Results Of Molecular Dynamics Simulations Research Articles

Discovery of a novel SHP2 allosteric inhibitor using virtual screening, FMO calculation, and molecular dynamic simulation.

SHP2 is a non-receptor protein tyrosine phosphatase to remove tyrosine phosphorylation. Functionally, SHP2 is an essential bridge to connect numerous oncogenic cell-signaling cascades including RAS-ERK, PI3K-AKT, JAK-STAT, and PD-1/PD-L1 pathways. This study aims to discover novel and potent SHP2 inhibitors using a hierarchical structure-based virtual screening strategy that combines molecular docking and the fragment molecular orbital method (FMO) for calculating binding affinity (referred to as the Dock-FMO protocol). For the SHP2 target, the FMO method prediction has a high correlation between the binding affinity of the protein-ligand interaction and experimental values (R2 = 0.55), demonstrating a significant advantage over the MM/PBSA (R2 = 0.02) and MM/GBSA (R2 = 0.15) methods. Therefore, we employed Dock-FMO virtual screening of ChemDiv database of ∼2,990,000 compounds to identify a novel SHP2 allosteric inhibitor bearing hydroxyimino acetamide scaffold. Experimental validation demonstrated that the new compound (E)-2-(hydroxyimino)-2-phenyl-N-(piperidin-4-ylmethyl)acetamide (7188-0011) effectively inhibited SHP2 in a dose-dependent manner. Molecular dynamics (MD) simulation analysis revealed the binding stability of compound 7188-0011 and the SHP2 protein, along with the key interacting residues in the allosteric binding site. Overall, our work has identified a novel and promising allosteric inhibitor that targets SHP2, providing a new starting point for further optimization to develop more potent inhibitors. All the molecular docking studies were employed to identify potential leads with Maestro v10.1. The protein-ligand binding affinities of potential leads were further predicted by FMO calculations at MP2/6-31G* level using GAMESS v2020 system. MD simulations were carried out with AmberTools18 by applying the FF14SB force field. MD trajectories were analyzed using VMD v1.9.3. MM/GB(PB)SA binding free energy analysis was carried out with the mmpbsa.py tool of AmberTools18. The docking and MD simulation results were visualized through PyMOL v2.5.0.

A new insight on a novel auxiliary collector 4-MBA synergize with BHA to enhance flotation of scheelite

The hydroxamic acid reagents are extremely pervasive in the collector of scheelite flotation. The high flotation cost is caused by its large dosage and high price. A novel auxiliary collector 4-methodybenzoicacid (4-MBA) was used in combination with benzohydroxamic acid (BHA) to optimize the flotation reagents system for scheelite in the study. A single 4-MBA has weak collection capacity for scheelite. Nevertheless, the combination of 4-MBA and BHA optimized the flotation system of scheelite by ensuring its recovery and reducing the reagent consumption. The results of solution surface tension and contact angle measurements showed that the surface tension of the mixed reagent solution is a relatively lower and the hydrophobicity of the scheelite surface is a relatively higher in the BHA and 4-MBA mixed reagent system. Additionally, a synergistic effect between BHA and 4-MBA on Pb2+ activated scheelite is revealed by the Zeta potential measurements, infrared spectroscopy (FT-IR) and X-ray photoelectron spectroscopy (XPS). The addition of 4-MBA promoted the physical and chemical adsorption of BHA. The results of molecular dynamics simulation (MDS) further explained that the collector adsorption layer of the surface of scheelite (112) is more compact under BHA and 4-MBA mixed reagent system, which prevents the vertical entry of water phase and improves the hydrophobicity of scheelite. Finally, the bench-scale flotation experiment verified that the addition of 4-MBA enhanced scheelite flotation with BHA, and decrease the flotation cost of scheelite.

Identification of potential FAK inhibitors using mol2vec molecular descriptor-based QSAR, molecular docking, ADMET study, and molecular dynamics simulation.

This study aims to identify potential focal adhesion kinase (FAK) inhibitors through an integrated computational approach, combining mol2vec descriptor-based QSAR, molecular docking, ADMET study, and molecular dynamics simulation. A dataset of 437 compounds with known FAK inhibitory activities was used to develop QSAR models using machine learning algorithms combined with mol2vec descriptors. Subsequently, the most promising compounds were subjected to molecular docking against FAK to evaluate their binding affinities and key interactions. ADMET study and molecular dynamics simulation were also employed to investigate the pharmacokinetic, drug-like properties, and the stability of the protein-ligand complexes. The results showed that the mol2vec descriptor-based QSAR model established by support vector regression demonstrated good predictive performance (R2 = 0.813, RMSE = 0.453, MAE = 0.263 in case of training set, and R2 = 0.729, RMSE = 0.635, MAE = 0.477 in case of test set), indicating their reliability in identifying potent FAK inhibitors. Using this QSAR model and molecular docking, compound 21 (ZINC000004523722) was identified as the most potential compound, with predicted logIC50 value and binding energy of 2.59 and - 9.3kcal/mol, respectively. The results of molecular dynamics simulation and ADMET study also further suggested its potential as a promising drug candidate. However, because our research was merely theoretical, additional in vitro and in vivo studies are required for the verification of these results.

High energy radiation tolerance of iron phosphate glasses: Molecular dynamics study

We report the results of massive parallel molecular dynamics simulations of high-energy radiation damage in phosphate glasses. This damage is created by overlapping multiple 70 keV collision cascades. We quantify different aspects of radiation-induced structural changes including at different stages of damage development, including coordination numbers, cluster sizes and density. The overall trend is that radiation damage causes polymerisation of the glass network and the loss of small and isolated clusters, however the details of this response vary with different glass compositions.

Molecular Dynamics and Binding Energetics of Fluspirilene With BACE1: Implications for Alzheimer's Disease Intervention

ABSTRACTAlzheimer's disease (AD) is a serious neurodegenerative disorder that results in cognitive deterioration, amnesia, and alterations in behavior, rendering it a significant issue in public health. The pathogenesis involves amyloid plaques highlighting the importance of targeting BACE1. This study explores fluspirilene, a di‐phenyl‐butyl‐piperidine as a potential BACE1 inhibitor for AD treatment. Fluspirilene was analyzed for ADMET. In silico molecular docking assessed fluspirilene's binding affinity with BACE1. Re‐docking a co‐crystallized ligand confirmed the docking process. Molecular dynamics simulations and related multifaceted computational analyses were conducted to assess the stability of docked complexes. Fluspirilene had good physicochemical and pharmacokinetic characteristics according to ADMET profiling. In silico molecular docking showed multiple BACE1 interactions with a binding affinity of −9.2 kcal/mol and fluspirilene–BACE1 complex stability was confirmed by molecular dynamics simulation results. Possible therapeutic applications in lowering Aβ generation and treating AD are indicated by the compound's pharmacokinetics, molecular interactions, and binding energetics. Validation and optimization of experiments are necessary for the clinical development of fluspirilene as a BACE1 inhibitor for AD.

Energy condensation and dipole alignment in protein dynamics.

The possibility that distant biomolecules in a cell interact via electromagnetic (e.m.) radiation was proposed many years ago to explain the high rate of encounters of partners in some enzymatic reactions. The results of two recent experiments designed to test the propensity of protein bovine serum albumin (BSA) to interact via e.m. radiation with other proteins were interpreted in a theoretical framework based on three main assumptions: (i) in order to experience this kind of interaction the protein must be in an out-of-equilibrium state; (ii) in this state there is a condensation of energy in low-frequency vibrational modes; and (iii) the hydration layers of water around the protein sustain the energy condensation. In the present paper we present the results of molecular dynamics simulations of BSA in four states: at equilibrium and out-of-equilibrium in water, and at room and high temperature in vacuum. By comparing physical properties of the system in the four states, our simulations provide a qualitative and quantitative assessment of the three assumptions on which the theoretical framework is based. Our results confirm the assumptions of the theoretical model showing energy condensation at low frequency and electretlike alignment between the protein's and the water's dipoles; they also allow a quantitative estimate of the contribution of the out-of-equilibrium state and of the water to the observed behavior of the protein. In particular, it has been found that in the out-of-equilibrium state the amplitude of the oscillation of the protein's dipole moment greatly increases, thereby enhancing a possible absorption or emission of e.m. radiation. The analysis of BSA's dynamics outlined in the present paper provides a procedure for checking the propensity of a biomolecule to interact via e.m. radiation with its biochemical partners.

Molecular insights into oil detachment from hydrophobic quartz surfaces in clay-hosted nanopores during steam–surfactant co-injection

Thermal recovery techniques for producing oil sands have substantial environmental impacts. Surfactants can efficiently improve thermal bitumen recovery and reduce the required amount of steam. Such a technique requires solid knowledge about the interaction mechanism between surfactants, bitumen, water, and rock at the nanoscale level. In particular, oil sands ores have extremely complex mineralogy as they contain many clay minerals (montmorillonite, illite, kaolinite). In this study, molecular dynamics simulation is carried out to elucidate the unclear mechanisms of clay minerals contributing to the bitumen recovery under a steam–anionic surfactant co-injection process. We found that the clay content significantly influenced an oil detachment process from hydrophobic quartz surfaces. Results reveal that the presence of montmorillonite, illite, and the siloxane surface of kaolinite in nanopores can enhance the oil detachment process from the hydrophobic surfaces because surfactant molecules have a stronger tendency to interact with bitumen and quartz. Conversely, the gibbsite surfaces of kaolinite curb the oil detachment process. Through interaction energy analysis, the siloxane surfaces of kaolinite result in the most straightforward oil detachment process. In addition, we found that the clay type presented in nanopores affected the wettability of the quartz surfaces. The quartz surfaces associated with the gibbsite surfaces of kaolinite show the strongest hydrophilicity. By comparing previous experimental findings with the results of molecular dynamics (MD) simulations, we observed consistent wetting characteristics. This alignment serves to validate the reliability of the simulation outcomes. The outcome of this paper makes up for the lack of knowledge of a surfactant-assisted bitumen recovery process and provides insights for further in-situ bitumen production engineering designs.

Understanding the filling effect of ice on the mechanical properties of calcium silicate hydrate gel

Ice exhibits good mechanical performance at low temperatures, and when it replaces the weakest pores in cement-based materials, it can noticeably enhance the overall mechanical properties of the material. However, the specific micro-mechanisms that contribute to the improvement of tensile mechanical properties in gel pores at low temperatures are still not fully understood. Based on the results of molecular dynamics simulations, significant roles have been attributed to pore size and temperature in the mechanical performance of gel pores at low temperatures. A thorough investigation was conducted on the process of tensile failure in saturated gel pores, as well as the changes in bonding interactions between calcium silicate hydrate (CSH)-ice and the unfrozen water film (UWF) at different pore sizes and temperatures. The results indicate that increasing pore size and decreasing temperature can improve the mechanical properties of saturated gel pores. With the decrease in temperature, the mechanical properties of the three gel pore systems with heights of 100 Å, 68 Å, and 54 Å were significantly enhanced. Under an engineering strain rate of 8×10−4/ps, the tensile strength and elastic modulus of gel pores increased from 0.57 GPa and 17.81 GPa at 250 K, to 0.97 GPa and 20.87 GPa at 150 K, respectively. To explain this phenomenon, further studies were conducted on the radial distribution function and dynamic hydrogen bonding behavior. The critical contribution of the hydrogen bond network to the mechanical performance of gel pores was discovered. The hydrogen bond structure which experienced the earliest damage, was investigated. As the strain increased, the hydrogen bonds continuously broke and reformed. This research provides a theoretical understanding of the mechanical properties of gel pores under low-temperature conditions.

Synthesis, Molecular Docking, Molecular Dynamic Simulation Studies, and Antitubercular Activity Evaluation of Substituted Benzimidazole Derivatives.

Tuberculosis, also known as TB, is a widespread bacterial infection that remains a significant global health issue. This study focuses on conducting a thorough investigation into the synthesis, evaluation of anti-Tb activity, molecular docking, and molecular dynamic simulation of substituted benzimidazole derivatives. A series of twelve substituted benzimidazole derivatives (1-12) were successfully synthesized, employing a scaffold consisting of electron-withdrawing and electron-donating groups. The newly synthesized compounds were defined by their FTIR, 1H NMR, and mass spectra. The microplate Alamar blue assay (MABA) was used to evaluate the antimycobacterial activity of the synthesized compound against Mycobacterium tuberculosis (Mtb). Compounds 7 (MIC = 0.8 g/mL) and 8 (MIC = 0.8 g/mL) demonstrated exceptional potential to inhibit M. tuberculosis compared to the standard drug (isoniazid). In addition, the synthesized compounds were docked with the Mtb KasA protein (PDB ID: 6P9K), and the results of molecular docking and molecular dynamic simulation confirmed the experimental results, as compounds 7 and 8 exhibited the highest binding energy of -7.36 and -7.17 kcal/mol, respectively. The simulation results such as the RMSD value, RMSF value, radius of gyration, and hydrogen bond analysis illustrated the optimum potential of compounds 7 and 8 to inhibit the M. tuberculosis strain. Hydrogen bond analysis suggested that compound 7 has greater stability and affinity towards the KasA protein compared to compound 8. Moreover, both compounds (7 and 8) were safe for acute inhalation and cutaneous sensitization. These two compounds have the potential to be potent M. tuberculosis inhibitors.

Selective Hydrolysis of Ovalbumin by Zr-Based Lacunary Polyoxotungstate in Surfactant Solutions.

This study aims to design an artificial metalloprotease based on a Zr-containing polyoxometalate Na8[Zr(W5O18)2] [Zr(W5)2] for the hydrolysis of ovalbumin (OVA) in the presence of different surfactants, which can be used in many areas of the biological and medical sciences, particularly for targeted proteolytic drug design. For this reason, parameters, including the free energy of binding, the chemical nature of amino acid residues, secondary structures, and electrostatic potentials, of Zr(W5)2-OVA and Zr(W5)2-OVA-surfactant were analyzed by molecular docking simulations. The investigations showed that the presence of surfactants decreases the binding affinity of Zr(W5)2 for OVA amino acids, and hydrogen bonds and van der Waals interactions are formed between Zr(W5)2 and OVA amino acids. Additionally, GROMACS further illustrated the significance of SDS and CTAB surfactants in influencing the conformational changes of the OVA that lead to selective protein hydrolysis. In agreement with molecular dynamics simulation results, the experimental analysis showed more protein hydrolysis for the Zr(W5)2-OVA-surfactant systems. For instance, circular dichroism spectroscopy indicated that Zr(W5)2-OVA-CTAB and Zr(W5)2-OVA-TX-100 were more hydrolytically efficient due to the increased level of β-structures rather than α-chains, which showed that surfactants can facilitate the accessibility of Zr(W5)2 to the cleavage sites by inducing partial unfolding of the OVA structure.

Identification of Novel Quinolone and Quinazoline Alkaloids as Phosphodiesterase 10A Inhibitors for Parkinson's Disease through a Computational Approach.

Phosphodiesterases (PDEs) are vital in signal transduction, specifically by hydrolyzing cAMP and cGMP. Within the PDE family, PDE10A is notable for its prominence in the striatum and its regulatory function over neurotransmitters in medium-spiny neurons. Given the dopamine deficiency in Parkinson's disease (PD) that affects striatal pathways, PDE10A inhibitors could offer therapeutic benefits by modulating D1 and D2 receptor signaling. This study was motivated by the successful history of quinazoline/quinazoline scaffolds in the inhibition of PDE10A. This study involved detailed in silico evaluations through docking followed by pharmacological, pharmacophoric, and pharmacokinetic analyses, prioritizing central nervous system (CNS)-active drug criteria. Seven cyclic peptides, those featuring the quinazoline/quinazoline moiety at both termini, exhibited notably enhanced docking scores compared to those of the remaining alkaloids within the screened library. We identified 7 quinolines and 1 quinazoline including Lepadin G, Aspernigerin, CJ-13536, Aurachin A, 2-Undecyl-4(1H)-quinolone, Huajiaosimuline 3-Prenyl-4-prenyloxyquinolin-2-one, and Isaindigotone that followed the standard CNS active drug criteria. The dominant quinoline ring in our study and its related quinazoline were central to our evaluations; therefore, the pharmacophoric features of these scaffolds were highlighted. The top alkaloids met all CNS-active drug properties; while nonmutagenic and without PAINS alerts, many indicated potential hepatotoxicity. Among the compounds, Huajiaosimuline was particularly significant due to its alignment with lead-likeness and CNS-active criteria. Aspernigerin demonstrated its affinity for numerous dopamine receptors, which signifies its potential to alter dopaminergic neurotransmission that is directly related to PD. Interestingly, the majority of these alkaloids had biological targets primarily associated with G protein-coupled receptors, critical in PD pathophysiology. They exhibit superior excretion parameters and toxicity end-points compared to the standard. Notably, selected alkaloids demonstrated stability in the binding pocket of PDE10A according to the molecular dynamic simulation results. Our findings emphasize the potential of these alkaloids as PDE10A inhibitors. Further experimental studies may be necessary to confirm their actual potency in inhibiting PDE10A before exploring their therapeutic potential in PD.

Interaction and Binding Kinetics of Different Substituted Pyrazines with HSA: Based on Multispectral, Physiological Activity, and Molecular Dynamics Simulations

Pyrazine is a kind of compound containing pyrazine ring structure, which has attracted the attention of researchers because of its special aroma and healthcare function. It is currently used in spices, pharmaceuticals, food additives, and other industries. Human serum albumin (HSA) is a transport and storage protein in the human circulatory system. Previous research reported that pyrazine can interact with albumin, but the interaction between pyrazine and HSA has not been reported. Consequently, this study is based on the multispectral method and molecular dynamics (MD) simulation, exploring the interaction between different pyrazines and HSA. The results show that the four pyrazines mainly quench the endogenous fluorescence of HSA through the static quenching mechanism. Molecular docking indicates that hydrophobic forces play a major role in the binding of pyrazines with HSA. At the same time, synchronous fluorescence spectroscopy, circular dichroism (CD), three-dimensional fluorescence spectroscopy, and resonance light scattering (RLS) showed that each pyrazine compound can change the conformation of HSA. MD simulation results show that the combination of four pyrazines and HSA can enhance the stability of HSA. Among them, 2,3,5,6-tetramethylpyrazine (TTMP) and 2,3,5-trimethylpyrazine (TMTP) binding is the most stable and the most unstable combination with HSA, respectively. In addition, the four pyrazines could affect the physiological activity of HSA. This study is of great significance to explore the mechanism of action of pyrazine compounds in vivo and can provide useful information for the application of pyrazine compounds in food.

Interaction mechanism and binding mode between different polyphenols and gellan gum

To investigate the impact of different polyphenols on the gel properties of gellan gum (GG) and the interaction mechanism, experiments and virtual molecular simulations were conducted based on nine representative polyphenols. Rheological analysis revealed that all the GG/polyphenol composite hydrogels were pseudoplastic fluids with a low viscosity. The storage modulus (G′) of hydrogel containing only GG was 28.3 Pa at 0.1 Hz. The addition of gallic acid (GA), puerarin (PUE) or cyanidin cation (CC) significantly increased the G′ of the hydrogel by 4.9-fold, 3.3-fold, and 2.6-fold, respectively. The introduction of GA reduced the water holding capacity (WHC) of the hydrogel to 62.0 %, while the other eight polyphenols increased the WHC to nearly 100 %. Regular, intact and dense honeycomb mesh structures were observed in the GG/GA, GG/PUE, GG/CC and GG/catechin microstructures. The molecular docking results indicated that, among the nine polyphenols, PUE had the strongest affinity for GG with an interaction energy of −18.64 kcal/mol. According to the results of molecular dynamics simulation, the total energy of the composite system interacting with water corresponded well with the G′ of the composite hydrogels. The GG/GA system with the highest G′ had the lowest total energy of −15655.82 kJ/mol. Hydrogen bonds were the main driving force for improving the strength and maintaining the structural stability of the composite hydrogels. Therefore, this study confirmed the various effects of nine polyphenols on GG hydrogels and provided a novel basis for investigating the synthesis and gelation mechanism of polysaccharide-polyphenol composite hydrogels.

Discovery of Benzoxazepines as a New Class of PIM1 Kinase Inhibitors Through Structure Based Virtual Screening, Biochemical Evaluation and Cytotoxicity Studies

AbstractPIM kinase is a serine/threonine protein kinase implicated in human cancers because it promotes cell proliferation while inhibiting apoptosis and is a crucial target for malignancy. In the present study, we used 700000 commercially available Chembridge small molecules library for structure‐based drug discovery to identify novel potent PIM1 kinase inhibitors. Based on the virtual screening results, ten compounds were chosen and screened enzymatically at 10 μM. Out of ten compounds, only two compounds, 22876894 (61 %) and 58626268 (63 %), inhibited PIM1 kinase. Subsequently, the enzymatic IC50 value for compounds 22876894 and 58626268 was calculated and found to be 0.8 μM and 3.9 μM. Cell viability was evaluated on human malignant cell lines HCT‐116 (colorectal carcinoma), U‐2OS (osteosarcoma), and non‐cancerous hTERT‐RPE‐1. It was found that compound 22876894 possessed significant inhibitory activity against HCT‐116 (IC50=12.1 μM), U‐2OS (IC50=23.2 μM), and hTERT‐RPE‐1 (IC50=12.7 μM) cell lines. The compound 58626268 possessed significant inhibitory activities against HCT‐116 (IC50=28.1 μM), U‐2OS (IC50=23.5 μM), and hTERT‐RPE‐1 (IC50=21 μM) cell lines. Further, the molecular dynamics simulation of identified compounds (22876894 and 58626268) was performed. Based on kinase profiling, cytotoxicity studies, and molecular dynamics simulation results, we claim 5‐{[7‐(1‐benzothien‐3‐yl)‐9‐hydroxy‐2,3‐dihydro‐1,4‐benzoxazepin‐4(5H)‐yl]carbonyl}pyridin‐2(1H)‐one (22876894) and 4‐(2‐aminoisonicotinoyl)‐7‐(1‐benzothien‐3‐yl)‐2,3,4,5‐tetrahydro‐1,4‐benzoxazepin‐9‐ol (58626268) as a selective and potential PIM1 kinase inhibitors.

Exploring the Antarctic aminopeptidase P from Pseudomonas sp. strain AMS3 through structural analysis and molecular dynamics simulation

Aminopeptidase P (APPro) is a crucial metalloaminopeptidase involved in amino acid cleavage from peptide N-termini, playing essential roles as versatile biocatalysts with applications ranging from pharmaceuticals to industrial processes. Despite acknowledging its potential for catalysis in lower temperatures, detailed molecular basis and biotechnological implications in cold environments are yet to be explored. Therefore, this research aims to investigate the molecular mechanisms underlying the cold-adapted characteristics of APPro from Pseudomonas sp. strain AMS3 (AMS3-APPro) through a detailed analysis of its structure and dynamics. In this study, structure analysis and molecular dynamics (MD) simulation of a predicted model of AMS3-APPro has been performed at different temperatures to assess structural flexibility and thermostability across a temperature range of 0–60 °C over 100 ns. The MD simulation results revealed that the structure were able to remain stable at low temperatures. Increased temperatures present a potential threat to the overall stability of AMS3-APPro by disrupting the intricate hydrogen bond networks crucial for maintaining structural integrity, thereby increasing the likelihood of protein unfolding. While the metal binding site at the catalytic core exhibits resilience at higher temperatures, highlighting its local structural integrity, the overall enzyme structure undergoes fluctuations and potential denaturation. This extensive structural instability surpasses the localized stability observed at the metal binding site. Consequently, these assessments offer in-depth understanding of the cold-adapted characteristics of AMS3-APPro, highlighting its capability to uphold its native conformation and stability in low-temperature environments. In summary, this research provides valuable insights into the cold-adapted features of AMS3-APPro, suggesting its efficient operation in low thermal conditions, particularly relevant for potential biotechnological applications in cold environments. Communicated by Ramaswamy H. Sarma

The role of glycosylation in non-productive adsorption of cellulase to lignin isolated from pretreated corn stover

Glycosylation, a general post-translational modification for fungal cellulase, has been shown to affect cellulase binding to its substrate. However, the exact impact of glycosylation on cellulase-lignin interaction remain unclear. Here, we demonstrated that the lignin isolated from tetrahydrofuran-pretreated corn stover exhibits strong adsorption capability to cellulase due to its negatively charged and porous structure. For the cellulases with varying glycosylation levels, the less-glycosylated protein showed high adsorption capability to lignin, and that trend was observed for the main cellulase components secreted by Penicillium oxilicum, including endoglucanase PoCel5B, cellobiohydrolase PoCel7A-2, and β-glucosidase PoBgl1. Additionally, N-glycan sites and motifs were examined using mass spectrometry, and protein structures with N-glycans were constructed, where PoBgl1 and PoCel7A-2 contained 13 and 1 glycosylated sites respectively. The results of molecular dynamics simulations indicated that the N-glycans impacted on the solvent-accessible surface area and secondary structure of protein, and the binding conformation of lignin fragment on cellulase, resulting in a decrease in binding energy (14 kcal/mol for PoBgl1 and 13 kcal/mol for PoCel7A-2), particularly for van der Waals and electrostatic interaction. Those findings suggested that glycosylation negatively impacted the lignin-cellulase interaction, providing a theoretical basis for the rational engineering of enzymes to reduce lignin-enzyme interaction.

Phenolic compounds of Theobroma cacao L. show potential against dengue RdRp protease enzyme inhibition by In-silico docking, DFT study, MD simulation and MMGBSA calculation.

Currently, there is no antiviral medication for dengue, a potentially fatal tropical infectious illness spread by two mosquito species, Aedes aegypti and Aedes albopictus. The RdRp protease of dengue virus is a potential therapeutic target. This study focused on the in silico drug discovery of RdRp protease inhibitors. To assess the potential inhibitory activity of 29 phenolic acids from Theobroma cacao L. against DENV3-NS5 RdRp, a range of computational methods were employed. These included docking, drug-likeness analysis, ADMET prediction, density functional theory (DFT) calculations, and molecular dynamics (MD) simulations. The aim of these studies was to confirm the stability of the ligand-protein complex and the binding pose identified during the docking experiment. Twenty-one compounds were found to have possible inhibitory activities against DENV according to the docking data, and they had a binding affinity of ≥-37.417 kcal/mol for DENV3- enzyme as compared to the reference compound panduratin A. Additionally, the drug-likeness investigation produced four hit compounds that were subjected to ADMET screening to obtain the lead compound, catechin. Based on ELUMO, EHOMO, and band energy gap, the DFT calculations showed strong electronegetivity, favouravle global softness and chemical reactivity with considerable intra-molecular charge transfer between electron-donor to electron-acceptor groups for catechin. The MD simulation result also demonstrated favourable RMSD, RMSF, SASA and H-bonds in at the binding pocket of DENV3-NS5 RdRp for catechin as compared to panduratin A. According to the present findings, catechin showed high binding affinity and sufficient drug-like properties with the appropriate ADMET profiles. Moreover, DFT and MD studies further supported the drug-like action of catechin as a potential therapeutic candidate. Therefore, further in vitro and in vivo research on cocoa and its phytochemical catechin should be taken into consideration to develop as a potential DENV inhibitor.

Molecular dynamics simulation and experimental study on the mechanical properties of PET nanocomposites filled with CaCO3, SiO2, and POE-g-GMA

Abstract This work investigated the mechanical properties of polyethylene terephthalate (PET) reinforced with calcium carbonate (CaCO3) and silica (SiO2) nanoparticles, respectively, and the improvement in toughness of the ternary system with the incorporation of graft-modified ethylene-1-octene copolymer (POE-g-GMA). PET nanocomposites were prepared by melt blending extrusion and injection molding. Molecular dynamics (MD) simulation was employed to construct models for binary system filled with nanoparticles and ternary system with the additional inclusion of POE-g-GMA elastomers. The results of mechanical property tests and MD simulation revealed that the binary system exhibited increased elastic modulus and tensile strength, mainly attributed to the effective reinforcement of rigid nanoparticles and the surface adsorption between nanoparticles and the PET matrix enhanced the interfacial interactions. CaCO3 indicated a more pronounced reinforcing effect, possibly due to the higher crystallinity of its composites. The incorporation of POE-g-GMA resulted in a significant improvement in impact strength and the elongation at break of PET nanocomposites. This enhancement in toughness is attributed to the elastomer’s ability to absorb a substantial amount of impact energy, while the elastic modulus is higher than that of pure PET.

Magnetic Supramolecular Spherical Arrays: Direct Formation of Micellar Cubic Mesophase by Lanthanide Metallomesogens with 7-Coordination Geometry.

Here, an unprecedented phenomenon in which 7-coordinate lanthanide metallomesogens, which align via hydrogen bonds mediated by coordinated H2O molecules, form micellar cubic mesophases at room temperature, creating body-centered cubic (BCC)-type supramolecular spherical arrays, is reported. The results of experiments and molecular dynamics simulations reveal that spherical assemblies of three complexes surrounded by an amorphous alkyl domain spontaneously align in an energetically stable orientation to form the BCC structure. This phenomenon differs greatly from the conventional self-assembling behavior of 6-coordinated metallomesogens, which form columnar assemblies due to strong intermolecular interactions. Since the magnetic and luminescent properties of different lanthanides vary, adding arbitrary functions to spherical arrays is possible by selecting suitable lanthanides to be used. The method developed in this study using 7-coordinate lanthanide metallomesogens as building blocks is expected to lead to the rational development of micellar cubic mesophases.

Unraveling Activation-Related Rearrangements and Intrinsic Divergence from Ligand-Specific Conformational Changes of the Dopamine D3 and D2 Receptors.

Effective rational drug discovery hinges on understanding the functional states of the target protein and distinguishing it from homologues. However, for the G protein coupled receptors, both activation-related conformational changes (ACCs) and intrinsic divergence among receptors can be misled or obscured by ligand-specific conformational changes (LCCs). Here, we unraveled ACCs and intrinsic divergence from LCCs of the dopamine D3 and D2 receptors (D3R and D2R), by analyzing their experimentally determined structures and the molecular dynamics (MD) simulation results of the receptors bound with various ligands. In addition to the ACCs common to other aminergic receptors, we revealed unique ACCs for these two receptors, including the extracellular portion of TM5 (TM5e) and TM6e shifting away from TM2e and TM3e, with a subtle rotation of TM5e. In identifying intrinsic divergence, we found more outward tilting of TM6e in the D2R compared to the D3R in both the experimental structures and simulations bound with ligands in different scaffolds. However, this difference was drastically reduced in the simulations bound with nonselective agonist quinpirole, suggesting a misleading effect of LCCs. Further, in the quinpirole-bound simulations, TM1 showed a greater disparity between these receptors, indicating that LCCs may also obscure intrinsic divergence. Importantly, our MD simulations revealed divergence in the dynamics of these receptors. Specifically, the D2R exhibited heightened flexibility compared to the D3R in the extracellular loops and TMs 5e, 6e, and 7e, associated with its greater ligand binding site plasticity. Our results lay the groundwork for crafting ligands specifically targeting the D2R and D3R with more precise pharmacological profiles.