Molecular Reaction Mechanism Research Articles

Molecular Mechanism of Copper-based Catalytic Reaction of Water Oxidation. In-situ Electrochemical Liquid Phase Transmission Electron Microscopy Study.

Molecular Mechanism of Copper-based Catalytic Reaction of Water Oxidation. In-situ Electrochemical Liquid Phase Transmission Electron Microscopy Study.

A detailed kinetic study on the tautomerization reactions of barbituric acid: A combined DFT-QTAIM analysis

A detailed kinetic study on the tautomerization reactions of barbituric acid (BA) at elevated temperatures from 270 K up to 1000 K was performed in this work. The B3LYP/6-311 + G(3df,2p) density functional theory (DFT) calculations were performed to evaluate the rate constants of transition states (TS) conversions of the tautomerization reactions. The connections from a given TS to the corresponding local minima of the reactant and product sides were confirmed by means of employing the intrinsic reaction coordinate (IRC) method. Moreover, the quantum theory of atoms in molecules (QTAIM) approach was employed to analyze the molecular mechanisms of reactions. The effects of vibrational normal mode frequencies of the reactant and TS were investigated on the curvature of the corresponding Arrhenius plot in the presence and absence of the tunneling effect. For each tautomerization reaction, the investigated reaction was partitioned into three different stages and four zones. The obtained results were plotted along with the corresponding reaction coordinates for each reaction considering and comparing different factors in agreement with already affirmed concepts. As a consequence, details of performed kinetic study on the tautomerization reactions of BA were successfully provided in this work.

Stochastic Transcription with Alterable Synthesis Rates

Background: Gene transcription is a random bursting process that leads to large variability in mRNA numbers in single cells. The main cause is largely attributed to random switching between periods of active and inactive gene transcription. In some experiments, it has been observed that variation in the number of active transcription sites causes the initiation rate to vary during elongation. Results: We established a mathematical model based on the molecular reaction mechanism in single cells and studied a stochastic transcription system consisting of two active states and one inactive state, in which mRNA molecules are produced with two different synthesis rates. Conclusions: By calculation, we obtained the average mRNA expression level, the noise strength, and the skewness of transcripts. We gave a necessary and sufficient condition that causes the average mRNA level to peak at a limited time. The model could help us to distinguish an appropriate mechanism that may be employed by cells to transcribe mRNA molecules. Our simulations were in agreement with some experimental data and showed that the skewness can measure the deviation of the distribution of transcripts from the mean value. Especially for mature mRNAs, their distributions were almost able to be determined by the mean, the noise (or the noise strength), and the skewness.

Rice resistance genes to leaf blight caused by Xanthomonas oryzae pv. Oryzae (review)

Rice is the most important food crop for the world population and has been cultivated for more than 10 centuries. It is affected by various viral, fungal and bacterial diseases, the most harmful of which is leaf blight, which is caused by the bacterium Xanthomonas oryzae pv. oryzae (Xoo). The most effective way to combat leaf blight is to use resistant varieties together with good agro-technical methods. In recent years, there has been carried out an extensive genetic and genomic study to identify the molecular mechanism of rice reaction to Xoo. As a result of long-term study by the Southeast Asian farmers there were identified 42 different leaf blight resistance genes, 9 of which were isolated and cloned. Currently, complete genome sequences are available for two different rice subspecies ‘Japonica’ and ‘Indica’ and three different races of the leaf blight pathogen. Therefore, there can be estimated an interaction between rice and Xoo, which will allow establishing host responses such as innate immunity and R gene-mediated immunity. Functional analysis of resistance genes may provide clues to the development of a broad spectrum and long-term resistance to leaf blight. There has been characterized a number of resistance (R) genes and related avirulence genes and effector virulence genes. This review, based on published works has presented the latest advances in the study of correlation between rice and the pathogen through R genes and their products. There has been also discussed breeding strategies in order to develop varieties with long-term and broad resistance to Xanthomonas oryzae.

From the Felkin‐Anh Rule to the Grignard Reaction: an Almost Circular 50 Year Adventure in the World of Molecular Structures and Reaction Mechanisms with Computational Chemistry**

AbstractThis rosarium article relates the adventure started 50 years ago of a computational chemist who was interested in molecules; what are they, what are their shape and how do they react. The story describes results, still valid today, obtained with highly simplified models of chemical reality and elementary computational methods and the gain resulting from the use of better models and more elaborate computational methods. It was necessary to select examples. In this presentation, focus is on hydride and dihydrogen complexes as well as on nucleophiles. Nucleophiles were considered as free hydrides in gas phase at the start of the rosarium while the Grignard reaction is treated with ab initio molecular mechanisms at the end of it.

An overview of antimicrobial properties of kombucha.

Kombucha is a traditional beverage of Manchurian origin, typically made by fermenting sugared black or green tea with the symbiotic consortium of bacteria and yeast (SCOBY). The beverage has gained increasing popularity in recent years, mainly due to its heralded health benefits. The fermentation process of kombucha also results in the production of various bioactive compounds with antimicrobial potential, making it a promising candidate in the exploration of alternative sources of antimicrobial agents, and may be helpful in combating the rising threat of antibiotic resistance. Literature survey performed on Web of Science, Scopus, and PubMed revealed the extensive research that has firmly established the antimicrobial activity of kombucha against a broad spectrum of bacteria and fungi. This activity could be attributed to the synergistic activities of the microbial species in the kombucha microbiota that led to the synthesis of compounds with antimicrobial properties such as acetic acid and various polyphenols. However, research thus far only involved screening for the antimicrobial activity of kombucha. Therefore, there is still a research gap about the molecular mechanism of the kombucha reaction against specific pathogens and its influence on human health upon consumption. Future research may focus on investigating this aspect. Further characterization of the biological activity of the microbial community in kombucha may also facilitate the discovery of novel antimicrobial compounds, such as bacteriocins produced by the microorganisms.

A Comparison of Partial Atomic Charges for Electronically Excited States.

Partial atomic charges are a useful and intuitive concept for understanding molecular properties and chemical reaction mechanisms, showing how changes in molecular geometry can affect the flow of electronic charge within a molecule. However, the use of partial atomic charges remains relatively uncommon in the characterization of excited-state electronic structure. Here, we show how well-established partial atomic charge methods perform for interatomic, intermolecular, and interbond electron transfer in electronically excited states. Our results demonstrate the utility of real-space partial atomic charges for interpreting the electronic structures that arise in excited-state processes. Furthermore, we show how this analysis can be used to demonstrate that analogous electronic structures arise near photochemically relevant conical intersection regions for several conjugated polyenes. On the basis of our analysis, we find that charges computed using the iterative Hirshfeld approach provide results which are consistent with chemical intuition and are transferable between homologous molecular systems.

Intact living-cell electrolaunching ionization mass spectrometry for single-cell metabolomics.

While single-cell mass spectrometry can reveal cellular heterogeneity and the molecular mechanisms of intracellular biochemical reactions, its application is limited by the insufficient detection sensitivity resulting from matrix interference and sample dilution. Herein, we propose an intact living-cell electrolaunching ionization mass spectrometry (ILCEI-MS) method. A capillary emitter with a narrow-bore, constant-inner-diameter ensures that the entire living cell enters the MS ion-transfer tube. Inlet ionization improves sample utilization, and no solvent is required, preventing sample dilution and matrix interference. Based on these features, the detection sensitivity is greatly improved, and the average signal-to-noise (S/N) ratio is about 20 : 1 of single-cell peaks in the TIC of ILCEI-MS. A high detection throughput of 51 cells per min was achieved by ILCEI-MS for the single-cell metabolic profiling of multiple cell lines, and 368 cellular metabolites were identified. Further, more than 4000 primary single cells digested from the fresh multi-organ tissues of mice were detected by ILCEI-MS, demonstrating its applicability and reliability.

A detailed theoretical investigation to unravel the molecular mechanism of the ligand-free copper-catalyzed Suzuki cross-coupling reaction.

The Suzuki-Miyaura coupling (SMC) represents a very efficacious method for constructing C-C bonds in organic synthesis. The ligand-free variants of SMC have been grabbing attention these days. Despite this momentousness, the mechanistic details of the ligand-free variants are scant in the literature. Herein, we have carried out a detailed mechanistic investigation into the ligand-free Cu-catalyzed SMC of unsaturated organic halides with aryl boronic acid with the aid of density functional theory (DFT) calculations employing the conductor-like polarizable continuum model (CPCM) method. The present study elucidates that in the absence of ancillary ligands on the metal, the substrates, base, and solvent molecules could act as pseudo-ancillary ligands to facilitate the cross-coupling reaction. The investigation further revealed that unsaturated halides like alkynyl halides/vinyl halides could act as good ancillary ligands for copper by forming a Cu-π intermediate and promoting a facile transmetalation process. However, regarding the oxidative addition and reductive elimination steps, a concerted pathway is observed contrary to Pd catalyzed Suzuki coupling, owing to the instability of Cu(III) species and the favourability of Csp2-Csp bond formation. In the whole set of mechanisms explored, oxidative addition/oxidative nucleophilic substitution was the rate-determining step in all the cases. A thermodynamically stable π-coordinated intermediate species where the substrate and base molecule are coordinated to the metal center is identified as the rate-determining species for the ligand-free Suzuki cross-coupling reaction. The presence of the aforesaid intermediate increases the energy span and consequently the activation barrier for the rate-determining step. This study unveiled a theoretical rationale for the high-temperature requirement in the ligand-free Cu-catalyzed SMC reaction.

Molecular reaction and dynamic mechanism of iodate reduction to molecular iodine by nitrogen(III) in aqueous solution.

This work studies the molecular reaction and dynamic mechanism of iodate reduction by nitrogen(III) in aqueous solution using the ab initio molecular dynamics (AIMD) method based on density functional theory (DFT). Two possible reaction pathways (without and with H+) are proposed. The thermodynamic parameters of the proposed reaction pathways are calculated. The theoretical calculation aspects of iodate reduction, including the atomic dipole moment corrected Hirshfeld population (ADCH) atomic charge values, the intrinsic reaction coordinate (IRC) curves, the calculated interaction regional indicator (IRI) isosurfaces with the corresponding sign(λ2)ρ scatter plots, electrostatic potential (ESP) analysis and molecular reaction dynamics are discussed in-depth. The results show that the reaction pathway with H+ is confirmed based on the Gibbs free energy analysis. The transition state proved that the iodate reduction with nitrous acid undergoes four steps according to oxygen-atom deprivation. The IRC curves describe the energy change of the chemical bonds of the reactant conformations in the four steps, with an energy reduction of 71.95, 69.35, 130.15, and 125.87 kJ mol-1, respectively. The ESP interpenetration diagram and IRI isosurfaces provide detailed information on the nucleophilicity and electrophilicity of the reactant conformations. By decreasing the O atom number in HIOx (x = 1, 2, 3), the maximum positive charge decreases, and the positive charge coverage area increases, thus resulting in energy reduction and consequently a more stable conformation. Molecular reaction dynamics analytical results indicated that a relatively stable status of the reactants of the four steps was achieved after around 200 fs, and that the HIO3-HNO2 reaction released the highest energy.

Understanding the Reaction Dynamics on Heterogeneous Catalysts Using a Simple Stochastic Approach.

Recent experimental advances on investigating nanoparticle catalysts with multiple active sites provided a large amount of quantitative information on catalytic processes. These observations stimulated significant theoretical efforts, but the underlying molecular mechanisms are still not well-understood. We introduce a simple theoretical method to analyze the reaction dynamics on catalysts with multiple active sites based on a discrete-state stochastic description and obtain a comprehensive description of the dynamics of chemical reactions on such catalysts. We explicitly determine how the dynamics of catalyzed chemical reactions depend on the number of active sites, on the number of intermediate chemical transitions, and on the topology of underlying chemical reactions. It is argued that the theory provides quantitative bounds for realistic dynamic properties of catalytic processes that can be directly applied to analyze the experimental observations. In addition, this theoretical approach clarifies several important aspects of the molecular mechanisms of chemical reactions on catalysts.

Structural Diversity of Ubiquitin E3 Ligase.

The post-translational modification of proteins regulates many biological processes. Their dysfunction relates to diseases. Ubiquitination is one of the post-translational modifications that target lysine residue and regulate many cellular processes. Three enzymes are required for achieving the ubiquitination reaction: ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3). E3s play a pivotal role in selecting substrates. Many structural studies have been conducted to reveal the molecular mechanism of the ubiquitination reaction. Recently, the structure of PCAF_N, a newly categorized E3 ligase, was reported. We present a review of the recent progress toward the structural understanding of E3 ligases.

Elucidating molecular mechanisms of two-dimensional chemical reactions

Elucidating molecular mechanisms of two-dimensional chemical reactions

Role of Reaction Intermediate Diffusion on the Performance of Platinum Electrodes in Solid Acid Fuel Cells

Understanding the reaction pathways for the hydrogen oxidation reaction (HOR) and the oxygen reduction reaction (ORR) is the key to design electrodes for solid acid fuel cells (SAFCs). In general, electrochemical reactions of a fuel cell are considered to occur at the triple-phase boundary where an electrocatalyst, electrolyte and gas phase are in contact. In this concept, diffusion processes of reaction intermediates from the catalyst to the electrolyte remain unconsidered. Here, we unravel the reaction pathways for open-structured Pt electrodes with various electrode thicknesses from 15 to 240 nm. These electrodes are characterized by a triple-phase boundary length and a thickness-depending double-phase boundary area. We reveal that the double-phase boundary is the active catalytic interface for the HOR. For Pt layers ≤ 60 nm, the HOR rate is rate-limited by the processes at the gas/catalyst and/or the catalyst/electrolyte interface while the hydrogen surface diffusion step is fast. For thicker layers (>60 nm), the diffusion of reaction intermediates on the surface of Pt becomes the limiting process. For the ORR, the predominant reaction pathway is via the triple-phase boundary. The double-phase boundary contributes additionally with a diffusion length of a few nanometers. Based on our results, we propose that the molecular reaction mechanism at the electrode interfaces based upon the triple-phase boundary concept may need to be extended to an effective area near the triple-phase boundary length to include all catalytically relevant diffusion processes of the reaction intermediates.

Understanding the molecular mechanism of the chlorine atom transfer between ammonia and hypochlorous acid with electron localisation function (ELF)

The nature of the chlorine atom transferred between ammonia and hypochlorous acid was investigated using the bonding evolution theory (BET). The application of topological analysis of electron localisation function (ELF) and Thom's catastrophe theory enabled a detailed description of the evolution of chemical bonds and non-bonding electron density. The BET analysis was performed at the DFT(MN15)/def2-TZVPPD computational level. The Hausdorff distance was used as a qualitative view on the evolution of the ELF field. The molecular mechanism of the chlorination reaction consisted of 11 structural stability domains (SSDs) and 10 ELF catastrophes. Four SSDs were observed before the transition state (TS). The TS was found in SSD V, and six SSDs were distinguished after the TS. The energy barriers were analysed with six different DFT functionals (B3LYP, CAM-B3LYP, LC-ωPBE, M11, MN15, ωB97XD) and def2-TZVPPD basis set. The energy barrier between transition state and reagents was smaller than transition state and products, thus the chlorination of ammonia is thermodynamically favourable. Alongside BET analysis, NPA (natural population analysis), AIM (atoms in molecules) and APT (atomic polar tensor) charge analysis was also applied to the transferred chlorine atom.

The Role of Conserved Residues in the DEDDh Motif: the Proton-Transfer Mechanism of HIV-1 RNase H

RNase H is a prototypical example for two-metal-ion catalysis in enzymes. An RNase H activity cleaving the ribonucleic acid (RNA) backbone of a DNA/RNA hybrid is present not only in important drug targets, such as the HIV-1 reverse transcriptase, but also in many other nucleases, such as Homo sapiens (Hs) and Escherichia coli (Ec) RNase H or, notably, in enzymes that are part of the CRISPR gene editing molecular machinery. Despite its importance, the reaction mechanism uncovering the proton-transfer events is not yet understood. In particular, it is not known, which group is the proton donor for the leaving group. Moreover, several different proton acceptors were proposed, and the exact identity of the proton acceptor is also elusive. Here, we revisit the mechanism for RNAse H, whereby we find that the highly conserved Glu residue of the DDE motif acts as a proton donor via a mechanism further stabilized by the 2′O atom of the sugar. Additionally, we also describe an alternative proton-transfer mechanism via a conserved catalytic His residue to deprotonate the attacking water molecule. Furthermore, our quantum mechanics/molecular mechanics (QM/MM) calculations combining Hamiltonian replica exchange with a finite-temperature string method provide an accurate free-energy profile for the reaction catalyzed by the HIV-1 RNase H. Our reported pathway is consistent with kinetic data obtained for mutant HIV-1, Hs, and Ec RNase H, with the calculated pKa values of the DEDD residues and with crystallographic studies. The overall reaction barrier of ∼19 kcal mol–1, encountered in the phosphate-cleavage step, matches the slow experimental rate of ∼1–100 min–1. Additionally, using molecular dynamics (MD) calculations, we sample the recently identified binding site for a third transient divalent metal ion in the vicinity of the scissile phosphate in the product complex. Our results account for the experimental observation of a third metal ion facilitating product release in an Aquifex aeolicus RNase III crystal structure and the Bh RNase H in crystallo reaction. Taken together, we provide a molecular mechanism of the nuclease catalytic reaction that is likely common for the broad family of two-metal-ion catalytic phosphate-cleaving enzymes with a DDE motif.

Exploring the Minimum-Energy Pathways and Free-Energy Profiles of Enzymatic Reactions with QM/MM Calculations.

Understanding molecular mechanisms of enzymatic reactions is of vital importance in biochemistry and biophysics. Here, we introduce new functions of hybrid quantum mechanical/molecular mechanical (QM/MM) calculations in the GENESIS program to compute the minimum-energy pathways (MEPs) and free-energy profiles of enzymatic reactions. For this purpose, an interface in GENESIS is developed to utilize a highly parallel electronic structure program, QSimulate-QM (https://qsimulate.com), calling it as a shared library from GENESIS. Second, algorithms to search the MEP are implemented, combining the string method (E et al. J. Chem. Phys. 2007, 126, 164103) with the energy minimization of the buffer MM region. The method implemented in GENESIS is applied to an enzyme, triosephosphate isomerase, which converts dihyroxyacetone phosphate to glyceraldehyde 3-phosphate in four proton-transfer processes. QM/MM-molecular dynamics simulations show performances of greater than 1 ns/day with the density functional tight binding (DFTB), and 10-30 ps/day with the hybrid density functional theory, B3LYP-D3. These performances allow us to compute not only MEP but also the potential of mean force (PMF) of the enzymatic reactions using the QM/MM calculations. The barrier height obtained as 13 kcal mol-1 with B3LYP-D3 in the QM/MM calculation is in agreement with the experimental results. The impact of conformational sampling in PMF calculations and the level of electronic structure calculations (DFTB vs B3LYP-D3) suggests reliable computational protocols for enzymatic reactions without high computational costs.

BF3-OEt2 Catalyzed C3-Alkylation of Indole: Synthesis of Indolylsuccinimidesand Their Cytotoxicity Studies.

A simple and efficient BF3-OEt2 promoted C3-alkylation of indole has been developed to obtain3-indolylsuccinimidesfrom commercially available indoles and maleimides, with excellent yields under mild reaction conditions. Furthermore, anti-proliferative activity of these conjugates was evaluated against HT-29 (Colorectal), Hepg2 (Liver) and A549 (Lung) human cancer cell lines. One of the compounds, 3w, having N,N-Dimethylatedindolylsuccinimide is a potent congener amongst the series with IC50 value 0.02 µM and 0.8 µM against HT-29 and Hepg2 cell lines, respectively, and compound 3i was most active amongst the series with IC50 value 1.5 µM against A549 cells. Molecular docking study and mechanism of reaction have briefly beendiscussed. This method is better than previous reports in view of yield and substrate scope including electron deficient indoles.

Covalent Histone Modification by an Electrophilic Derivative of the Anti-HIV Drug Nevirapine.

Nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor widely used in combined antiretroviral therapy and to prevent mother-to-child transmission of the human immunodeficiency virus type 1, is associated with several adverse side effects. Using 12-mesyloxy-nevirapine, a model electrophile of the reactive metabolites derived from the NVP Phase I metabolite, 12-hydroxy-NVP, we demonstrate that the nucleophilic core and C-terminal residues of histones are targets for covalent adduct formation. We identified multiple NVP-modification sites at lysine (e.g., H2BK47, H4K32), histidine (e.g., H2BH110, H4H76), and serine (e.g., H2BS33) residues of the four histones using a mass spectrometry-based bottom-up proteomic analysis. In particular, H2BK47, H2BH110, H2AH83, and H4H76 were found to be potential hot spots for NVP incorporation. Notably, a remarkable selectivity to the imidazole ring of histidine was observed, with modification by NVP detected in three out of the 11 histidine residues of histones. This suggests that NVP-modified histidine residues of histones are prospective markers of the drug’s bioactivation and/or toxicity. Importantly, NVP-derived modifications were identified at sites known to determine chromatin structure (e.g., H4H76) or that can undergo multiple types of post-translational modifications (e.g., H2BK47, H4H76). These results open new insights into the molecular mechanisms of drug-induced adverse reactions.

Unveiling the molecular mechanisms of the cycloaddition reactions of aryl hetaryl thioketones and C,N-disubstituted nitrilimines.

Many synthetic routes to constructing biologically active heterocyclic compounds are made feasible through the (3 + 2) cycloaddition (32CA) reactions. Due to a large number of possible combinations of several heteroatoms from either the three-atom components (TACs) or the ethylene derivatives, the potential of the 32CA reactions in heterocyclic syntheses is versatile. Herein, the cycloaddition reaction of thiophene-2-carbothialdehyde derivatives and C,N-disubstituted nitrilimines have been studied through density functional theory (DFT) calculations at the B3LYP/6-311G(d,p) level of theory. In the present study, a one-step 32CA and two-step (4 + 3) cycloaddition (43CA) reaction mechanisms involved in TACs reactions and ethylene derivative have been investigated. In all reactions considered, the one-step 32CA cycloaddition is preferred over the two-step 43CA. The TAC chemoselectively adds across the thiocarbonyl group present in the ethylene derivative in a 32CA fashion to form the corresponding cycloadduct. Analysis of the electrophilic [Formula: see text] and nucleophilic [Formula: see text] Parr functions at the various reaction centers in the ethylene derivative show that the TAC adds across the atomic centers with the largest Parr functions, which is in total agreement with the experimental observation. The selectivities observed in the titled reactions are kinetically controlled.