Substrate Site Research Articles

Tailoring-Orientated Deposition of Li2S for Extreme Fast-Charging Lithium-Sulfur Batteries.

Precipitation/dissolution of insulating Li2S has long been recognized as the rate-determining step in lithium-sulfur (Li-S) batteries, which dramatically undermines sulfur utilization at elevated charging rates. Herein, we present an orientated Li2S deposition strategy to achieve extreme fast charging (XFC, ≤15 min) through synergistic control of porosity, electronic conductivity, and anchoring sites of electrode substrate. Via magnesiothermic reduction of a zeolitic imidazolate framework, a nitrogen-doped and hierarchical porous carbon with highly graphitic phase was developed. This design effectively reduces interfacial resistance and ensures efficient sequestration of polysulfides during deposition, leading to (110)-preferred growth of Li2S nanocrystalline between (002)-dominated graphitic layers. Our approach directs an alternative Li2S deposition pathway to the commonly reported lateral growth and 3D thickening growth mode, ameliorating the electrode passivation. Therefore, a Li-S cell capable of charging/discharging at 5C (12 min) while maintaining excellent cycling stability (82% capacity retention) for 1000 cycles is demonstrated. Even under high S loading (8.3 mg cm-2) and low electrolyte/sulfur ratio (3.8 mL mg-1), the sulfur cathode still delivers a high areal capacity of >7 mAh cm-2 for 80 cycles.

Structural determinants of protein kinase A essential for CFTR channel activation

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), the anion channel mutated in cystic fibrosis (CF) patients, is activated by the catalytic subunit of protein kinase A (PKA-C). PKA-C activates CFTR both noncatalytically, through binding, and catalytically, through phosphorylation of multiple serines in CFTR's regulatory (R) domain. Here, we identify key molecular determinants of the CFTR/PKA-C interaction essential for these processes. By comparing CFTR current activation in the presence of ATP or an ATP analog unsuitable for phosphotransfer, as well as pseudosubstrate peptides of various lengths, we identify two distinct specific regions of the PKA-C surface which interact with CFTR to cause noncatalytic and catalytic CFTR stimulation, respectively. Whereas the "substrate site" mediates CFTR phosphorylation, a distinct hydrophobic patch (the "docking site") is responsible for noncatalytic CFTR activation, achieved by stabilizing the R domain in a "released" conformation permissive to channel gating. Furthermore, by comparing PKA-C variants with different posttranslational modification patterns, we find that direct membrane tethering of the kinase through its N-terminal myristoyl group is an unappreciated fundamental requirement for CFTR activation: PKA-C demyristoylation abolishes noncatalytic, and profoundly slows catalytic, CFTR stimulation. For the F508del CFTR mutant, present in ~90% of CF patients, maximal activation by demyristoylated PKA-C is reduced by ~10-fold compared to that by myristoylated PKA-C. Finally, in bacterial genera that contain common CF pathogens, we identify virulence factors that demyristoylate PKA-C in vitro, raising the possibility that during recurrent bacterial infections in CF patients, PKA-C demyristoylation may contribute to the exacerbation of lung disease.

The efficient metal- and halogen-free polymer catalyst for the intensification on CO2 cycloaddition

An environmentally friendly polymer catalyst (PAS) was synthesized via inverse emulsion polymerization using acrylic acid (AA) and 1-vinyl imidazole (VI) as monomers. The excellent catalytic activity of PAS was attributed to the synergistic effects of the carboxyl groups (-COOH) as hydrogen bond donors and N-heterocyclic carbene (NHCs) as electron donor, as well as the swelling properties of the polymer, which can enrich the substrate into the polymer network, increasing the contact between the substrate and active sites. Characterization results from thermogravimetric (TG) analysis and small-angle X-ray scattering (SAXS) showed that the excessive imidazole addition disrupted the polymer's chain-like structure, significantly reducing its swelling properties. And, the catalytic performance is influenced by both the amount of imidazole in PAS and the swelling properties of the polymer. Finally, the reaction mechanism of the CO2 cycloaddition reaction catalyzed by PAS was proposed and validated through density functional theory (DFT) calculations.

Sumoylation of thymine DNA glycosylase impairs productive binding to substrate sites in DNA

The base excision repair enzyme thymine DNA glycosylase (TDG) protects against mutations by removing thymine or uracil from guanine mispairs and functions in active DNA demethylation by excising 5-formylcytosine (fC) and 5-carboxylcytosine (caC). Post-translational modification of TDG by SUMO (small ubiquitin-like modifier) reduces its glycosylase activity but the mechanism remains unclear. We investigated this problem using biochemical and biophysical approaches and a TDG construct comprising residues 82-340 (of 410) that includes the SUMOylation site and the motif for non-covalent SUMO binding. Single turnover kinetics experiments were collected at multiple enzyme concentrations ([E]) and the hyperbolic dependence of activity (kobs) on [E] yielded the maximal glycosylase activity (kmax), the enzyme concentration giving half-maximal activity (K0.5), and the catalytic efficiency (kmax/K0.5). Sumoylation of TDG (or TDG82-340) causes large reductions in catalytic efficiency for G·T, G·U, G·fC, and G·caC DNA substrates, due largely to weakened substrate affinity (increased K0.5). 19F NMR experiments show that sumoylation of TDG82-340 reduces productive binding to G·U mispairs and dramatically impairs binding to G·T mispairs. A mutation in the TDG SUMO-interacting motif (SIM), E310Q, shown previously to perturb noncovalent binding of SUMO to unmodified TDG, rescues the glycosylase activity of sumoylated TDG82-340. Similarly, NMR studies show the mutation restores productive binding of sumoylated TDG82-340 to G·U and G·T pairs. Together, the results indicate that intramolecular SUMO-SIM interactions mediate the adverse effect of sumoylation on TDG activity and suggest a model whereby the disruption of SUMO-SIM interactions enables productive binding of sumoylated TDG to substrate sites in DNA.

In situ generation of cuprous oxide in metal-organic framework for significantly enhanced room-temperature ammonia sensing: Synergy enabling excellent sensitivity and selectivity

Development of effective strategies to improve the response sensitivity of metal-organic frameworks (MOFs) to target gases is imperative to further enhancing their application potential in gas sensing. In this work, series of CuHHTP/Cu2O (HHTP = 2,3,6,7,10,11-hexahydroxytriphenylene) composites are successfully constructed by in-situ electrochemical reduction treatment of CuHHTP, and the changing trend of first increasing and then decreasing with increase of CuHHTP electrochemical reduction degree for their sensitivity to NH3 detection is revealed. When the average size of Cu2O nanoparticles generated in CuHHTP is 3.6 nm, the corresponding CuHHTP/Cu2O-A composite exhibits the best NH3 sensing performance compared to pristine CuHHTP, including significantly enhanced response sensitivity, ultralow experimental detection limit of 10 ppb, superior selectivity, good reproducibility, and excellent response stability even after placed for 90 days. More impressively, thanks to integration and synergy of the uniformly-dispersed small-sized Cu2O nanoparticles with significantly enhanced adsorption activity and capacity for NH3, the released large amount of uncoordinated hydroxyl groups that can interact with NH3, as well as the active sites of the CuHHTP substrate itself, the 10 ppb experimental detection limit for the CuHHTP/Cu2O-A-based sensors is not only the lowest one reported in the past 10 years for NH3 sensors based on copper-containing MOF and oxide materials, but also superior to that of 0.1–1 ppm for the existing commercial NH3 sensors. This work opens the avenue for design and development of novel MOF-based sensing materials.

Biochar aging, soil microbiota and chemistry of charcoal kilns in Mediterranean forests

AbstractCharcoal kilns, old structures used for charcoal production in the forest, preserve a charcoal-enriched topsoil representing a suitable proxy for studying the long-term effect of biochar addition to soil. Two kiln platforms located at Gelbison and Vesole mountain sites in Southern Italy were selected due to their comparable climates but distinct parent rocks. We conducted standard soil chemical analyses and used next-generation sequencing to explore bacterial and fungal microbiome. Anthracology identified charcoal species, while scanning electron microscopy (SEM) with energy dispersive X-ray spectroscopy (EDS) characterized charcoal particles. Reflectance Fourier transform infrared spectroscopy (DRIFTS) assessed biochar surface oxidation. Additionally, a bioassay with soybean, maize, and Tomato investigated the impact of kiln soil on plant performance. Our results showed that kiln soils did not exhibit higher pH, cation exchange capacity, or greater richness in cations. EDS and FTIR analyses showed that charcoal buried in forest soil for decades undergoes significant oxidation, with increased O/C ratio and the presence of oxygenated functional groups. Charcoal surfaces were selectively enriched with Ca2+ on limestone substrate sites but with Al and Si over sedimentary (flysch) substrate. While differences in the kiln soil and its surroundings were noticeable, they were not drastic in terms of microbial diversity and composition. Surprisingly, the bioassay indicated that the kiln microbiota had a more positive impact on plant growth compared to external forest soil. In conclusion, this study highlights the unique nature of kiln microsites and begins to unveil the enduring effects of charcoal accumulation on soil chemistry and microbiota in forest soil. Graphical Abstract

Kajian Farmakoinformatika Senyawa Caulerchlorin dan Racemosin sebagai kandidat Antimalaria

Caulerchlorin and racemosin were bioactive compounds containing in Caulerpa racemosa macroalgae. Previous study, those compounds promoted therapeutical target on metabolic syndrome. However, the therapeutical activity on Malaria not yet defined. Therefore, this study investigated potential activity of caulerchlorin and racemosin from Caulerpa racemosa as antimalarial activity through pharmacoinformatic study. Caulerchlorin and racemosin structures were retrieved from PubChem NCBI and the Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) structure was taken out from Protein database with ID 5GJG. Orotic acid was used as native ligand or control. Ligands were predicted their antiplasmodial activity and toxicity. Ligands and protein were interacted by redocking using Molegro Virtual Docker version 6.0 and analyzed by using PyMol 2.3 and Discovery Studio version 21.1.1. Two bioactive compounds also showed antiplasmodial activity and were not mutagenicity and hepatotoxicity affections. Molecular docking performed that caulerchlorin and racemosin exhibited same active residues as well as orotic acid as native substrate. Binding energy revealed two compounds, caulerchlorin and racemosin showed lower binding energy than orotic acid. In summary caulerchlorin and racemosin were potentially inhibited PfDHODH activity by binding substrate sites of PfDHODH protein.

Anchoring cobalt dual-atom pairs on open hollow-structured carbon via a facile in-situ synthetic strategy for enhanced advanced oxidation processes

Atomically dispersed catalysts offer unprecedented opportunities for high-efficiency Fenton-like oxidation of organic pollutants in water. However, the hazardous metal leaching of atomically dispersed catalysts hinders their practical application for wastewater treatment, while the inaccessible interior active sites in carbon substrates have been commonly overlooked. Herein, we develop a straightforward approach for tightly anchoring cobalt dual-atom pairs on nitrogen-doped open hollow carbon structure (Co-NOHC) via an in-situ polyelectrolyte nanosphere-guided strategy. The unique open hollow carbon structure benefits the electron/mass transfer and maximizes the exposure of active sites. As a result, the as-synthesized Co-NOHC exhibits outstanding peroxymonosulfate activation activity and Fenton-like performance in oxidation by taking rhodamine B degradation as an example. Remarkably, the turnover frequency of the Co-NOHC is 6.5, 26.5, and 9.3 times higher than that of the Co2+, cobalt, and its oxides, respectively, and its catalytic activity also greatly outperforms the pristine zeolitic-imidazole frameworks derived Co-based atomically dispersed catalysts. More importantly, benefitted from the stable anchoring of cobalt dual atoms, the Co2+ leaching from the Co-NOHC is greatly alleviated, as low as 0.1 mg/L after the catalytic reaction, showing outstanding stability as compared to most atomically dispersed catalysts. Furthermore, the reactive active species, including SO4−, OH and O2− radicals, and electron-transfer mechanism are demonstrated to dominate the rhodamine B removal. This work offers a new consideration for promoting the development of the advanced catalysts and their potential applications in advanced oxidation process.

Selectivity analysis of diaminopyrimidine-based inhibitors of MTHFD1, MTHFD2 and MTHFD2L

The mitochondrial enzyme methylenetetrahydrofolate dehydrogenase (MTHFD2) is involved in purine and thymidine synthesis via 1C metabolism. MTHFD2 is exclusively overexpressed in cancer cells but absent in most healthy adult human tissues. However, the two close homologs of MTHFD2 known as MTHFD1 and MTHFD2L are expressed in healthy adult human tissues and share a great structural resemblance to MTHFD2 with 54% and 89% sequence similarity, respectively. It is therefore notably challenging to find selective inhibitors of MTHFD2 due to the structural similarity, in particular protein binding site similarity with MTHFD1 and MTHFD2L. Tricyclic coumarin-based compounds (substrate site binders) and xanthine derivatives (allosteric site binders) are the only selective inhibitors of MTHFD2 reported till date. Nanomolar potent diaminopyrimidine-based inhibitors of MTHFD2 have been reported recently, however, they also demonstrate significant inhibitory activities against MTHFD1 and MTHFD2L. In this study, we have employed extensive computational modeling involving molecular docking and molecular dynamics simulations in order to investigate the binding modes and key interactions of diaminopyrimidine-based inhibitors at the substrate binding sites of MTHFD1, MTHFD2 and MTHFD2L, and compare with the tricyclic coumarin-based selective MTHFD2 inhibitor. The outcomes of our study provide significant insights into desirable and undesirable structural elements for rational structure-based design of new and selective inhibitors of MTHFD2 against cancer.

A colorimetric sensor based on multiple elements doped carbon dot nanozyme for rapid detection of 1-naphthol in human urine samples

The residual carbaryl in crops can cause serious damage to the human kidney and nervous system after entering the human body, which may be metabolized to 1-naphthol (1-NAP) and excreted through urine. 1-NAP is often used as the biomarker for carbaryl exposure, so the intake or leakage of carbaryl can be monitored by detecting the concentration of 1-NAP. Herein, Co, N, P ternary co-doped carbon dots (CoNP-CDs) derived from vitamin B12 were synthesized by a facile hydrothermal method. CoNP-CDs exhibited oxidase-like activity and excellent peroxidase-like activity, which was attributed to the Fenton-like reaction of Co2+/Co3+ and the presence of pyrrole N and P elements, which together provided multiple active sites for chromogenic substrates. Due to the dual enzyme-like activity of CoNP-CDs, hydroxyl radicals (OH) and superoxide radicals (O2−) were generated during the catalytic process, which could rapidly oxidize colorless 3,3′,5,5′-tetramethyl benzidine (TMB) to blue oxidation products (oxTMB). The α-carbon in 1-NAP can be attacked by OH, and the catalytic oxidation process of TMB can be inhibited by the consumption of OH, so that the blue color of the solution became lighter. Based on this principle, a smartphone-assisted colorimetric sensing platform was constructed for the detection of 1-NAP, and which resulted in a linear range of 1.07–37.3 μM and a visual detection limit of 0.68 μM. Moreover, the colorimetric sensing system showed satisfactory recoveries in the detection of human urine samples. The colorimetric sensing system owned the advantages of fast response, strong selectivity and simple operation, and provided a potential strategy for the on-site detection of 1-NAP.

Synthesis of Mo-Pt/CeO2 Dual Single-Atom Nanozyme for Multifunctional Biochemical Detection Applications.

Elaborated structural modulation of Pt-based artificial nanozymes can efficiently improve their catalytic activity and expand their applications in clinical diagnosis and biochemical sensing. Herein, a highly efficient dual-site peroxidase mimic composed of highly dispersed Pt and Mo atoms is reported. The obtained Mo-Pt/CeO2 exhibits exceptional peroxidase-like catalytic activity, with a Vmax as high as 34.16 × 10-8 m s-1, which is 37.5 times higher than that of the single-site counterpart. Mechanism studies suggest that the Mo atoms can not only serve as adsorption and activation sites for the H2O2 substrate but also regulate the charge density of Pt centers to promote the generation ability of •OH. As a result, the synergistic effect between the dual active sites significantly improves the catalytic efficiency. Significantly, the application of the Mo-Pt/CeO2 catalyst's excellent peroxidase-like activity is extended to various biochemical detection applications, including the trace detection of glucose and cysteine, as well as the assessment of antioxidants' antioxidant capacity. This work reveals the great potential of rational design dual-site active centers for constructing high-performance artificial nanozymes.

Sulfotransferase-mediated phase II drug metabolism prediction of substrates and sites using accessibility and reactivity-based algorithms.

Sulphotransferases (SULTs) are a major phase II metabolic enzyme class contributing ~20 % to the Phase II metabolism of FDA-approved drugs. Ignoring the potential for SULT-mediated metabolism leaves a strong potential for drug-drug interactions, often causing late-stage drug discovery failures or black-boxed warnings on FDA labels. The existing models use only accessibility descriptors and machine learning (ML) methods for class and site of sulfonation (SOS) predictions for SULT. In this study, a variety of accessibility, reactivity, and hybrid models and algorithms have been developed to make accurate substrate and SOS predictions. Unlike the literature models, reactivity parameters for the aliphatic or aromatic hydroxyl groups (R/Ar-O-H), the Bond Dissociation Energy (BDE) gave accurate models with a True Positive Rate (TPR)=0.84 for SOS predictions. We offer mechanistic insights to explain these novel findings that are not recognized in the literature. The accessibility parameters like the ratio of Chemgauss4 Score (CGS) and Molecular Weight (MW) CGS/MW and distance from cofactor (Dis) were essential for class predictions and showed TPR=0.72. Substrates consistently had lower BDE, Dis, and CGS/MW than non-substrates. Hybrid models also performed acceptablely for SOS predictions. Using the best models, Algorithms gave an acceptable performance in class prediction: TPR=0.62, False Positive Rate (FPR)=0.24, Balanced accuracy (BA)=0.69, and SOS prediction: TPR=0.98, FPR=0.60, and BA=0.69. A rule-based method was added to improve the predictive performance, which improved the algorithm TPR, FPR, and BA. Validation using an external dataset of drug-like compounds gave class prediction: TPR=0.67, FPR=0.00, and SOS prediction: TPR=0.80 and FPR=0.44 for the best Algorithm. Comparisons with standard ML models also show that our algorithm shows higher predictive performance for classification on external datasets. Overall, these models and algorithms (SOS predictor) give accurate substrate class and site (SOS) predictions for SULT-mediated Phase II metabolism and will be valuable to the drug discovery community in academia and industry. The SOS predictor is freely available for academic/non-profit research via the GitHub link.

Crystallographic fragment-binding studies of the Mycobacterium tuberculosis trifunctional enzyme suggest binding pockets for the tails of the acyl-CoA substrates at its active sites and a potential substrate-channeling path between them.

The Mycobacterium tuberculosis trifunctional enzyme (MtTFE) is an α2β2 tetrameric enzyme in which the α-chain harbors the 2E-enoyl-CoA hydratase (ECH) and 3S-hydroxyacyl-CoA dehydrogenase (HAD) active sites, and the β-chain provides the 3-ketoacyl-CoA thiolase (KAT) active site. Linear, medium-chain and long-chain 2E-enoyl-CoA molecules are the preferred substrates of MtTFE. Previous crystallographic binding and modeling studies identified binding sites for the acyl-CoA substrates at the three active sites, as well as the NAD binding pocket at the HAD active site. These studies also identified three additional CoA binding sites on the surface of MtTFE that are different from the active sites. It has been proposed that one of these additional sites could be of functional relevance for the substrate channeling (by surface crawling) of reaction intermediates between the three active sites. Here, 226 fragments were screened in a crystallographic fragment-binding study of MtTFE crystals, resulting in the structures of 16 MtTFE-fragment complexes. Analysis of the 121 fragment-binding events shows that the ECH active site is the `binding hotspot' for the tested fragments, with 41 binding events. The mode of binding of the fragments bound at the active sites provides additional insight into how the long-chain acyl moiety of the substrates can be accommodated at their proposed binding pockets. In addition, the 20 fragment-binding events between the active sites identify potential transient binding sites of reaction intermediates relevant to the possible channeling of substrates between these active sites. These results provide a basis for further studies to understand the functional relevance of thelatter binding sites and to identify substrates for which channeling is crucial.

Rapid Synthesis of Nickel Hydroxide/Pt-Based Alloy Heterointerface for Hydrogen Evolution in Full pH Range.

The huge application potential of nanoelectrocatalysts can become available only under the condition of scalable and reproducible preparation of nanomaterials (NMs). It is easily overlooked that most of the preparation methods for efficient platinum (Pt)-based electrocatalysts are complicated in process and time-/energy-consuming, which is not conducive to scalable and sustainable production. Herein, we propose a rapid and facile method to in situ construct a heterointerface between nickel hydroxide (Ni(OH)2) and NiPt alloy, in which the preparation steps are easy-to-operate and can be finished in 1 h. Furthermore, the ensemble effect between the Ni(OH)2 substrate and NiPt active sites benefits the water dissociation process in nonacidic conditions, while the electronic effect in NiPt contributes to the downshifted d-band center of Pt and the proper Gibbs free energy of hydrogen species. As a result, the well-designed and quickly constructed Ni(OH)2-Ni3Pt heterointerfaces reveal lower overpotentials for HER compared with most reported Pt-based and commercial Pt/C catalysts in nonacidic conditions. This study is expected to provide useful reference information for the development of facile and robust methods for the preparation of more efficient Pt-based electrocatalysts.

Development of an Enzyme-responsive Nanoemulsion-type Optode based on a Novel Response Mechanism with Independent Substrate and Fluorescent Sites

Development of an Enzyme-responsive Nanoemulsion-type Optode based on a Novel Response Mechanism with Independent Substrate and Fluorescent Sites

Origin of Chemoselectivity of Halohydrin Dehalogenase-Catalyzed Epoxide Ring-Opening Reactions.

By performing molecular dynamics (MD), quantum mechanical/molecular mechanical (QM/MM) calculations, and QM cluster calculations, the origin of chemoselectivity of halohydrin dehalogenase (HHDH)-catalyzed ring-opening reactions of epoxide with the nucleophilic reagent NO2- has been explored. Four possible chemoselective pathways were considered, and the computed results indicate that the pathway associated with the nucleophilic attack on the Cα position of epoxide by NO2- is most energetically favorable and has an energy barrier of 12.9 kcal/mol, which is close to 14.1 kcal/mol derived from experimental kinetic data. A hydrogen bonding network formed by residues Ser140, Tyr153, and Arg157 can strengthen the electrophilicity of the active site of the epoxide substrate to affect chemoselectivity. To predict the energy barrier trends of the chemoselective transition states, multiple analyses including distortion analysis and electrophilic Parr function (Pk+) analysis were carried out with or without an enzyme environment. The obtained insights should be valuable for the rational design of enzyme-catalyzed and biomimetic organocatalytic epoxide ring-opening reactions with special chemoselectivity.

High sensitive setup of gold nanorods substrates for explosives detection using surface enhanced Raman spectroscopy

Surface enhanced Raman spectroscopy (SERS) is a sensitive analytical technique that has been widely utilised for detection of trace levels of organic species. The detection of trace levels of poor vapour pressure molecules such as explosives is a critical challenging due to the low concentration of adsorbed molecules on the surface sites of the SERS substrate. In this work, gold nanorods were fabricated with analyte samples and provided highly sensitivity of SERS detection along with low limit-of-detection (LOD) for explosives down to pM of 2,4- dinitrotoluene (DNT) and nM of both 2,4,6-trinitrotoluene (TNT) and 1,3,5-trinitroperhydro-1,3,5-triazine (RDX) with highly specificity. The sensitivity of the detection was developed by optimising the adsorption of the molecules on nanorods sites, where nanorods and analyte solution were mixed followed by rigorous stirring. This procedure allowed extra molecules to be adsorbed on the nanorods surface, thus, high SERS enhanced has been observed with high specific identification of target probes. This approach showed a powerful method for rapid detection of explosives based SERS technique especially for illicit samples, where the enhancement factor calculated for analytes was in the range 3.17×108 to 2.69×1011.

SHP2-EGFR States in Dephosphorylation Can Inform Selective SHP2 Inhibitors, Dampening RasGAP Action.

SHP2 is a positive regulator of the EGFR-dependent Ras/MAPK pathway. It dephosphorylates a regulatory phosphorylation site in EGFR that serves as the binding site to RasGAP (RASA1 or p120RasGAP). RASA1 is activated by binding to the EGFR phosphate group. Active RASA1 deactivates Ras by hydrolyzing Ras-bound GTP to GDP. Thus, SHP2 dephosphorylation of EGFR effectively prevents RASA1-mediated deactivation of Ras, thereby stimulating proliferation. Despite knowledge of this vital regulation in cell life, mechanistic in-depth structural understanding of the involvement of SHP2, EGFR, and RASA1 in the Ras/MAPK pathway has largely remained elusive. Here we elucidate the interactions, the factors influencing EGFR's recruitment of RASA1, and SHP2's recognition of the substrate site in EGFR. We reveal that RASA1 specifically interacts with the DEpY992LIP motif in EGFR featuring a proline residue at the +3 position C-terminal to pY primarily through its nSH2 domain. This interaction is strengthened by the robust attraction of two acidic residues, E991 and D990, of EGFR to two basic residues in the BC-loop near the pY-binding pocket of RASA1's nSH2. In the stable precatalytic state of SHP2 with EGFR (DADEpY992LIPQ), the E-loop of SHP2's active site favors the interaction with the (-2)-position D990 and (-4)-position D988 N-terminal to pY992 in EGFR, while the pY-loop constrains the (+4)-position Q996 C-terminal to pY992. These specific interactions not only provide a structural basis for identifying negative regulatory sites in other RTKs but can inform selective, high-affinity active-site SHP2 inhibitors tailored for SHP2 mutants.

Phenotypic and genetic variations of endangered Lysimachia maritima at global distribution limit

Species can respond to environmental pressures through genetic and phenotypic variation. Lysimachia maritima (L.) Galasso, Banfi & Soldano, a perennial halophyte, is distributed sporadically along the east coast in south Korea and is designated as an endangered plant species in Korea and ‘Least Concern’ in the IUCN Red List. To understand the phenotypic and genetic variations of L. maritima among sites and the environmental factors contributing to these differences, field surveys and genetic analyses were conducted. The principal component analysis of the environmental characteristics revealed that soil type, temperature, soil moisture content, and organic matter content were major factors determining variations among sites. L. maritima in Goseong (GS) and Yangyang (YY) sites faced significant limitations in its distribution due to competition with Phragmites australis for limited soil water and nutrients. There were significant phenotypic differences of L. maritima among sites. In sand-based sites of GS and YY, studied growth characteristics of L. maritima except stem length in YY and the number of seed-bearing individuals were smaller than those in organic soil substrate sites of US and PH, where L. maritima grew vigorously and were almost exclusively in the sexual reproductive phase. Genetic diversity at species level was high (h= 0.31, I= 0.46) but genetic diversities at site level were low, varying among sites (h= 0.133 ∼ 0.244). Also, genetic variation of L. maritima was higher within sites (58.32%) than among sites (41.68%). This indicates that L. maritima might prefer outcrossing more than selfing. L. maritima were strongly differentiated among sites (Gst= 0.336) because of limited gene flow (Nm= 0.987). Geographical isolation might have led to differentiated genetic structure in L. maritima, contributing to the formation of its spatial genetic structure. This high genetic diversity is crucial for the biodiversity of L. maritima at its global distribution limit, and this study emphasize the necessity of conserving distribution limit in the sense of soil characteristics.

Theoretical study of CO2 hydrogenation to methanol on modified Au/In2O3 catalysts: Effects of hydrogen spillover and activation energy prediction for hydrogen transfer

With the increasing attention in environmental issues caused by CO2 emissions, methanol conversion by CO2 hydrogenation is an effective strategy to solve this existing energy dilemma. The rationale behind hydrogen spillover on methanol synthesis is unraveled via density functional theory (DFT) calculations in this work, furthermore, the activation energy of hydrogen transfer process as affected by spillover is also summarized in a general paradigm for facilitating the understanding of hydrogenation characteristics. The results demonstrate that the spillover strategy significantly facilitates the hydrogenation reaction by supplying available hydrogen adatoms. This effect is particularly pronounced during the stage when OH is formed directly at the substrate site and combines with H to produce H2O, leading to a substantial reduction in activation energy from the initial 3.74 eV to 0.78 eV. In addition, a comprehensive predictive model for the kinetic characteristics of hydrogen spillover process is established based on the machine learning algorithm and SISSO guidance. By employing the combined approach of SISSO and neural network, we have achieved a stable prediction performance for activation energy with R2 = 0.99 and RMSE = 0.07 eV. The variable of ChgFSAu is identified as the most representative factor in describing the activation energy, demonstrating a correlation coefficient of -0.60. The extended multidimensional expression of DistAu further highlights its close connection to activation energy, achieving an RMSE value of 0.41 eV. To sum up, this work elucidates the possible thoughts of catalyst design with spillover effect and gives reference for the description screening towards the chemical reactions similar to hydrogen spillover.