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Phenolic environmental endocrine-disrupting chemicals (PEDCs) are persistent EDCs that are widely found in food packaging materials and environmental media and seriously threaten human health and ecological security. Human estrogen-related receptor γ (hERRγ) has been proposed as a mediator for the low-dose effects of many environmental PEDCs; however, the atomic-level descriptions of dynamical structural features and interactions of hERRγ and PEDCs are still unclarified. Herein, how three PEDCs, 4-(1-methylpropyl)phenol (4-sec-butylphenol), 5,6,7,8-tetrahydro-2-naphthol (tetrahydro-2-napthol), and 2,2-bis(4-hydroxy-3,5-dimethoxyphenyl)propane (BP(2,2)(Me)), interact with hERRγ to produce its estrogenic disruption effects was studied. Molecular docking and multiple molecular dynamics (MD) simulations were first conducted to distinguish the detailed interaction pattern of hERRγ with PEDCs. These binding structures revealed that residues around Leu271, Leu309, Leu345, and Phe435 are important when binding with PEDCs. Furthermore, the binding energies of PEDCs with hERRγ were also characterized using the molecular mechanics/Poisson Boltzmann surface area (MM-PBSA) and solvated interaction energy (SIE) methods, and the results showed that the interactions of CH-π, π-π, and hydrogen bonds are the major contributors for hERRγ binding to these three PEDCs. What is striking is that the methoxide groups of BP(2,2)(Me), as hydrophobic groups, can help to reduce the binding energy of PEDCs binding with hERRγ. These results provide important guidance for further understanding the influence of PEDCs on human health problems.

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BACKGROUND: Odorant-binding proteins (OBPs) in insects are key to detection and recognition of external chemical signals associated with survival. OBP7 in Spodoptera frugiperda's larval stage (SfruOBP7) may search for host plants by sensing plant volatiles, which are important sources of pest attractants and repellents. However, the atomic-level basis of binding modes remains elusive. RESULTS: SfruOBP7 structure was constructed through homology modeling, and complex models of six plant volatiles ((E)-2-hexenol, α-pinene, (Z)-3-hexenyl acetate, lauric acid, O-cymene and 1-octanol) and SfruOBP7 were obtained through molecular docking. To study the detailed interactions between the six plant volatile molecules and SfruOBP7, we conducted three 300 ns molecular dynamics simulations for each study object. The correlation coefficients between binding free energy obtained by molecular mechanics/generalized Born surface area together with solvated interaction energy methods and experimental values are 0.90 and 0.88, respectively, showing a good correlation. By comparing binding free energy along with interaction patterns between SfruOBP7 and the six volatile molecules, hotspot residues of SfruOBP7 when binding with different volatile molecules were determined. Hydrophobic interactions stemming from van der Waals interactions play a significant role in SfruOBP7 and these plant volatile systems. CONCLUSION: The optimized three-dimensional structure of SfruOBP7 and its binding modes with six plant volatiles revealed their interactions, thus providing a means for estimating the binding energies of other plant volatiles. Our study will help to guide the rational design of effective and selective insect attractants. © 2024 Society of Chemical Industry.

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CONTEXT: Human estrogen-related receptor γ (hERRγ) is a key protein involved in various endocrines and metabolic signaling. Numerous environmental endocrine-disrupting chemicals (EDCs) can impact related physiological activities through receptor signaling pathways. Focused on hERRγ with 4-isopropylphenol, bisphenol-F (BPF), and BP(2,2)(Un) complexes, we executed molecular docking and multiple molecular dynamics (MD) simulations along with molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) and solvation interaction energy (SIE) calculation to study the detailed dynamical structural characteristics and interactions between them. Molecular docking showed that hydrogen bonds and hydrophobic interactions were the prime interactions to keep the stability of BPF-hERRγ and hERRγ-BP(2,2)(Un) complexes. Through MD simulations, we observed that all complexes reach equilibrium during the initial 50 ns of simulation, but these three EDCs lead to local structure changes in hERRγ. Energy results further identified key residues L268, V313, L345, and F435 around the binding pockets through CH-π, π-π, and hydrogen bonds interactions play an important stabilizing role in the recognition with EDCs. And most noticeable of all, hydrophobic methoxide groups in BP(2,2)(Un) is useful for decreasing the binding ability between EDCs and hERRγ. These results may contribute to evaluate latent diseases associated with EDCs exposure at the micro level and find potential substitutes. METHOD: Autodock4.2 was used to conduct the molecular docking, sietraj program was performed to calculate the energy, and VMD software was used to visualize the structure. Amber18 was conducted to perform the MD simulation and other analyses.

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There is an urgent need to assess material degradation in situ and in real time for their promising application in regeneration therapy. However, traditional monitoring methods in vitro cannot always profile the complicated behavior in vivo. This study designed and synthesized a new biodegradable polyurethane (PU-P) scaffold with polycaprolactone glycol, isophorone diisocyanate, and l-lysine ethyl ester dihydrochloride. To monitor the degradation process of PU-P, calcein was introduced into the backbone (PU-5) as a chromophore tracing in different sites of the body and undegradable fluorescent scaffold (CPU-5) as the control group. Both PU-P and PU-5 can be enzymatically degraded, and the degradation products are molecularly small and biosafe. Meanwhile, by virtue of calcein anchoring with urethane, polymer chains of PU-5 have maintained the conformational stability and extended the system conjugation, raising a structure-induced emission effect that successfully achieved a significant enhancement in the fluorescence intensity better than pristine calcein. Evidently, unlike the weak fluorescent response of CPU-5, PU-5 and its degradation can be clearly imaged and monitored in real time after implantation in the subcutaneous tissue of nude mice. Meanwhile, the in situ osteogeneration has also been promoted after the two degradable scaffolds have been implanted in the rabbit femoral condyles and degraded with time. To sum up, the strategy of underpinning tracers into degradable polymer chains provides a possible and effective way for real-time monitoring of the degradation process of implants in vivo.

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ß-amyloid cleaving enzyme 1 (BACE1) is regarded as an important target of drug design toward the treatment of Alzheimer's disease (AD). In this study, three separate molecular dynamics (MD) simulations and calculations of binding free energies were carried out to comparatively determine the identification mechanism of BACE1 for three inhibitors, 60W, 954 and 60X. The analyses of MD trajectories indicated that the presence of three inhibitors influences the structural stability, flexibility and internal dynamics of BACE1. Binding free energies calculated by using solvated interaction energy (SIE) and molecular mechanics generalized Born surface area (MM-GBSA) methods reveal that the hydrophobic interactions provide decisive forces for inhibitor-BACE1 binding. The calculations of residue-based free energy decomposition suggest that the sidechains of residues L91, D93, S96, V130, Q134, W137, F169 and I179 play key roles in inhibitor-BACE1 binding, which provides a direction for future drug design toward the treatment of AD.

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Environmental endocrine disruptors (EEDs), a class of molecules that are widespread in our environment, may adversely affect the endocrine system. Exploring the interactions between these compounds and their potential targets is important for assessing their role in the organism. Focused on the human estrogen-related receptor γ (hERRγ) with BPA, BPB, HPTE, BPE, BP(2,2)(Et), and BP(2,2)(MeO) complexes, respectively, we groped for the mechanisms of conformational changes and interactions of hERRγ when binding to these six EEDs by combining multiple molecular dynamics (MD) simulations with energy prediction (MM-PBSA and solvated interaction energy (SIE)). Dynamics analysis results revealed these six EEDs have different effects on the internal dynamics of hERRγ, resulting in significant changes in the interaction of key residues around Leu268, Val313, Leu345, and Phe435 with EEDs, and thus affected its binding energy with these EEDs. The energy calculations further demonstrated that van der Waals interactions are critical for these EEDs binding to hERRγ. These results present detailed molecular insight into the interaction features between EEDs and hERRγ and help guide the search for safer alternatives to BPA.

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The study investigates the mechanism of teleconnection between the variability of sea ice extent (SIE) in the Indian Ocean sector of the Southern Ocean and the variability of Indian summer monsoon rainfall. We utilized reanalysis, satellite, in-situ observation data, and model output from the coupled model intercomparison project phase 5 (CMIP5) from 1979 to 2013. The empirical orthogonal function (EOF) and correlation analysis show that the first and third modes of principal component (PC1 and PC3) of SIE in the Indian Ocean sector during April-May-June (AMJ) are significantly correlated with the second mode of principal component (PC2) of Indian summer monsoon rainfall. The reanalysis data revealed that the changes in the SIE in the Indian Ocean sector excite meridional wave train responses along the Indian Ocean for both principal component modes. Positive (negative) SIE anomalies based on first and third EOFs (EOF1 and EOF3), contribute to the strengthening (weakening) of the Polar, Ferrel, and Hadley cells, inducing stronger (weaker) convective activity over the Indian latitudes. The stronger (weaker) convective activity over the Indian region leads to more (less) rainfall over the region during high (low) ice phase years. Furthermore, a stronger (weaker) polar jet during the high (low) ice phase is also noted. The selected CMIP5 models captured certain atmospheric teleconnection features found in the reanalysis. During AMJ, the SIE simulated by the NorESM1-M model was significantly positively correlated with Indian summer monsoon rainfall, whereas the IPSL-CM54-LR model showed a negative correlation.

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Recently, reverse genetics systems of plant negative-stranded RNA (NSR) viruses have been developed to study virus-host interactions. Nonetheless, genetic rescue of plant NSR viruses in both insect vectors and monocot plants is very limited. Northern cereal mosaic virus (NCMV), a plant cytorhabdovirus, causes severe diseases in cereal plants through transmission by the small brown planthopper (SBPH, Laodelphax striatellus) in a propagative manner. In this study, we first developed a minireplicon system of NCMV in Nicotiana benthamiana plants, and then recovered a recombinant NCMV virus (rNCMV-RFP), with a red fluorescent protein (RFP) insertion, in SBPHs and barley plants. We further used rNCMV-RFP and green fluorescent protein (GFP)-tagged barley yellow striate mosaic virus (rBYSMV-GFP), a closely related cytorhabdovirus, to study superinfection exclusion, a widely observed phenomenon in dicot plants rarely studied in monocot plants. Interestingly, cellular superinfection exclusion of rBYSMV-GFP and rNCMV-RFP was observed in barley leaves. Our results demonstrate that two insect-transmitted cytorhabdoviruses are enemies rather than friends at the cellular level during coinfections in plants.

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The aim of this work is to investigate niche variations in endemic Silene velutina (Caryophyllaceae, Angiosperms) on Mediterranean islands that differ in size. Six populations on both large and small islands were sampled across the geographic range of the species. For each population, 10 plots (1 × 2 m, with a 25 cm grill) were randomly placed to quantify environmental (abiotic and biotic factors and disturbance) and population (demographic structure and reproductive success) parameters. Niche parameters related to substrate, plant cover, community diversity and composition and disturbance showed significant variation in relation to island size. At the regional scale, we detected a broader niche on large islands associated with spatial heterogeneity and island size. In contrast, at the local scale, populations on small islands showed a broader niche, potentially due to a release from competition (low diversity and plant cover and absence of phanerophytes). Populations on large islands had a demographic structure biased towards vegetative individuals (seedlings and juveniles) with few reproductive individuals, while those on small islands had a majority of adults. Together, the results on niche breadth and demographic structure concord with the idea of a strategy based on adult persistence on small islands.

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MAIN CONCLUSION: A conserved cysteine residue (C266)-mediated homo-dimerization of SIE3 is required for the ubiquitination and degradation of SIP1 transcription factor in Lotus japonicas CTLH/CRA/RING-containing proteins have been shown to possess E3-ligase activities and are crucial for the regulation of numerous cellular signaling pathways. In our previous studies, SIE3 (SymRK-Interacting E3 ubiquitin ligase), a CTLH/CRA/RING-containing protein from Lotus japonicus, has been shown to associate with both Symbiosis Receptor Kinase (SymRK) and SIP1 (SymRK interacting protein 1) transcription factor, and ubiquitinate SymRK (Yuan et al. Plant Physiol 160 (1):106-117, 2012; Feng et al. Front Plant Sci 11: 795, 2020). Besides, we previously also demonstrated that the residue, cysteine-266 in the CRA (CT11-RanBPM) domain is required for homodimerization of SIE3 and cysteine-266 residue-mediated homodimerization is important for the symbiosic function of SIE3 (Feng et al. 2020). In this report, SIE3 was shown to induce the ubiquitination and degradation of SIP1. The cysteine-266 residue is essential for the E3-ligase activity and is highly conserved in the SIE3-like proteins. Our works refined the working model that homodimerization of SIE3 is required for ubiquitin-related degradation of SIP1 and found a conserved cysteine residue plays a key role in the activity of a plant dimeric E3 ligase.

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The symbiosis receptor kinase SymRK plays an essential role in symbiotic signal transduction and nodule organogenesis. Several proteins bind to SymRK, but how the symbiosis signals are transduced from SymRK to downstream components remains elusive. We previously demonstrated that both SymRK interacting protein 1 (SIP1, an ARID-type DNA-binding protein) and SymRK interacting E3 ligase [SIE3, a RING (Really Interesting New Gene)-containing E3 ligase] interact with SymRK to regulate downstream cellular responses in Lotus japonicus during the legume-rhizobia symbiosis. Here, we show that SIE3 interacts with SIP1 in both yeast cells and Nicotiana benthamiana. SIE3 associated with itself and formed a homodimer. The cysteine 266 residue was found to be essential for SIE3 dimerization and for promoting nodulation in transgenic hairy roots of L. japonicus. Our findings provide a foundation for further investigating the regulatory mechanisms of the SymRK-mediated signaling pathway, as well as the biological function of E3 ligase dimerization in nodule organogenesis.

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Activin Receptor-Like Kinase 5 (ALK-5) is related to some types of cancer, such as breast, lung, and pancreas. In this study, we have used molecular docking, molecular dynamics simulations, and free energy calculations in order to explore key interactions between ALK-5 and six bioactive ligands with different ranges of biological activity. The motivation of this work is the lack of crystal structure for inhibitor-protein complexes for this set of ligands. The understanding of the molecular structure and the protein-ligand interaction could give support for the development of new drugs against cancer. The results show that the calculated binding free energy using MM-GBSA, MM-PBSA, and SIE is correlated with experimental data with r2 = 0.88, 0.80, and 0.94, respectively, which indicates that the calculated binding free energy is in excellent agreement with experimental data. In addition, the results demonstrate that H bonds with Lys232, Glu245, Tyr249, His283, Asp351, and one structural water molecule play an important role for the inhibition of ALK-5. Overall, we discussed the main interactions between ALK-5 and six inhibitors that may be used as starting points for designing new molecules to the treatment of cancer.

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The Farnesoid X receptor (FXR) exhibits significant backbone movement in response to the binding of various ligands and can be a challenge for pose prediction algorithms. As part of the D3R Grand Challenge 2, we tested Wilma-SIE, a rigid-protein docking method, on a set of 36 FXR ligands for which the crystal structures had originally been blinded. These ligands covered several classes of compounds. To overcome the rigid protein limitations of the method, we used an ensemble of publicly available structures for FXR from the PDB. The use of the ensemble allowed Wilma-SIE to predict poses with average and median RMSDs of 2.3 and 1.4 Å, respectively. It was quite clear, however, that had we used a single structure for the receptor the success rate would have been much lower. The most successful predictions were obtained on chemical classes for which one or more crystal structures of the receptor bound to a molecule of the same class was available. In the absence of a crystal structure for the class, observing a consensus binding mode for the ligands of the class using one or more receptor structures of other classes seemed to be indicative of a reasonable pose prediction. Affinity prediction proved to be more challenging with generally poor correlation with experimental IC50s (Kendall tau ~ 0.3). Even when the 36 crystal structures were used the accuracy of the predicted affinities was not appreciably improved. A possible cause of difficulty is the internal energy strain arising from conformational differences in the receptor across complexes, which may need to be properly estimated and incorporated into the SIE scoring function.

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We study the orbital-dependence of three (parameter-free) double-hybrid density functionals, namely the PBE0-DH, the PBE-QIDH models, and the SOS1-PBE-QIDH spin-opposite-scaled variant of the latter. To do it, we feed all their energy terms with different sets of orbitals obtained previously from self-consistent density functional theory calculations using several exchange-correlation functionals (e.g., PBE, PBE0, PBEH&H), or directly with HF-PBE orbitals, to see their effect on selected datasets for atomization and reaction energies, the latter proned to marked self-interaction errors. We find that the PBE-QIDH double-hybrid model shows a great consistency, as the best results are always obtained for the set of orbitals corresponding to its hybrid scheme, which prompts us to recommend this model without any other fitting or reparameterization. © 2017 Wiley Periodicals, Inc.

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BACKGROUND: Herein, the predicted atomic structures of five representative sequence variants of the reverse transcriptase protein (RT) of hepatitis B virus (HBV), sampled from patients with rapid or slow response to tenofovir disoproxil fumarate (TDF) treatment, have been examined to identify structural variations between them in order to assess structural and functional properties of HBV-RT variants associated with the differential responses to TDF treatment. RESULTS: We utilized a hybrid computational approach to model the atomistic structures of HBV-RT/DNA-RNA/dATP and HBV-RT/DNA-RNA/TFV-DP (tenofovir diphosphate) complexes with the native hybrid DNA-RNA substrate in place. Multi-nanosecond molecular dynamics (MD) simulations of HBV-RT/DNA-RNA/dATP complexes revealed strong coupling of the natural nucleotide substrate, dATP, to the active site of the RT, and the differential involvement of the two putative magnesium cations (Mg(2+)) at the active site, whereby one Mg(2+) directly bridges the interaction between dATP and HBV-RT and the other serves as a coordinator to maintain an optimal configuration of the active site. Solvated interaction energy (SIE) calculated in MD simulations of HBV-RT/DNA-RNA/TFV-DP complexes indicate no differential binding affinity between TFV-DP and HBV-RT variants identified in patients with slow or rapid response to TDF treatment. CONCLUSION: The predicted atomic structures accurately represent functional states of HBV-RT. The equivalent interaction between TFV-DP and each examined HBV-RT variants suggests that binding affinity of TFV-DP to HBV-RT is not associated with delayed viral clearance.

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This study examined the effects of 3 mol % yttria-stabilized tetragonal zirconia polycrystal (3Y-TZP) ceramic surface treatments on the tensile bond strength and surface characteristics of enamel. To measure the tensile bond strength, the 3Y-TZP and tooth specimens were manufactured in a mini-dumbbell shape and divided into four groups based on the type of 3Y-TZP surface treatment: polishing (P), 110 µm alumina sandblasting (S), 110 µm alumina sandblasting combined with selective infiltration etching (SS), and 110 µm alumina sandblasting combined with MDP (10-methacryloyloxydecyl dihydrogen phosphate)-containing silane primer (SP). After surface treatment, the surface roughness, wettability, and surface changes were examined, and the tensile bond strength was measured. The mean values (from lowest to highest) for tensile bond strength (MPa) were as follows: P, 8.94 ± 2.30; S, 21.33 ± 2.00; SS, 26.67 ± 4.76; and SP, 31.74 ± 2.66. Compared to the P group, the mean surface roughness was significantly increased, and the mean contact angle was significantly decreased, while wettability was increased in the other groups. Therefore, surface treatment with 110 µm alumina sandblasting and MDP-containing silane primer is suitable for clinical applications, as it considerably improves the bond strength between 3Y-TZP and enamel.

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The single crystal X-ray structure of the extracellular portion of the L,D-transpeptidase (ex-LdtMt2 - residues 120-408) enzyme was recently reported. It was observed that imipenem and meropenem inhibit activity of this enzyme, responsible for generating L,D-transpeptide linkages in the peptidoglycan layer of Mycobacterium tuberculosis. Imipenem is more active and isothermal titration calorimetry experiments revealed that meropenem is subjected to an entropy penalty upon binding to the enzyme. Herein, we report a molecular modeling approach to obtain a molecular view of the inhibitor/enzyme interactions. The average binding free energies for nine commercially available inhibitors were calculated using MM/GBSA and Solvation Interaction Energy (SIE) approaches and the calculated energies corresponded well with the available experimentally observed results. The method reproduces the same order of binding energies as experimentally observed for imipenem and meropenem. We have also demonstrated that SIE is a reasonably accurate and cost-effective free energy method, which can be used to predict carbapenem affinities for this enzyme. A theoretical explanation was offered for the experimental entropy penalty observed for meropenem, creating optimism that this computational model can serve as a potential computational model for other researchers in the field.

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In drug discovery the reliable prediction of binding free energies is of crucial importance. Methods that combine molecular mechanics force fields with continuum solvent models have become popular because of their high accuracy and relatively good computational efficiency. In this research we studied the performance of molecular mechanics generalized Born surface area (MM-GBSA), molecular mechanics Poisson-Boltzmann surface area (MM-PBSA), and solvated interaction energy (SIE) both in their virtual screening efficiency and their ability to predict experimentally determined binding affinities for five different protein targets. The protein-ligand complexes were derived with two different approaches important in virtual screening: molecular docking and ligand-based similarity search methods. The results show significant differences between the different binding energy calculation methods. However, the length of the molecular dynamics simulation was not of crucial importance for accuracy of results.

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AIM OF THE WORK: Assessment of directions and ways of cancer spreading in the anterior commissure of the larynx, depending on the tumor location, age, sex of patients in a clinical trial and in microscopic serial section study. MATERIALS AND METHODS: The study included 50 larynx preparations obtained from open partial and total laryngectomies (F-7; M-43). For the assessment of larynx anterior commissure microscopic status 28 larynx preparations with macroscopic free anterior commissure were used. For study of the directions and ways of tumor spreading in the anterior commissure served 22 larynx with macroscopic infiltration of anterior commissure. Anterior Commissure (AC) and TNM classifications was used to determine the location and tumor stage. Larynx anterior commissure was extracted and divided into 3 subregions: supraglottic, glottic and subglottic. RESULTS: The direction and the way of cancer propagation in larynx anterior commissure structures is dependent on morphological changes that occur with aging. Cancer spreads in the anterior commissure along the fibers anchoring voice muscle within the Broyles ligament and is seen in tumor cells microembolism. CONCLUSIONS: In patients with cancer of the larynx without macroscopically visible neoplastic lesions in the anterior commissure, cannot be excluded its microinfilration. Changed with age anterior commissure' Broyles ligament by the process of neovascularization and ossification is not an effective protection against the spread of cancer. Directions and the ways of cancer spread in the anterior commissure is similar in men and women. AC classification can be important in qualifying patients for organ preservation surgery and should be supplemented by an additional AC4 degree, taking into account subglottic changes in the anterior commissure of the larynx.

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