Search Results (46)

Adenosine triphosphate (ATP) serves as a central energy currency and signaling molecule in cellular processes, with ATP-binding sites in proteins playing critical roles in enzymatic catalysis, signal transduction, and gene regulation. The accurate identification of ATP-binding sites is essential for understanding protein function mechanisms and facilitating drug discovery, enzyme engineering, and disease pathway analysis. In this study, we present a novel hybrid deep learning framework that synergizes heterogeneous learning paradigms based on protein sequence information for accurate ATP-binding site prediction. Our approach integrates two complementary base classifiers. One is a Transformer-based model, which leverages high-level contextual embeddings generated by Evolutionary Scale Modeling 2 (ESM-2), a state-of-the-art protein language model, combined with a local–global dual-attention mechanism that enables the model to simultaneously characterize short-segment and long-range contextual dependencies across the entire protein sequence. The other is a deep Q-network (DQN)-inspired classifier that achieves residue-level prediction as a sequential decision-making process. The final predictions are generated using a weighted ensemble strategy, where optimal weights are determined via cross-validations to leverage the strengths of both models. The prediction results on benchmark independent testing sets indicate that our method achieves satisfactory performance on key metrics. Beyond predictive efficacy, this work uncovers the intrinsic biological mechanisms underlying protein–ATP interactions, including the synergistic roles of local structural motifs and global conformational constraints, as well as family-specific binding patterns, endowing the research with substantial biological significance. The research in this work offers a deeper understanding of the protein–ligand recognition mechanisms and supportive efforts on large-scale functional annotations that are critical for system biology and drug target discovery. Full article

The synthesis of enantiomerically pure chiral β-nitroalcohols is a crucial objective in asymmetric catalysis. In order to efficiently obtain such chiral products, we developed a series of thermoresponsive, oxazoline–copper catalysts (Cu^II-PN_xFe_yO_z) via sequential reversible addition–fragmentation chain transfer (RAFT) polymerization. These catalysts can self-assemble in water into single-chain nanoparticles (SCNPs) with biomimetic behavior, in which intramolecular hydrophobic and metal-coordination interactions generate a confined hydrophobic cavity. Comprehensive characterization by FT-IR, TEM, DLS, CD, CA, and ICP analysis confirmed the nanostructure and composition. When applied to the aqueous-phase asymmetric Henry reaction between nitromethane and 4-nitrobenzaldehyde, the optimal catalyst (2.0 mol%) achieved a quantitative yield (96%) with excellent enantioselectivity (up to 99%) within 12 h. Furthermore, the thermosensitive poly(N-isopropylacrylamide, NIPAAm) block enabled facile catalyst recovery through temperature-induced precipitation above its lower critical solution temperature (LCST). This work presents an efficient and recyclable biomimetic catalytic system, offering a novel strategy for designing sustainable chiral catalysts for green organic synthesis. Full article

Polymyxin antibiotics are often the last line of defense against multidrug-resistant Gram-negative pathogens. A key resistance mechanism involves the addition of 4-amino-4-deoxy-L-arabinose (L-Ara4N) to lipid A, mediated by the bifunctional enzyme ArnA. However, the evolutionary rationale and structural basis for ArnA’s domain fusion, hexameric assembly, and catalytic coordination remain mechanistically unresolved. Here, we integrate evolutionary genomics, high-resolution cryo-electron microscopy (cryo-EM), and computational protein design to provide a comprehensive mechanistic analysis of ArnA. Our evolutionary analysis reveals that the dehydrogenase (DH) and formyltransferase (TF) domains evolved independently and were selectively fused in Gammaproteobacteria, suggesting an adaptive advantage. A 2.89 Å cryo-EM structure of apo-ArnA resolves the flexible interdomain linker and reveals a DH-driven hexameric architecture essential for enzymatic activity. 3D variability analysis captures intrinsic conformational dynamics, indicating a molecular switch that may coordinate sequential catalysis and substrate channeling. Structure-based peptide inhibitors targeting the hexamerization and predicted ArnA–ArnB interaction interfaces were computationally designed, offering a novel strategy for disrupting L-Ara4N biosynthesis. These findings illuminate a previously uncharacterized structural mechanism of antimicrobial resistance and lay the groundwork for therapeutic intervention. Full article

This study presents a multilayer magnetic Janus sub-micrometric particle (MMJSP) as a nanoreactor for lipase catalysis. The core of the nanoparticle is constructed from a core-shell Fe₃O₄@SiO₂ framework, which serves as a precursor for the sequential amino and aldehyde modifications using 3-aminopropyltriethoxysilane and benzaldehyde. Following localized etching and subsequent modification with N,N-dimethyldodecylamine, a Janus nanoparticle with distinct hydrophilic and hydrophobic domains is synthesized. The resulting MMJSP demonstrates a stable attachment to the reaction interface and significantly enhances lipase performance, exhibiting 1.4-fold and 1.6-fold enhancements in activity after immobilization during 1 h hydrolysis and 24 h esterification reactions, respectively. Additionally, the storage stability of the immobilized lipase is improved by 100% over a period of 30 days. Reusability assessments reveal that the immobilized enzyme retains 80.7% activity after 10 cycles of esterification and 80.6% after 50 cycles of hydrolysis, with the magnetic properties allowing for rapid separation and recovery of the immobilized enzyme. Full article

Magnetic materials with intriguing structural and functional modifications demonstrate broad application potential in various fields, including drug delivery, absorption, extraction, separation, and catalysis. In particular, the catalytic hydrogenation of functionalized organic nitro compounds represents a significant research focus in contemporary catalysis studies. A facile synthesis of Fe₃O₄@C–Pt core-shell nanocatalysts was developed in this work through a sequential process involving (1) one-pot hydrothermal synthesis followed by N₂-annealing to obtain the Fe₃O₄@C core and (2) subsequent solvothermal deposition of platinum nanoparticles. Comprehensive characterization was performed using FT-IR, XRD, Raman spectroscopy, TEM, XPS, BET surface area analysis, TGA, and VSM techniques. The resulting magnetic nanocatalysts exhibited uniformly dispersed Pt nanoparticles and demonstrated exceptional catalytic performance in nitroarene hydrogenation reactions. Remarkably, the system showed excellent functional group tolerance across all 20 substituted nitroarenes, consistently yielding corresponding aromatic amine products with >93% conversion efficiency. Furthermore, the magnetic responsiveness of Fe₃O₄@C–Pt enabled convenient catalyst recovery through simple magnetic separation, with maintained catalytic activity over 10 consecutive reuse cycles without significant performance degradation. Full article

Tetrasubstituted furans and their derivatives represent a versatile class of important heterocyclic frameworks widely distributed in natural products. These scaffolds also demonstrate significant potential in pharmaceutical chemistry, materials science, and organic synthesis methodologies. In this study, we successfully established a synergistic catalytic system utilizing benzoylacetonitriles, aldehydes, and benzoyl chlorides as substrates, facilitated by tributylphosphine and immobilized lipase (Novozym 435), to achieve efficient synthesis of cyano-containing tetrasubstituted furans. Under optimized conditions, we obtained a series of target products exhibiting exceptional substrate tolerance with good to excellent isolated yields ranging from 80% to 94%. Additionally, we proposed a reasonable reaction mechanism and verified it through controlled experiments. This methodology not only expands the synthetic utility of lipase in non-natural transformations but also establishes a paradigm of green chemistry for the construction of tetrasubstituted furans. Full article

Herein, we report the first mechanochemical strategy for the Ru-catalyzed deoxygenative borylation of free phenols via C–O bond cleavage. This Ru-catalyzed phenolic borylation approach has been successfully extended to the Suzuki–Miyaura-type cross-coupling of phenols with aryl bromides. The protocol accepts a wide scope of phenolic substrates, allowing the synthesis of aryl pinacolboranes and biphenyl structures in excellent yields and serving as a better alternative to classical cross-coupling reactions in the context of pot, atom, and step economy synthesis. Full article

This study focuses on optimizing C2 yields in the oxidative coupling of methane (OCM), a pivotal process for sustainable chemical production. By harnessing advanced machine learning (ML) techniques, this research aimed to predict C2 yields and identify the factors that drive catalytic performance. The Extra Trees Regressor emerged as the most effective model after a comprehensive evaluation across multiple datasets and methodologies. Key to the method was the use of an innovative Aggregated Catalyst Physicochemical Descriptor (ACPD) and stratified cross-validation, which effectively addressed feature complexity and target skewness. Hyperparameter optimization using Modified Sequential Model-Based Optimization (SMBO) further enhanced the model’s performance, achieving optimized R² values of 61.7%, 75.9%, and 92.0% for datasets A, B, and C, respectively, with corresponding reductions in the Mean Squared Error (MSE) and Root Mean Squared Error (RMSE). Additionally, SHAP (SHapley Additive exPlanations) analysis provided a detailed understanding of the model’s decision-making process, revealing the relative importance of individual features and their contributions to the predictive outcomes. This research not only achieved state-of-the-art predictive accuracy, but also deepened our understanding of the underlying chemical dynamics, offering practical guidance for catalyst design and operational optimization. These findings mark a significant advancement in catalysis, paving the way for future innovations in sustainable chemical manufacturing. Full article

A novel sequential one-pot bimetallic catalytic system combining Fe(III)-catalyzed alkynylation and a Rh(I)-catalyzed [2+2+2] reaction was successfully developed. The σ-Lewis acid properties of iron (III) and the π-Lewis acid properties of rhodium (I) catalysts were unified in an unprecedented intermolecular alkynylation/cyclotrimerization one-pot process. Using this unique Fe/Rh bimetallic relay catalytic system, a variety of benzo and pyrridinoisoindolinone derivatives were obtained under mild conditions from easily available N-(propargyl) hydroxy aminals, as the simplest N-acyliminium ion precursors, and several alkynes. Full article

The current paradigm of low-T combustion and autoignition of hydrocarbons is based on the sequential two-step oxygenation of fuel radicals. The key chain-branching occurs when the second oxygenation adduct (OOQOOH) is isomerized releasing an OH radical and a key ketohydroperoxide (KHP) intermediate. The subsequent homolytic dissociation of relatively weak O–O bonds in KHP generates two more radicals in the oxidation chain leading to ignition. Based on the recently introduced intramolecular “catalytic hydrogen atom transfer” mechanism (J. Phys. Chem. 2024, 128, 2169), abbreviated here as I-CHAT, we have identified a novel unimolecular decomposition channel for KHPs to form their classical isomers—enol hydroperoxides (EHP). The uncertainty in the contribution of enols is typically due to the high computed barriers for conventional (“direct”) keto–enol tautomerization. Remarkably, the I-CHAT dramatically reduces such barriers. The novel mechanism can be regarded as an intramolecular version of the intermolecular relay transfer of H-atoms mediated by an external molecule following the general classification of such processes (Catal. Rev.-Sci. Eng. 2014, 56, 403). Here, we present a detailed mechanistic and kinetic analysis of the I-CHAT-facilitated pathways applied to n-hexane, n-heptane, and n-pentane models as prototype molecules for gasoline, diesel, and hybrid rocket fuels. We particularly examined the formation kinetics and subsequent dissociation of the γ-enol-hydroperoxide isomer of the most abundant pentane-derived isomer γ-C5-KHP observed experimentally. To gain molecular-level insight into the I-CHAT catalysis, we have also explored the role of the internal catalyst moieties using truncated models. All applied models demonstrated a significant reduction in the isomerization barriers, primarily due to the decreased ring strain in transition states. In addition, the longer-range and sequential H-migration processes were also identified and illustrated via a combined double keto–enol conversion of heptane-2,6-diketo-4-hydroperoxide as a potential chain-branching model. To assess the possible impact of the I-CHAT channels on global fuel combustion characteristics, we performed a detailed kinetic analysis of the isomerization and decomposition of γ-C5-KHP comparing I-CHAT with key alternative reactions—direct dissociation and Korcek channels. Calculated rate parameters were implemented into a modified version of the n-pentane kinetic model developed earlier using RMG automated model generation tools (ACS Omega, 2023, 8, 4908). Simulations of ignition delay times revealed the significant effect of the new pathways, suggesting an important role of the I-CHAT pathways in the low-T combustion of large alkanes. Full article

Exploring the microscopic reaction mechanism of dicyandiamide (DCD) synthesis using calcium cyanamide (CaCN₂) is highly desirable because of the low conversion of reactants and selectivity of DCD products. DCD synthesis consists of a two-step sequential hydrolysis of CaCN₂, followed by dimerization of cyanamide to DCD in an alkaline environment. Density functional theory (DFT) results revealed that the rate-limiting step (RLS) was the formation of a C-N bond between the cyanamide and cyanamide anion in the dimerization of the DCD reaction. Secondary reactions of cyanamide with water, hydrogen sulfide, and DCD were also analyzed. The effects of solvation on the principal and secondary reactions were systematically explored. A single explicit water molecule can significantly lower the free energy barrier of the RLS. Water molecules facilitate the C-N bonding of the reactants in DCD reactions, resulting in a reduction in the free energy barrier of the RLS. The facilitation of double explicit water for the reaction is weaker than that of single explicit water and even yields negative catalysis. The effect of the [OH(H₂O)₃]⁻ cluster lowering the reaction barrier with the hydrogen-bonding network is the most remarkable, which can alter the reaction path by the direct and indirect involvement of OH⁻ ions. Furthermore, the reaction rate constants were computed by canonical variational theory with the Eckart tunneling correction (CVT/Eckart) and fitted to the Arrhenius expression. The reaction mechanism and kinetics revealed at the microscopic level provide efficient and clean production of DCD with certain theoretical guidance. Full article

The mechanism of transcription proceeds through the formation of R-loop structures containing a DNA–RNA heteroduplex and a single-stranded DNA segment that should be placed inside the elongation complex; therefore, these nucleic acid segments are limited in length. The attachment of each nucleotide to the 3′ end of an RNA strand requires a repeating cycle of incoming nucleoside triphosphate binding, catalysis, and enzyme translocation. Within these steps of transcription elongation, RNA polymerase sequentially goes through several states and is post-translocated, catalytic, and pre-translocated. Moreover, the backward movement of the polymerase, which is essential for transcription pausing and proofreading activity, gives rise to a backtracked state. In the present study, to analyze both the efficacy of transcription elongation complex (TEC) formation and the rate of RNA synthesis, we used a set of model R-loops that mimic the pre-translocated state, post-translocated state, backtracked state, and a misincorporation event. It was shown that TEC assembly proceeds as an equilibrium process, including the simultaneous formation of a catalytically competent TEC as well as a catalytically inactive conformation. Our data suggest that the inactive complex of RNA polymerase with an R-loop undergoes slow conformational changes, resulting in a catalytically competent TEC. It was revealed that the structural features of R-loops affect the ratio between active and inactive states of the TEC, the rate of conformational rearrangements required for the induced-fit transition from the inactive state to the catalytically competent TEC, and the rates of accumulation of both the total RNA products and long RNA products. Full article

Sequential Pd-catalyzed one-pot synthetic methodologies have emerged as a powerful and versatile approach in organic synthesis, enabling the construction of complex heterocyclic architectures with high efficiency, selectivity, and atom economy. This review discusses key advancements in multistep, sequentially Pd-catalyzed one-pot processes for accessing heterocyclic derivatives, focusing on classic reactions like Suzuki–Miyaura, Sonogashira, Heck, and hydroamination and extending to specialized techniques such as directed C-H activation. The concatenation of these steps has advanced the scope of one-pot strategies. A section is dedicated to exploring the cooperative use of palladium with other metals, particularly copper, ruthenium, and gold, which has broadened the range of accessible heterocyclic derivatives. Highlighted applications include the synthesis of biologically and pharmaceutically relevant compounds, such as tris(hetero)aryl systems, spiro-oxindoles, and indole derivatives. These one-pot strategies not only streamline synthesis but also align with green chemistry principles by minimizing purification steps and reducing waste and energy consumption. The review also addresses current challenges and limitations in these methodologies, offering insights into ongoing efforts to optimize reaction conditions and expand the applicability of sequential Pd-catalyzed processes. Full article

The synthesis of enantiomeric forms of D-amino acids can be achieved by a two-step “hydantoinase process” based on the sequential catalysis of substrates by specific enzymes, D-carbamoylase and D-hydantoinase. Here, we describe the structural features of D-carbamoylase from Pseudomonas, the encoded gene of which was chemically synthesized and cloned into Escherichia coli. A significant fraction of the overexpressed recombinant protein forms insoluble inclusion bodies, which are partially converted to a soluble state upon treatment with N-lauroylsarcosine or upon incubation of cells at 28 °C. Purified His-tagged protein exhibits the highest activity towards N-carbamoyl-D-alanine and N-carbamoyl-D-tryptophan. Comprehensive virtual analysis of the interactions of bulky carbamylated amino acids with D-carbamoylase provided valuable information. Molecular docking analysis revealed the location of the substrate binding site in the three-dimensional structure of D-carbamoylase. Molecular dynamics simulations showed that the binding pocket of the enzyme in complex with N-carbamoyl-D-tryptophan was stabilized within 100 nanoseconds. The free energy data showed that Arg176 and Asn173 formed hydrogen bonds between the enzyme and substrates. The studies of D-carbamoylases and the properties of our previously obtained D-hydantoinase suggest the possibility of developing a harmonized biotechnological process for the production of new drugs and peptide hormones. Full article

Cytochrome P450 (P450) enzymes dominate steroid metabolism. In general, the simple C-hydroxylation reactions are mechanistically straightforward and are generally agreed to involve a perferryl oxygen species (formally FeO³⁺). Several of the steroid transformations are more complex and involve C-C bond scission. We initiated mechanistic studies with several of these (i.e., 11A1, 17A1, 19A1, and 51A1) and have now established that the dominant modes of catalysis for P450s 19A1 and 51A1 involve a ferric peroxide anion (i.e., Fe³⁺O₂¯) instead of a perferryl ion complex (FeO³⁺), as demonstrated with ¹⁸O incorporation studies. P450 17A1 is less clear. The indicated P450 reactions all involve sequential oxidations, and we have explored the processivity of these multi-step reactions. P450 19A1 is distributive, i.e., intermediate products dissociate and reassociate, but P450s 11A1 and 51A1 are highly processive. P450 17A1 shows intermediate processivity, as expected from the release of 17-hydroxysteroids for the biosynthesis of key molecules, and P450 19A1 is very distributive. P450 11B2 catalyzes a processive multi-step oxidation process with the complexity of a chemical closure of an intermediate to a locked lactol form. Full article