block the CSF-1/CSF-1R induced phosphorylation signaling pathway in both osteoclast and osteoblast resulting in hindrance of RANK expression and formation of Reactive oxygen species (ROS) in osteoclast and osteoblast respectively, thus declines the RANKL/OPG ratio, lowering the osteoclast survival, proliferation and differentiation. [Display omitted] [ABSTRACT FROM AUTHOR]

Fungal infection of invasive nature is an alarming threat globally and a leading cause of human morbidity and mortality as they are opportunistic in nature. Rising resistance to current clinically approved marketed products for fungal infections is a major concern for humans. Dihydrofolate Reductase (DHFRase) is an essential enzyme in folate metabolic pathway responsible for DNA synthesis and is ubiquitous to all organisms, and also acts as a key target for developing antifungal drugs. In this study, potential mutant DHFRase inhibitors were screened with the help of hierarchical mode of docking of virtual library of antifungal compounds and molecular dynamic (MD) simulation. The identification of best hits was done by using the docking, binding energy prediction and further, which was supported by their predicted pharmacokinetics. MD simulation of the human DHFRase enzyme with the reference lead compound i.e. PY957 and most promising hit found i.e. ChemDiv-C390-0455 and to validate the stability of enzyme-ligand complex in best 07 retrieved hit as a potential mutant DHFRase inhibitor. The key residues Glh30, Phe34, Phe64, Phe31 of the binding pocket acknowledged as essential were found to be matching with the key interactions of the selected hit. Computed root mean square deviation (RMSD) and root mean square fluctuation (RMSF) in MD simulation of complex of DHFRase enzyme with PY957 and ChemDiv-C390-0455 were read less than 2.25 Å during 100 nanoseconds simulation for both complex. Dihydrofolate Reductase is an essential enzyme for the biosynthesis of fungal DNA which is a key target for developing antifungal agents. Structure-Based Computational approach using diverse antifungal compounds against the mutant DHFRase enzyme. Molecular dynamic simulation study revealed the stability of the protein-ligand complex along with the analysis of structural features in retrieved hits. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation has been identified to be the key player in most neurodegenerative diseases. If neuroinflammation is left to be unresolved, chronic neuroinflammation will be establish. Such situation is due to the overly-activated microglia which have the tendency to secrete an abundance amount of pro-inflammatory cytokines into the neuron microenvironment. The abundance of pro-inflammatory cytokines will later cause toxic and death to neurons. Toll-like receptor 4 (TLR4)/MD-2 complex found on the cell surface of microglia is responsible for the attachment of LPS and activation of nuclear factor-κB (NF-κB) downstream signalling pathway. Albeit vitexin has been shown to possess anti-inflammatory property, however, little is known on its ability to bind at the binding site of TLR4/MD-2 complex of microglia as well as to be an antagonist for LPS. Results: The present study reveals that both vitexin and donepezil are able to bind at the close proximity of LPS binding site located at the TLR4/MD-2 complex with the binding energy of − 4.35 and − 9.14 kcal/mol, respectively. During molecular dynamic simulations, both vitexin and donepezil formed stable complex with TLR4/MD-2 throughout the 100 ns time length with the root mean square deviation (RMSD) values of 2.5 Å and 4.0 Å, respectively. The root mean square fluctuation (RMSF) reveals that both compounds are stable. Interestingly, the radius of gyration (rGyr) for donepezil shows notable fluctuations when compare with vitexin. The MM-GBSA results showed that vitexin has higher binding energy in comparison with donepezil. Conclusions: Taken together, the findings suggest that vitexin is able to bind at the binding site of TLR4/MD-2 complex with more stability than donepezil throughout the course of 100 ns simulation. Hence, vitexin has the potential to be an antagonist candidate for LPS. [ABSTRACT FROM AUTHOR]

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) is highly pathogenic to humans and has created an unprecedented global health care threat. Globally, intense efforts are going on to discover a vaccine or new drug molecules to control the COVID‐19. However, till today, there is no effective therapeutics or treatment available for COVID‐19. In this study, we aim to find out potential small molecule inhibitors for SARS‐CoV‐2 main protease (Mpro) from the known DrugBank database version 5.1.8. We applied structure‐based virtual screening of the database containing 11875 numbers of drug candidates to identify potential hits for SARS‐CoV‐2 Mpro inhibitors. Seven potential inhibitors having admirable XP glide score ranging from −15.071 to −8.704 kcal/mol and good binding affinity with the active sites amino acids of Mpro were identified. The selected hits were further analyzed with 50 ns molecular dynamics (MD) simulation to examine the stability of protein‐ligand complexes. The root mean square deviation and potential energy plot indicates the stability of the complexes during the 50 ns MD simulation. The MM‐GBSA analysis also showed good binding energy of the selected hits (−83.2718 to −58.6618 kcal/mol). Further analysis revealed critical hydrogen bonds and hydrophobic interactions between compounds and the target protein. The compounds bind to biologically important regions of Mpro, indicating their potential to inhibit the functionality of this component. [ABSTRACT FROM AUTHOR]

Protein folding, vital to life and death, is the basis of biological physics. The information about the protein folding process and dynamics is of tremendous significance in the protein-folding field, and the research about protein folding pathways has attracted considerable attention. Here, four protein systems (1HOD, 2AJJ, 2DX3, 2RLG) are performed the folding simulation starting from the linear structures in order to investigate their folding mechanisms using the classical molecular dynamics (MD) and the self-guided Langevin dynamics (SGLD), respectively. The latter can increase the low-frequency motion, which is particularly related to the folding process of protein. Compared with MD, there is a significant improvement through SGLD method, such as the evolution of the radius of gyration, root mean square deviation, cluster analysis, native contact, helix content, process of the protein folding and the free energy landscape. This research shows that the extended states successfully fold into the corresponding native structures within 95 ns using SGLD. Furthermore, the result of multiple trajectories again supports the above conclusion. However, classical MD ultimately fails to show any stable helix formation at the same simulation time. The detailed folding pathway and mechanism of these proteins are elucidated using the SGLD method in this report. [ABSTRACT FROM AUTHOR]

Copyright of China Surfactant Detergent & Cosmetics (1001-1803) is the property of China Surfactant Detergent & Cosmetics Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Nanodiscs are binary discoidal complexes of a phospholipid bilayer circumscribed by belt-like helical scaffold proteins. Using coarse-grained and all-atom molecular dynamics simulations, we explore the stability, size, and structure of nanodiscs formed between the N-terminal domain of apolipoprotein E3 (apoE3-NT) and variable number of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) molecules. We study both parallel and antiparallel double-belt configurations, consisting of four proteins per nanodisc. Our simulations predict nanodiscs containing between 240 and 420 DMPC molecules to be stable. The antiparallel configurations exhibit an average of 1.6 times more amino acid interactions between protein chains and 2 times more ionic contacts, compared to the parallel configuration. With one exception, DMPC order parameters are consistently larger in the antiparallel configuration than in the parallel one. In most cases, the root mean square deviation of the positions of the protein backbone atoms is smaller in the antiparallel configuration. We further report nanodisc size, thickness, radius of gyration, and solvent accessible surface area. Combining all investigated parameters, we hypothesize the antiparallel protein configuration leading to more stable and more rigid nanodiscs than the parallel one. [Display omitted] • Nanodiscs with 240–420 DMPC and 4 apoE3-NT protein chains are stable. • Predicted diameters are in accordance with experimental measurements. • Antiparallel protein configuration leads to more ionic protein–protein contacts. • Antiparallel protein configuration leads to larger DMPC order parameters. • Nanodiscs with antiparallel protein configuration are predicted to be more stable. [ABSTRACT FROM AUTHOR]

Spinodal decomposition of Ti 1 − x Al x N crystal structure significantly impacts their physical properties, particularly at the atomic scale. In this study, we employed systematic three-dimensional molecular dynamics simulations to understand the process of material removal in TiAlN. Orthogonal simulations were conducted with cutting depth and Al content as variables to analyze their impact on the phase transformation mechanism and the resulting surface finish. The simulations reveal that the aluminum content and depth of cut significantly influence the phase transformation process of supersaturated TiAlN crystals through spinodal decomposition. It is observed that the aluminum content has a maximum stable solubility of approximately 0.6 in TiAlN crystals, above which the system undergoes significant spinodal decomposition during cutting to produce hexagonal phases with lower hardness. Increasing the aluminum content leads to wider phase change and deeper sub-surface damage in the system. On the other hand, the cutting depth will promote phase transformation by affecting the stress distribution, thereby increasing the root mean square roughness of the height profile. [Display omitted] • Simulate the nanoscale cutting and roughness creation in supersaturated TiAlN. • Explore the effect of phase transition in the material removal mechanism in TiAlN. • Investigate the effect of Al content and depth of cut (DoC) on the phase transition. • The specific energy and roughness are functions of Al content and depth of cut. [ABSTRACT FROM AUTHOR]

The new coronavirus (SARS-CoV-2) halts the world economy and caused unbearable medical emergency due to high transmission rate and also no effective vaccine and drugs has been developed which brought the world pandemic situations. The main protease (Mpro) of SARS-CoV-2 may act as an effective target for drug development due to the conservation level. Herein, we have employed a rigorous literature review pipeline to enlist 3063 compounds from more than 200 plants from the Asian region. Therefore, the virtual screening procedure helps us to shortlist the total compounds into 19 based on their better binding energy. Moreover, the Prime MM-GBSA procedure screened the compound dataset further where curcumin, gartanin and robinetin had a score of (−59.439, −52.421 and − 47.544) kcal/mol, respectively. The top three ligands based on binding energy and MM-GBSA scores have most of the binding in the catalytic groove Cys145, His41, Met165, required for the target protein inhibition. The molecular dynamics simulation study confirms the docked complex rigidity and stability by exploring root mean square deviations, root mean square fluctuations, solvent accessible surface area, radius of gyration and hydrogen bond analysis from simulation trajectories. The post-molecular dynamics analysis also confirms the interactions of the curcumin, gartanin and robinetin in the similar binding pockets. Our computational drug designing approach may contribute to the development of drugs against SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Comparative modelling helps compare the structure and functions of a given protein, to track the path of its origin and evolution and also guide in structure-based drug discovery. Presently, this has been applied for modelling the tertiary structure of highly conserved eukaryotic TCTP (translationally controlled tumour protein) which is involved in a plethora of functions during growth and development and also acts as a biomarker for many cancers like lung, breast, and prostate cancer. The modelled TCTP structures of different organisms belonging to the eukaryotic group showed similar spatial arrangement of structural units except loops and similar patterns of root mean square deviation (RMSD), root mean square fluctuation, and radius of gyration (Rg) inspected through molecular dynamics simulations. Essential dynamics (ED) analyses revealed different domains that exhibited different motions for the assistance in its multifunctional properties. Construction of a free-energy landscape (FEL) based on Rg versus RMSD was employed to characterize the folding behaviours of structures and observe that all proteins had nearly similar conformation and topologies, indicating common thermodynamic/kinetic pathways. A physico-chemical interaction study demonstrated the helices and sheets were well stabilized with ample amounts of bonding compared to turns or loops and charged residues were more accessible to solvent molecules. Hence, the current study reveals the important structural features of TCTP that aid in diverse functions in a wide range of organisms, thus extending our knowledge of TCTP and also providing a venue for designing the potent inhibitors against it. [ABSTRACT FROM AUTHOR]

A series of novel pyrazole-phenyl semicarbazone derivatives were designed, synthesized, and screened for in vitro α-glucosidase inhibitory activity. Given the importance of hydrogen bonding in promoting the α-glucosidase inhibitory activity, pharmacophore modification was established. The docking results rationalized the idea of the design. All newly synthesized compounds exhibited excellent in vitro yeast α-glucosidase inhibition (IC 50 values in the range of 65.1–695.0 μM) even much more potent than standard drug acarbose (IC 50 = 750.0 μM). Among them, compounds 8o displayed the most potent α-glucosidase inhibitory activity (IC 50 = 65.1 ± 0.3 μM). Kinetic study of compound 8o revealed that it inhibited α-glucosidase in a competitive mode (K i = 87.0 μM). Limited SAR suggested that electronic properties of substitutions have little effect on inhibitory potential of compounds. Cytotoxic studies demonstrated that the active compounds (8o, 8k, 8p, 8l, 8i, and 8a) compounds are also non-cytotoxic. The binding modes of the most potent compounds 8o, 8k, 8p, 8l and 8i was studied through in silico docking studies. Molecular dynamic simulations have been performed in order to explain the dynamic behavior and structural changes of the systems by the calculation of the root mean square deviation (RMSD) and root mean square fluctuation (RMSF). [ABSTRACT FROM AUTHOR]

Summary: The thermophysical properties of phase change material (PCM) directly affect the performance of underwater vehicles. The accuracy of the phase change transfer model is an important index for evaluating the performance of PCM as well. In this paper, a molecular dynamics approach is proposed to obtain the thermophysical properties of PCM under different pressures. On such a basis, the modified models of "temperature‐pressure‐density," "temperature‐pressure‐thermal conductivity" and "pressure‐specific heat capacity" are established. By comparing the simulation results with the unmodified phase change transfer model and the laboratory experimental results, it can be seen that the modified phase change transfer model has higher accuracy. Furthermore, an ocean thermal energy conversion system for underwater vehicles is deployed in the South China Sea to test the utilization performance. By the contrast between the simulated calculation of the modified model and the sea trial results, it is found that the root mean square (RMS) of accumulator pressure between the simulation and sea trial is 0.2565, and the energy storage volume RMS is 1.6868. When the accumulator pressure reaches 205 bar, the time error is 0.58%, and the energy storage volume error is 3.16%. The results indicate that the modified model is effective in practical application. [ABSTRACT FROM AUTHOR]

• HPX im5mobilization on Ti 3 C 2 and Ti 3 C 2 OH surfaces is explored by the MD simulation method. • It has been found that and van der Waals and electrostatic interactions regulate enzyme immobilization. • During absorption process, the HPX composition remains unchanged, indicating the excellent biocompatibility of Ti 3 C 2 and Ti 3 C 2 OH. • The MD simulation results illustrated that the structure of the HPX is more protected on the Ti 3 C 2 surface. In this study, the molecular dynamics simulation is performed to investigate the adsorption of horseradish peroxidase (HRP, a model enzyme) on Ti 3 C 2 and Ti 3 C 2 OH (as templates for enzyme immobilization). It has been found that van der Waals and electrostatic interactions regulate enzyme immobilization, whereas the hydrogen bonding between enzyme and MXene is involved in the adsorption process. The simulation outcomes indicate that various MXene can effectually adsorb HRP, and the adsorption strength is more for the Ti 3 C 2 @HRP complex, as revealed by energy analysis (interaction energy = −710.92 vs −449.02 kJ mol−1). Moreover, the root means square deviation, root means square fluctuation and secondary structure analysis indicate that Ti 3 C 2 protects the conformation of enzymes more than Ti 3 C 2 OH. Hence, HRP can be effectually immobilized after the Ti 3 C 2 in comparison to the Ti 3 C 2 OH. In the following, the evaluation of 2-thiouracil (2-Thi) ability to modulate HRP activity is investigated. The obtained results show that 2-Thi inhibitor has a great capacity to inhibit HRP enzyme. Eventually, the stability of immobilized HRP at higher temperatures (330 and 363 K) and acidic pH is examined. The present work suggests theoretical insights into realizing the biocompatibility of MXenes and instructs for modeling efficacious synthetic inhibitors. [ABSTRACT FROM AUTHOR]

D -Allose is a rare cis-caprose with a wide range of physiological functions, which has a wide range of applications in medicine, food, and other industries. L -Rhamnose isomerase (L -Rhi) is the earliest enzyme found to catalyze the production of D -allose from D -psicose. This catalyst has a high conversion rate, but its specificity for substrates is limited; thus, it cannot fulfill the requirements of industrial production of D -allose. In this study, L -Rhi derived from Bacillus subtilis was employed as the research subject, and D -psicose as the conversion substrate. Two mutant libraries were constructed through alanine scanning, saturation mutation, and rational design based on the analysis of the secondary structure, tertiary structure, and interactions with ligands of the enzyme. The yield of D -allose produced by these mutants was assessed; it was found that the conversion rate of mutant D325M to D -allose was increased by 55.73 %, and the D325S improved by 15.34 %, while mutant W184H increased by 10.37 % at 55 °C, respectively. According to modeling analysis, manganese (Mn2+) had no significant effect on the production of D -psicose from D -psicose by L -Rhi. The results of molecular dynamics simulation demonstrated that the mutants W184H, D325M, and D325S had more stable protein structures while binding with the substrate D -psicose, as evidenced by its root mean square deviation (RMSD), root mean square fluctuation (RMSF), and binding free energy values. It was more conducive to binding D -psicose and facilitating its conversion to D -allose, providing the basis for the production of D -allose. • The yield of D -allose generated by positive L -Rhi mutants increased by 55.73 %, 15.34 %, and 10.37 %, respectively. • There was no metal ion binding and the binding position of the substrate had altered in the mutants D325M and D325S. • The optimum temperature of the mutants decreased and ligand-enzyme complexes were more stable. [ABSTRACT FROM AUTHOR]

The statistical properties of rough surfaces at the nanoscale are studied using classical molecular dynamics. Atomistic fcc blocks of gold are generated with different crystal orientations, and with rough surfaces having the same root-mean-square roughness with variable power spectral density (PSD) slopes and roll-off wavenumbers. The process of rough surface generation may result in thermodynamically unstable sharp spatial features. In order to relax the structure, the blocks are equilibrated at 300 K . It is found that all surfaces experience changes in their roughness, regardless of their crystal orientation or temperature, although the changes are only temperature-independent when T ≤ 0.4 T m . Based on the analyzed PSDs of the equilibrated substrates, two methods for generating pseudo-stable rough surfaces are introduced and discussed. [ABSTRACT FROM AUTHOR]

• Ethanol molecules disrupt the passage of calcium ions in the channel. • Diffusion coefficient in the absence of ethanol is 2500 nm2/ps and in the presence of ethanol it is 200 nm2/ps. • The flow of ions in the channels is controlled due to the presence of ethanol molecules. Drinking too much alcohol can lead to the development of chronic diseases and other serious problems including: heart disease, high blood pressure, stroke, digestive problems and liver disease. Over the past two decades, researchers have confirmed that ethanol is the primary agent in altering the function of voltage-gated calcium channels that lead to clock responses and behavioral responses to alcohol. In this study, the ethanol influence on calcium channel operation has been studied by molecular dynamics simulation of L-type calcium channels in the presence and absence of ethanol. Density, radius distribution, average potential force, radius gyration, pore radius, root mean square deviation and root mean square fluctuation are the performed analysis in this study. According to the results obtained; Ethanol blocks the calcium channel and interferes with calcium ions passage. Also, calcium ions show a greater tendency to interact with the residues inside the protein channel in the presence of ethanol. [ABSTRACT FROM AUTHOR]

4,6-α-glucanotransferase (4,6-α-GT), as a member of the glycoside hydrolase 70 (GH70) family, converts starch/maltooligosaccharides into α,1–6 bond-containing α-glucan and possesses potential applications in food, medical and related industries but does not satisfy the high-temperature requirement due to its poor thermostability. In this study, a 4,6-α-GT (ΔGtfB) from Limosilactobacillus fermentum NCC 3057 was used as a model enzyme to improve its thermostability. The loops of ΔGtfB as the target region were optimized using directed evolution, sequence alignment, and computer-aided design. A total of 11 positive mutants were obtained and iteratively combined to obtain a combined mutant CM9, with high resistance to temperature (50 °C). The activity of mutant CM9 was 2.08-fold the activity of the wild type, accompanied by a 5 °C higher optimal temperature, a 5.76 °C higher melting point (T m , 59.46 °C), and an 11.95-fold longer half-life time (t 1/2). The results showed that most of the polar residues in the loop region of ΔGtfB are mutated into rigid proline residues. Molecular dynamics simulation demonstrated that the root mean square fluctuation of CM9 significantly decreased by "Breathing" movement reduction of the loop region. This study provides a new strategy for improving the thermostability of 4,6-α-GT through rational loop region modification. • The half-life of ΔGtfB derived from L. fermentum NCC 3057 at 50 °C was increased by 11.95 times through multiple strategies • The introduction of proline residues in the loop region of ΔGtfB improves its structural rigidity • An iterative combinatorial strategy can efficiently combine ΔGtfB mutants with increased thermostability • Molecular dynamics simulations were used to analyze the mechanism of increased thermal stability of ΔGtfB mutants. [ABSTRACT FROM AUTHOR]

The size effect must be considered for dynamic modeling of an AFM since the dimensions of the AFM, are in micro-scale. In this study, a three-dimensional multi-scale method based on a non-classical continuum mechanic theory is developed in order to include material length scale parameter (MLSP) in the dynamic behavior of manipulation carried out by AFM. First, the governing equations of Macro Field (MF) are derived using the modified coupled stress theory and the Kirchhoff plate model. Moreover, Nano Field (NF) is modeled using the molecular dynamics equations. The MF and the NF are then combined employing the multi-scale algorithm. Rectangular and dagger cantilevers are taken into account to obtain manipulation results. The influence of two types of tip on the manipulation results is also investigated. The obtained results show that the deformations of the AFM components in non-classic models are less than the one in the classical model. Furthermore, Root Mean Square (RMS) results for a nano-particle demonstrates that damage and deformation of the nano-particle are underestimated by the classical model. The investigations carried out in the present study show the significance of employing the non-classical theory for analyzing AFM performance, particularly for estimation of separation time span. [ABSTRACT FROM AUTHOR]

• Water desalination laws and related mechanisms of HCM were investigated by the MD simulations. • Microscopic mechanism of raw water temperature affects HCM membrane flux was clarified. • Diffusion form of free-state water molecules in the membrane micropores of HCM was ascertained. With LAMMPS software, the non-equilibrium molecular dynamics (NEMD) simulations study was conducted for the membrane distillation process with the hydrophobic α-Al 2 O 3 ceramic membrane (HCM). It could further help to explain the macroscopic laws and phenomena that appeared in the membrane distillation tests with HCM. In this study, the average temperature (T r) of raw water and the negative pressure (P con) on the cold side of HCM were taken as the investigation variables to research the microscopic water desalination performance of HCM, transport/diffusion properties of water molecules, and related mechanisms. The results showed that the root means square displacement (MSD) of water molecules on the cold side of HCM positively changed with time by the linear trend. The height of the transmembrane energy barrier mainly depends on the atomic structure of the HCM. The diffusion type of free-state water molecules in the membrane micropores of HCM was the main ballistic-transport-like accompanied by rebound-jump. The influence level of T r on the number of water molecules in the cold side of HCM was much greater than that of P con under the dynamic equilibrium state. The essential reason T r determined the HCM molecular flux was that it changed the hydrogen bond lifetime in the microporous membrane of HCM. [ABSTRACT FROM AUTHOR]

To produce the high quality products and improve the stability of Jinhua hams, the activities of cathepsins and their correlation with processing parameters were explored. The effect of heat treatment on the structure of cathepsin B, together with potential of hydrogen and NaCl concentration, were investigated. At 45 °C, the activity of cathepsin B was maximum and it decreased rapidly at high temperature. The decrease on sulfhydryl group content indicated that the enzyme activity varied due to the breaking of disulfide bond in molecule. Infrared spectroscopy indicated that the secondary structure of cathepsin B had altered. Meanwhile, the root mean squared deviation and the root mean square fluctuation curves reflected that the cathepsin B vitality was in a decline under high temperature. In addition, in the presence of 0.6 mol ⋅ L−1 NaCl, lots of conformational changes were evidenced. Under acidic conditions (pH = 6), there were more formed hydrogen bonds, and the hydrogen bonding interactions became stronger. Simulation results contributed to providing an important theoretical basis for understanding the roles of processing parameters on the quality control of Jinhua ham. • Cathepsin structure determines its function, replacing the potential enzyme activity. • Structural maps of cathepsin B in different conditions are visualized. • Explain the mechanism of optimum temperature, pH and NaCl inhibiting enzyme activity. [ABSTRACT FROM AUTHOR]

• Dipeptidyl-peptidase-IV is the key enzyme for inhibition of incretins in Type-II diabetes mellitus. • Molecular Docking, molecular dynamic, QMMM analysis and pharmacokinetic parameters (ADME studies) were performed for the hits. • Identification of best hits from Amberboa ramosa and phytochemical library using computational techniques. • Compound 2 (5‑hydroxy-7,8-dimethoxyflavone) is the most validated structure from in-silico studies. Diabetes is a chronic metabolic disorder, and as per the global burden, it is estimated that around 462 million people will be affected due to the cause of this disease. Currently, several drug treatments are available, but the need for herbal medicine is required for the management of diabetes. The present study focuses on the identification of potential compounds from the Amberboa ramosa plant and weed out similar potential compounds from a phytochemical library based on the best hits from the selected plant for the inhibition of dipeptidyl peptidase-IV (DPP-IV) enzyme using computational approaches. The results demonstrate that 3β,4α,8α-trihydroxy-4β-(hydroxymethyl)-1αH,5αH,6βH,7αH-guai-10(14),11(13)‑dien-6,12-olide (Compound 1) and 5‑hydroxy-7,8-dimethoxyflavone (Compound 2) showed maximum binding energy and dock score among all the compounds obtained from A. ramosa whereas, NPC170675 (Compound 3) was obtained from the phytochemical library. The molecular dynamics reveal that among all the three compounds, the root mean square deviation (RMSD) of compound 3 was found to be stable after 20 ns throughout the simulation. Compound 2 from A. ramosa was found to be more stable as compared to compound 1 in the active site during the simulation of 100 ns. Among all the three phytocompounds, compound 2 possesses lowest ΔG Bind energy of -51.096 kcal/mol in the post-simulation binding free energy analysis. The molecular reactivity analysis using hybrid QMMM approach shows compound 2 has the highest softness value in both the free (6.410 eV) and bound (6.817 eV) states, as well as the lowest hardness (0.078 eV/0.073 eV) and HOMO–LUMO gap (0.156 eV), indicating that it is more reactive than the others. Hence, compound 2 from A. ramosa is the most validated ligand from the in-silico findings. Thus, the exploration of phytoconstituents from A. ramosa plant and phytochemical library could be used in the management of Type-II diabetes mellitus. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Five modelling approaches are combined to construct a reasonable 3D structure of BaAADC. • The dynamic behaviour of BaAADC at high temperatures is demonstrated by comparative molecular dynamics simulations. • Dynamics calculations identify a range of highly flexible residues in BaAADC. • Salt bridge analysis provides information on thermally unstable ion pairs that can be used for further modifications. • This study reveals the mechanism of poor heat resistance of BaAADC for the first time at the molecular level. As an excellent biocatalyst, aromatic l -amino acid decarboxylase from Bacillus atrophaeus (Ba AADC) catalyzes the production of various vital aromatic biogenic amines. However, its weak heat resistance makes Ba AADC unsuitable for industrial production. Here, we generated the three-dimensional structure of Ba AADC and used molecular dynamics simulations to investigate the dynamic behavior of Ba AADC at different temperatures (303–343 K) to investigate the association between its thermal stability and internal residues. We have shown that the natural structure of Ba AADC is altered at high temperatures, with more striking alterations in secondary structure at the active site, fewer internal hydrogen bonding, and greater amino acid flexibility in the active pocket. Based on the root mean square fluctuations, the residues ASN46, GLU54, ALA113, ASP324, VAL329, and GLU332 were confirmed to be the most flexible. Salt bridge analysis revealed ion pairs ASP182-ARG197, ASP299-ARG347, GLU121-ARG344, GLU326-ARG316, GLU337-ARG316, GLU341-ARG347, and GLU470-ARG427 were partially responsible for the inactivation of Ba AADC at high temperatures. In addition, strategies to improve the thermostability of Ba AADC were discussed. This research might provide light on the development and modification of thermostable Ba AADC. [ABSTRACT FROM AUTHOR]

A priori density predictions of 32 molecules were attempted by combining the effective fragment potential version 2 (EFP2) and NPT molecular dynamics (MD) simulations. Our EFP2-MD procedure accurately predicted the density maximum of water as a function of temperature, showing its promising performance in the prediction of molecular density. With the help of a uniform scale factor of 0.9099, the mean absolute deviation and root-mean-square deviation of 32 molecular density predictions as compared to experiments are 0.037 and 0.002 g/cm3, respectively. They exhibit remarkable accuracy considering the fact that EFP2 is a purely theoretical parameter. [ABSTRACT FROM AUTHOR]

Molecular dynamics simulations and 2D-NOESY spectroscopy were applied to study the conformations and hydrogen-bonding interactions of ACE-inhibitory tripeptide Gly-Glu-Phe (GEF) in aqueous and DMSO solutions. The properties of GEF in simulations were characterized by intramolecular distance, root-mean-square deviation, solvent-accessible surface, and radius of gyration. Interestingly, the GEF molecule showed different behavior in different solvents. In aqueous solution, the GEF was highly flexible, and it could quickly convert from extended state to folded state. However, in DMSO solution, the extended conformations were hardly observed. The GEF molecule preferred extended state in aqueous compared to DMSO solution, which was confirmed by 2D-NOESY. [ABSTRACT FROM AUTHOR]

In the recent SAMPL5 challenge, participants submitted predictions for cyclohexane/water distribution coefficients for a set of 53 small molecules. Distribution coefficients (log D) replace the hydration free energies that were a central part of the past five SAMPL challenges. A wide variety of computational methods were represented by the 76 submissions from 18 participating groups. Here, we analyze submissions by a variety of error metrics and provide details for a number of reference calculations we performed. As in the SAMPL4 challenge, we assessed the ability of participants to evaluate not just their statistical uncertainty, but their model uncertainty-how well they can predict the magnitude of their model or force field error for specific predictions. Unfortunately, this remains an area where prediction and analysis need improvement. In SAMPL4 the top performing submissions achieved a root-mean-squared error (RMSE) around 1.5 kcal/mol. If we anticipate accuracy in log D predictions to be similar to the hydration free energy predictions in SAMPL4, the expected error here would be around 1.54 log units. Only a few submissions had an RMSE below 2.5 log units in their predicted log D values. However, distribution coefficients introduced complexities not present in past SAMPL challenges, including tautomer enumeration, that are likely to be important in predicting biomolecular properties of interest to drug discovery, therefore some decrease in accuracy would be expected. Overall, the SAMPL5 distribution coefficient challenge provided great insight into the importance of modeling a variety of physical effects. We believe these types of measurements will be a promising source of data for future blind challenges, especially in view of the relatively straightforward nature of the experiments and the level of insight provided. [ABSTRACT FROM AUTHOR]

Liver X Receptors (LXRs) are members of the nuclear receptor superfamily that regulate cholesterol metabolism. LXRs have been suggested as promising targets against many neurodegenerative diseases (NDDs). The present study was aimed to identify novel non-steroidal molecules that may potentially modulate LXR activity. The structure-based virtual screening (SBVS) was used to search for suitable compounds from the Asinex library. The top hits were selected and filtered based on their binding affinity for LXR α and β isoforms. Based on molecular docking and scoring results, 24 compounds were selected that had binding energy in the range of − 13.9 to − 12 for LXRα and − 12.5 to − 11 for LXRβ, which were higher than the reference ligands (GW3965 and TO901317). Further, the five hits referred to as model 29, 64, 202, 250, 313 were selected by virtue of their binding interactions with amino acid residues at the active site of LXRs. The selected hits were then subjected to absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis and blood-brain permeability prediction. It was observed that the selected hits had better pharmacokinetic properties with no toxicity and could cross blood-brain barrier. Further, the selected hits were analysed for dynamic evolution of the system with LXRs by molecular dynamics (MD) simulation at 100 ns using GROMACS. The MD simulation results validated that selected hits possess a remarkable amount of flexibility, stability, compactness, binding energy and exhibited limited conformational modification. The root mean square deviation (RMSD) values of the top-scoring hits complexed with LXRα and LXRβ were 0.05–0.6 nm and 0.05–0.45 nm respectively, which is greater than the protein itself. Altogether the study identified potential non-steroidal LXR modulators that appear to be effective against various neurodegenerative conditions involving perturbed cholesterol and lipid homeostasis. • In silico approach was used to identify non-steroidal LXR modulators for targeting neurological conditions. • Five hits were selected from the Asinex library based on drug-likeness and pharmacokinetic properties. • The selected hits had no predicted toxicity and were CNS permeable. • Molecular dynamic simulation studies indicated that the selected hits possess remarkable stability. • The identified non-steroidal LXR modulators appear to be effective against neurological conditions. [ABSTRACT FROM AUTHOR]

An impressive class of formally substitution-inert polynuclear platinum complexes known as Substitution-inert Polynuclear Platinum (II) Complexes (SI-PPCs) present an attractive approach for medicinal inorganic chemistry through high-affinity non-covalent interactions with biomolecules, such as DNA and Glycosaminoglycans (GAGs). This interaction occurs through the formation of non-covalent cyclic structures called clamps and forks with the phosphate and sulfate groups present in these biomolecules. This work shows several analyses of the non-covalent interactions formed between heparin (PDB code: 1HPN) and SI-PPCs obtained through molecular dynamics (MD) simulations. Root Mean Square Deviation (RMSD) results showed that the "non-covalent" di-nuclear platinum compound, DiplatinNC ([{ trans -Pt(NH 3) 2 (NH 2 (CH 2) 6 NH 3 +)} 2 -μ-NH 2 (CH 2) 6 NH 2 ]6+) and AH44 ([{Pt(NH 3) 3 } 2 {(μ-(H 2 N(CH 2) 6 NH 2) 2 -(trans -Pt(NH 3) 2 }]6+, 0,0,0/t,t,t,) complexes, which are both 6+ charged complexes, were the most rigid. On the other hand, the Root Mean Square Fluctuation (RMSF) showed that there is a reduction in the atomic fluctuation of atoms in the central region of the heparin molecule; the solvent accessible surface area (SASA) analysis also indicates a reduction in the accessible area by the heparin when interacting with SI-PPCs. The evaluation of H-Bond data confirms the formation of the non-covalent interactions, which may suggest a decrease in the action of 1HPN by preventing the action of enzymes on this substrate. In addition, thermodynamic results indicate that this interaction is spontaneous, considering the negative variations in the Gibbs free energy presented by the studied systems. Substitution-inert Polynuclear Platinum (II) Complexes interact with the heparin model, 1HPN, resulting in metalloshield and modulation of biological function to inhibit the metastasis process. [Display omitted] • Platinum (II) centers preferentially bind to sulfate groups generating changes in heparin. • Molecular dynamics closely analyzes interactions for a full depict of ligand trajectories. • Analysis of H-bonds proof the formation of non-covalent structures. • Triplatin complexes exhibited the highest number of native contacts and H-Bonds. • Metalloshield and modulation of biological function inhibit the metastasis process. [ABSTRACT FROM AUTHOR]

Protein receptor conformations, obtained from molecular dynamics (MD) simulations, have become a promising treatment of its explicit flexibility in molecular docking experiments applied to drug discovery and development. However, incorporating the entire ensemble of MD conformations in docking experiments to screen large candidate compound libraries is currently an unfeasible task. Clustering algorithms have been widely used as a means to reduce such ensembles to a manageable size. Most studies investigate different algorithms using pairwise Root-Mean Square Deviation (RMSD) values for all, or part of the MD conformations. Nevertheless, the RMSD only may not be the most appropriate gauge to cluster conformations when the target receptor has a plastic active site, since they are influenced by changes that occur on other parts of the structure. Hence, we have applied two partitioning methods (k-means and k-medoids) and four agglomerative hierarchical methods (Complete linkage, Ward’s, Unweighted Pair Group Method and Weighted Pair Group Method) to analyze and compare the quality of partitions between a data set composed of properties from an enzyme receptor substrate-binding cavity and two data sets created using different RMSD approaches. Ensembles of representative MD conformations were generated by selecting a medoid of each group from all partitions analyzed. We investigated the performance of our new method for evaluating binding conformation of drug candidates to the InhA enzyme, which were performed by cross-docking experiments between a 20 ns MD trajectory and 20 different ligands. Statistical analyses showed that the novel ensemble, which is represented by only 0.48% of the MD conformations, was able to reproduce 75% of all dynamic behaviors within the binding cavity for the docking experiments performed. Moreover, this new approach not only outperforms the other two RMSD-clustering solutions, but it also shows to be a promising strategy to distill biologically relevant information from MD trajectories, especially for docking purposes. [ABSTRACT FROM AUTHOR]

Several recent works have shown that protein structure can predict site-specific evolutionary sequence variation. In particular, sites that are buried and/or have many contacts with other sites in a structure have been shown to evolve more slowly, on average, than surface sites with few contacts. Here, we present a comprehensive study of the extent to which numerous structural properties can predict sequence variation. The quantities we considered include buriedness (as measured by relative solvent accessibility), packing density (as measured by contact number), structural flexibility (as measured by B factors, root-mean-square fluctuations, and variation in dihedral angles), and variability in designed structures. We obtained structural flexibility measures both from molecular dynamics simulations performed on nine non-homologous viral protein structures and from variation in homologous variants of those proteins, where they were available. We obtained measures of variability in designed structures from flexible-backbone design in the Rosetta software. We found that most of the structural properties correlate with site variation in the majority of structures, though the correlations are generally weak (correlation coefficients of 0.1-0.4). Moreover, we found that buriedness and packing density were better predictors of evolutionary variation than structural flexibility. Finally, variability in designed structures was a weaker predictor of evolutionary variability than buriedness or packing density, but it was comparable in its predictive power to the best structural flexibility measures. We conclude that simple measures of buriedness and packing density are better predictors of evolutionary variation than the more complicated predictors obtained from dynamic simulations, ensembles of homologous structures, or computational protein design. [ABSTRACT FROM AUTHOR]

• The poly [ADP-Ribose] polymerase 1 is a successful target against cancers. • N H/N-Me Aziridine derivatives as anti-cancer compounds targeting the apoptotic pathway. • Molecular descriptors, ADMET, BOILED-Egg, BAS, DBVS, Docking, MD simulations. • Earlier synthesized 21 Aziridine derivatives screened to identify the inhibitor against PARP1. The Poly [ADP-Ribose] polymerase 1 (PARP1) has recently been thought to be one of the potentially successful targets against cancer, specifically for ovarian and BRCA mutated breast cancers. Here, unprotected (N H/N-Me) aziridine derivatives were recognized as potential anti-cancer compounds targeting the apoptotic pathway using a combined molecular descriptors (MDs) computation, prediction of activity spectra for substances (PASS), adsorption, distribution, metabolism, excretion and toxicity (ADMET) evaluation, Brain Or IntestinaL EstimateD (BOILED-Egg), Bioactivity score (BAS), docking-based virtual screening (DBVS), integral docking and molecular dynamics (MD) simulation. Twenty one N H/N-Me aziridine derivatives were screened to identify molecules binding to the PARP1 followed by docking and MD simulation. Compound 3a shows a good binding profile, with the PARP1 as observed by the molecular docking evaluations. The docking complexes of the lead compound 3a with the target PARP1 were found stable during molecular dynamics simulations as represented by the obtained parameters including radius of gyration (Rg) and root mean square deviation (RMSD). The compound 3a yielded good binding free energy using the analysis of molecular mechanics generalized born surface area (MM-GBSA) and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA). Therefore, the findings of this study unravels that the compounds 3a is a lead anticancer candidate against selected target PARP1. [Display omitted] [ABSTRACT FROM AUTHOR]

• QSAR model was generated with good statistical results based on 6- arylquinazolin-4-amine derivatives as DYRK1A inhibitors. • New potential DYRK1A inhibitors were designed based on the QSAR model with high-predicted activity. • Molecular docking study was used to analyze the interaction between the best ligands and the DYRK1A receptor. • The newly designed compounds N2 and N11 have good ADMET properties and drug likeness. • The molecular dynamics simulation supported the interaction stability of newly designed compounds N2 and N11 in the DYRK1A active site, Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a protein kinase with diverse functions in neuronal development and adult brain physiology. QSAR study was performed for a diverse set of thirty-three6-arylquinazolin-4-amine derivatives as DYRK1A inhibitors. The QSAR model with HOMO, LUMO, qC sub , SAG and MW descriptors showed satisfactory internal and external validation parameters (R t r a i n 2 =0.867, R a d j 2 =0.831, Q L O O 2 = 0.755, F = 24.682 and R p r e d 2 =0.856). The excellent statistical results obtained for the developed model, strongly suggest that the model is reasonable for the prediction of the activity of new inhibitors. Therefore, we have designed several new potent DYRK1A inhibitors and validated their inhibitory activity by molecular docking methods using Autodock tools. Based in silico analysis, two novel compounds N2 and N11have been designed, which they have been identified hydrophobic and hydrogen bonds, with the binding pockets of active site4YLJ. Furthermore, the two newly designed compounds exhibited good ADMET properties, their molecular dynamics studies have shown a favorable energetic state and dynamic stability, characterized by root mean square deviation (RMSD), root mean square fluctuation (RMSF) and hydrogen bond. The outcomes of this study can be used to show the interest of DYRK1A inhibition for Alzheimer treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

• Molecular dynamics was applied to provide conformational information for COSMO-SAC model. • Variations of conformational structures of the long-chain polar compound shows profound impact on its σ-profile. • The new proposed COSMO-SAC(2010)CF in predicting liquid–liquid equilibrium of studied mixtures is significantly improved. The multi-conformational structures sampling of a molecule, considered as conformational information, is found to be crucial for applying COSMO-SAC to systems containing compounds with flexible molecular structures, such as alkylene glycol derivatives. In this study, a hybrid modeling approach that combines the COSMO-SAC model with classical molecular dynamics (MD) is proposed to investigate the phase behavior of systems containing alkylene glycol derivatives. The accuracy in predicting liquid–liquid equilibrium (LLE) was found to be strongly influenced by conformational populations obtaining from MD simulations under different solvation environments. The overall root mean square deviation (RMSD) in predicting LLE mutual solubility from COSMO-SAC for seven selected mixtures containing alkylene glycol derivatives reduces from 19.1% to 10.1% when conformation distribution is included. The new approach significantly improves the accuracy in predicting phase behaviors for alkylene glycol derivatives solutions and can be applied to systems containing compounds with flexible molecular structures. [ABSTRACT FROM AUTHOR]

[Display omitted] • All solvents may be preferable for solubilization except water. • Reactivity of CPB changes with the dielectric constant of solvents directly affecting the reactivity indexes. • Compactness of the ligand bound protein complex and suggesting an equilibrated as well as converged structure. Pyrazole is one the most promising nitrogen containing chemical groups with pharmacological effects. The solvation effects, spectroscopic analysis and molecular dynamics (MD) simulations with reactivity analysis of 1-{3-(4-chlorophenyl)-5-[4-(propan-2-yl)phenyl]-4.5-dihydro-1H-pyrazol-1-yl}-butan-1-one (CPB) are reported. The solvation energies were calculated via solvation model based on density (SMD) model in solvents, all of the values obtained were negative, a comparison of the predicted values suggests that all solvents may be preferable for CPB solubilization except water. Root mean square fluctuations of the whole C-alpha atom of 5BST at a function of 100 ns time scale displayed less deviation indicating very stable and compact protein ligand complex. [ABSTRACT FROM AUTHOR]