ABSTRACT
Whereas [4 + 2] cycloadditions are among the most powerful tools in the chemist's synthetic arsenal, controlling reactivity and selectivity of [6 + 4] cycloadditions has proven to be extremely challenging. Such transformations, especially if compatible with simple hydrocarbon-based substrates, could ultimately provide a general approach to highly valuable and otherwise difficult to access 10-membered rings. We report here that highly acidic and confined imidodiphosphorimidate catalysts do not catalyze this reaction under homogeneous conditions. Notably, however, they can spontaneously precipitate an insoluble and double helix-shaped noncovalent organic framework, which acts as a distinctively reactive and stereoselective catalyst of [6 + 4] cycloadditions of simple dienes with tropone.
ABSTRACT
The photocatalyst (PC) zinc tetraphenylporphyrin (ZnTPP) is highly efficient for photoinduced electron/energy transfer reversible addition-fragmentation chain transfer (PET-RAFT) polymerization. However, ZnTPP suffers from poor absorbance of orange light by the so-called Q-band of the absorption spectrum (maximum absorption wavelength λmax = 600 nm, at which molar extinction coefficient εmax = 1.0×104 L/(mol·cm)), hindering photo-curing applications that entail long light penetration paths. Over the past decade, there has not been any competing candidate in terms of efficiency, despite a myriad of efforts in PC design. By theoretical evaluation, here we rationally introduce a peripheral benzo moiety on each of the pyrrole rings of ZnTPP, giving zinc tetraphenyl tetrabenzoporphyrin (ZnTPTBP). This modification not only enlarges the conjugation length of the system, but also alters the a1u occupied π molecular orbital energy level and breaks the accidental degeneracy between the a1u and a2u orbitals, which is responsible for the low absorption intensity of the Q-band. As a consequence, not only is there a pronounced hyperchromic and bathochromic effect (λmax = 655 nm and εmax = 5.2×104 L/(mol·cm)) of the Q-band, but the hyperchromic effect is achieved without increasing the intensity of the less useful, low wavelength absorption peaks of the PC. Remarkably, this strong 655 nm absorption takes advantage of deep-red (650-700 nm) light, a major component of solar light exhibiting good atmosphere penetration, exploited by the natural PC chlorophyll a as well. Compared with ZnTPP, ZnTPTBP displayed a 49% increase in PET-RAFT polymerization rate with good control, marking a significant leap in the area of photo-controlled polymerization.
ABSTRACT
Catalytic π-arene activation is based on catalysts that allow for arene exchange. To date, cyclopentadiene (Cp)-derived catalysts are the most commonly used in π-arene activation despite their low arene exchange rates. Herein, we report the synthesis, analysis, and catalytic application of Ru(II) complexes supported by phenoxo ligands, which are isolobal alternatives to Cp. The phenoxo complexes exhibit arene exchange rates significantly faster than those of the corresponding Cp complexes. The rate can be further increased through the choice of appropriate counterions. The mechanism of the arene exchange process is elucidated by kinetic and computational analyses. We demonstrate the utility of the new catalysts through an SNAr reaction between fluorobenzene and alcohols, including secondary alcohols that could not be used previously in related reactions. Moreover, the catalytic thermal decarboxylation of phenylacetic acids is presented.
ABSTRACT
ConspectusLondon dispersion (LD) forces are ubiquitous in chemistry, playing a pivotal role in a wide range of chemical processes. For example, they influence the structure of molecular crystals, the selectivity of organocatalytic transformations, and the formation of biomolecular assemblies. Harnessing these forces for chemical applications requires consistent quantification of the LD energy across a broad and diverse spectrum of chemical scenarios. Despite the great progress made in recent years in the development of experimental strategies for LD quantification, quantum chemical methods remain one of the most useful tools in the hand of chemists for the study of these weak interactions. Unfortunately, the accurate quantification of LD effects in complex systems poses many challenges for electronic structure theories. One of the problems stems from the fact that LD forces originate from long-range electronic dynamic correlation, and hence, their rigorous description requires the use of complex, highly correlated wave function-based methods. These methods typically feature a steep scaling with the system size, limiting their applicability to small model systems. Another core challenge lies in disentangling short-range from long-range dynamic correlation, which from a rigorous quantum mechanical perspective is not possible.In this Account, we describe our research endeavors in the development of broadly applicable computational methods for LD quantification in molecular chemistry as well as challenging applications of these schemes in various domains of chemical research. Our strategy lies in the use of local correlation theories to reduce the computational cost associated with complex electronic structure methods while providing at the same time a simple means of decomposition of dynamic correlation into its long-range and short-range components. In particular, the local energy decomposition (LED) scheme at the domain-based local pair natural orbital coupled cluster (DLPNO-CCSD(T)) level has emerged as a powerful tool in our research, offering a clear-cut quantitative definition of the LD energy that remains valid across a plethora of different chemical scenarios. Typical applications of this scheme are examined, encompassing protein-ligand interactions and reactivity studies involving many fragments and complex electronic structures. In addition, our research also involves the development of novel cost-effective methodologies, which exploit the LED definition of the LD energy, for LD energy quantification that are, in principle, applicable to systems with thousands of atoms. The Hartree-Fock plus London Dispersion (HFLD) scheme, correcting the HF interaction energy using an approximate CCSD(T)-based LD energy, is a useful, parameter-free electronic structure method for the study of LD effects in systems with hundreds of molecular fragments. However, the usefulness of the LED scheme reaches beyond providing an interpretation of the calculated DLPNO-CCSD(T) or DLPNO-MP2 interaction energies. For example, the dispersion energies obtained from the LED can be fruitfully used in order to parametrize semiempirical dispersion models. We will demonstrate this in the context of an emerging semiempirical method, namely, the Natural Orbital Tied Constructed Hamiltonian (NOTCH) method. NOTCH incorporates LED-derived LD energies and shows promising accuracy at a minimum amount of empiricism. Thus, it holds substantial promise for large and complex systems.
ABSTRACT
Particulate methane monooxygenase (pMMO) plays a critical role in catalyzing the conversion of methane to methanol, constituting the initial step in the C1 metabolic pathway within methanotrophic bacteria. However, the membrane-bound pMMO's structure and catalytic mechanism, notably the copper's valence state and genuine active site for methane oxidation, have remained elusive. Based on the recently characterized structure of membrane-bound pMMO, extensive computational studies were conducted to address these long-standing issues. A comprehensive analysis comparing the quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulated structures with cryo-EM data indicates that both the CuC and CuD sites tend to stay in the Cu(I) valence state within the membrane environment. Additionally, the concurrent presence of Cu(I) at both CuC and CuD sites leads to the significant reduction of the ligand-binding cavity situated between them, making it less likely to accommodate a reductant molecule such as durohydroquinone (DQH2). Subsequent QM/MM calculations reveal that the CuD(I) site is more reactive than the CuC(I) site in oxygen activation, en route to H2O2 formation and the generation of Cu(II)-Oâ¢- species. Finally, our simulations demonstrate that the natural reductant ubiquinol (CoQH2) assumes a productive binding conformation at the CuD(I) site but not at the CuC(I) site. This provides evidence that the true active site of membrane-bound pMMOs may be CuD rather than CuC. These findings clarify pMMO's catalytic mechanism and emphasize the membrane environment's pivotal role in modulating the coordination structure and the activity of copper centers within pMMO.
Subject(s)
Copper , Reducing Agents , Copper/chemistry , Hydrogen Peroxide , Methane/chemistry , Oxidation-Reduction , Oxygenases/metabolismABSTRACT
Open-shell molecules rarely fluoresce, due to their typically faster non-radiative relaxation rates compared to closed-shell ones. Even rarer is the fluorescence from states that have two more unpaired electrons than the open-shell ground state, since they involve excitations from closed-shell orbitals to vacant-shell orbitals, which are typically higher in energy compared to excitations from or out of open-shell orbitals. States that are dominated by the former type of excitations are known as tripdoublet states when they can be described as a triplet excitation antiferromagnetically coupled to a doublet state, and their description by unrestricted single-reference methods (e.g., U-TDDFT) is notoriously inaccurate due to large spin contamination. In this work, we applied our spin-adapted TDDFT method, X-TDDFT, and the efficient and accurate static-dynamic-static second order perturbation theory (SDSPT2), to the study of the excited states as well as their relaxation pathways of copper(II) porphyrin; previous experimental works suggested that the photoluminescence of some substituted copper(II) porphyrins originate from a tripdoublet state, formed by a triplet ligand π â π* excitation antiferromagnetically coupled with the unpaired d electron. Our results demonstrated favorable agreement between the X-TDDFT, SDSPT2 and experimental excitation energies, and revealed noticeable improvements of X-TDDFT compared to U-TDDFT, not only for vertical excitation energies but also for adiabatic energy differences. These suggest that X-TDDFT is a reliable tool for the study of tripdoublet state fluorescence. Intriguingly, we showed that the aforementioned tripdoublet state is only slightly above the lowest doublet excited state and lies only slightly higher than the lowest quartet state, which suggests that the tripdoublet of copper(II) porphyrin is long-lived enough to fluoresce due to a lack of efficient non-radiative relaxation pathways; an explanation for this unusual state ordering is given. Indeed, thermal vibration correlation function (TVCF)-based calculations of internal conversion, intersystem crossing, and radiative transition rates confirm that copper(II) porphyrin emits thermally activated delayed fluorescence (TADF) and a small amount of phosphorescence at low temperature (83 K), in accordance with experiment. The present contribution is concluded by a few possible approaches of designing new molecules that fluoresce from tripdoublet states.
ABSTRACT
Direct C-H fluorination is an efficient strategy to construct aromatic C-F bonds, but the cleavage of specific C-H bonds in the presence of other functional groups and the high barrier of C-F bond formation make the transformation challenging. Progress for the electrophilic fluorination of arenes has been reported, but a similar transformation for electron-deficient azaarenes has remained elusive due to the high energy of the corresponding Wheland intermediates. Nucleophilic fluorination of electron-deficient azaarenes is difficult owing to the identity of the Meisenheimer intermediate after fluoride attack, from which fluoride elimination to regenerate the substrate is favored over hydride elimination to form the product. Herein, we report a new concept for C-H nucleophilic fluorination without the formation of azaarene Meisenheimer intermediates through a chain process with an asynchronous concerted F--e--H+ transfer. The concerted nucleophilic aromatic substitution strategy allows for the first successful nucleophilic oxidative fluorination of quinolines.
ABSTRACT
In this work, we develop a new semiempirical method, dubbed NOTCH (Natural Orbital Tied Constructed Hamiltonian). Compared to existing semiempirical methods, NOTCH is less empirical in its functional form as well as parameterization. Specifically, in NOTCH, (1) the core electrons are treated explicitly; (2) the nuclear-nuclear repulsion term is calculated analytically, without any empirical parameterization; (3) the contraction coefficients of the atomic orbital (AO) basis depend on the coordinates of the neighboring atoms, which allows the size of AOs to depend on the molecular environment, despite the fact that a minimal basis set is used; (4) the one-center integrals of free atoms are derived from scalar relativistic multireference equation-of-motion coupled cluster calculations instead of empirical fitting, drastically reducing the number of necessary empirical parameters; (5) the (AA|AB) and (AB|AB)-type two-center integrals are explicitly included, going beyond the neglect of differential diatomic overlap approximation; and (6) the integrals depend on the atomic charges, effectively mimicking the "breathing" of AOs when the atomic charge varies. For this preliminary report, the model has been parameterized for the elements H-Ne, giving only 8 empirical global parameters. Preliminary results on the ionization potentials, electron affinities, and excitation energies of atoms and diatomic molecules, as well as the equilibrium geometries, vibrational frequencies dipole moments, and bond dissociation energies of diatomic molecules, show that the accuracy of NOTCH rivals or exceeds those of popular semiempirical methods (including PM3, PM7, OM2, OM3, GFN-xTB, and GFN2-xTB) as well as the cost-effective ab initio method Hartree-Fock-3c.
ABSTRACT
Myocardial infarction (MI) is a coronary artery-related disease and ranks as the leading cause of sudden death globally. Resveratrol (Res) is a bioactive component and has presented antioxidant, anti-inflammatory and anti-microbial properties. However, the effect of Res on ferroptosis during MI progression remains elusive. Here, we aimed to explore the function of Res in the regulation of ferroptosis and myocardial injury in MI. We observed that the treatment of Res attenuated the MI-related myocardium injury and fibrosis in the rats. The expression of collagen 1 and α-SMA was induced in MI rats, in which the treatment of Res could decrease the expression. Treatment of Res suppressed the levels of IL-6 and IL-1ß in MI rats. The GSH levels were inhibited and MDA, lipid ROS, and Fe2+ levels were induced in MI rats, in which the treatment of Res could reverse the phenotypes. Meanwhile, the expression of GPX4 and SLC7A11 was reduced in MI rats, while the treatment of Res could rescue the expression in the model. Meanwhile, Res relieved oxygen-glucose deprivation (OGD)-induced cardiomyocyte injury. Importantly, Res repressed OGD-induced cardiomyocyte ferroptosis in vitro. Mechanically, we identified that Res was able to enhance GPX4 expression by inducing KAT5 expression. We confirmed that KAT5 alleviated OGD-induced cardiomyocyte injury and ferroptosis. The depletion of KAT5 or GPX4 could reverse the effect of Res on OGD-induced cardiomyocyte injury. Thus, we concluded that Res attenuated myocardial injury by inhibiting ferroptosis via inducing KAT5/GPX4 in myocardial infarction. Our finding provides new evidence of the potential therapeutic effect of Res on MI by targeting ferroptosis.
ABSTRACT
BACKGROUND: Excessive myocardial oxidative stress could lead to the congestive heart failure. NADPH oxidase is involved in the pathological process of left ventricular (LV) remodeling and dysfunction. ß3-Adrenergic receptor (AR) could regulate cardiac dysfunction proved by recent researches. The molecular mechanism of ß3-AR regulating oxidative stress, especially NADPH oxidase, remains to be determined. METHODS: Cardiac hypertrophy was constructed by the transverse aortic constriction (TAC) model. ROS and NADPH oxidase subunits expression were assessed after ß3-AR agonist (BRL) or inhibitor (SR) administration in cardiac hypertrophy. Moreover, the cardiac function, fibrosis, heart size, oxidative stress, and cardiomyocytes apoptosis were also detected. RESULTS: ß3-AR activation significantly alleviated cardiac hypertrophy and remodeling in pressure-overloaded mice. ß3-AR stimulation also improved heart function and reduced cardiomyocytes apoptosis, oxidative stress, and fibrosis. Meanwhile, ß3-AR stimulation inhibited superoxide anion production and decreased NADPH oxidase activity. Furthermore, BRL treatment increased the neuronal NOS (nNOS) expression in cardiac hypertrophy. CONCLUSION: ß3-AR stimulation alleviated cardiac dysfunction and reduced cardiomyocytes apoptosis, oxidative stress, and fibrosis by inhibiting NADPH oxidases. In addition, the protective effect of ß3-AR is largely attributed to nNOS activation in cardiac hypertrophy.
Subject(s)
Adrenergic beta-Agonists/pharmacology , Oxidative Stress/drug effects , Receptors, Adrenergic, beta-3/metabolism , Ventricular Remodeling/drug effects , Animals , Cardiomegaly/metabolism , Mice, Inbred C57BL , Myocardium/metabolism , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Reactive Oxygen Species/metabolism , Receptors, Adrenergic, beta-3/drug effectsABSTRACT
First-order nonadiabatic coupling (NAC) matrix elements (fo-NACMEs) are the basic quantities in theoretical descriptions of electronically nonadiabatic processes that are ubiquitous in molecular physics and chemistry. Given the large size of systems of chemical interests, time-dependent density functional theory (TDDFT) is usually the first choice of methods. However, the lack of many-electron wave functions in TDDFT renders the formulation of NAC-TDDFT for fo-NACMEs conceptually difficult. Because of this, various variants of NAC-TDDFT have been proposed in the literature from different standing points, including the Hellmann-Feynman-like expression and auxiliary/pseudo-wave function (AWF)-, equation-of-motion (EOM)-, and time-dependent perturbation theory (TDPT)-based formulations. Based on critical analyses, the following conclusions are made here: (1) The Hellmann-Feynman-like expression, which is rooted in exact wave function theory, is hardly useful due to huge demand on basis sets. (2) Although most popular, the AWF variants of NAC-TDDFT are not theoretically founded and become ambiguous particularly for the fo-NACMEs between two excited states, although they do agree with the EOM and TDPT variants under the Tamm-Dancoff approximation. (3) The TDPT variant of NAC-TDDFT is theoretically most rigorous but suffers from numerical instabilities on the one hand and does not differ to a significant extent from the EOM variant on the other hand. (4) As such, the EOM variant of NAC-TDDFT for the fo-NACMEs between the ground and excited states and between two excited states is solely the right choice in practice. These formal analyses are fully supported by numerical experimentations, taking azulene as a showcase. The proper implementation of the EOM variant of NAC-TDDFT is also highlighted, showing that the fo-NACMEs between the ground and excited states and between two excited states are computationally very much the same as the analytic energy gradients of DFT and TDDFT, respectively. Possible future developments of the EOM variant of NAC-TDDFT are also highlighted. Its extensions to spin-adapted open-shell TDDFT and proper treatment of spin-orbit couplings (which are another source of force for electronically nonadiabatic processes) are particularly warranted in the near future.
ABSTRACT
An iterative orbital interaction (iOI) approach is proposed to solve, in a bottom-up fashion, the self-consistent field problem in quantum chemistry. While it belongs grossly to the family of fragment-based quantum chemical methods, iOI is distinctive in that (1) it divides and conquers not only the energy but also the wave function and that (2) the subsystem sizes are automatically determined by successively merging neighboring small subsystems until they are just enough for converging the wave function to a given accuracy. Orthonormal occupied and virtual localized molecular orbitals are obtained in a natural manner, which can be used for all post-SCF purposes.
ABSTRACT
Delta self-consistent-field methods are widely used in studies of electronically excited states. However, the nonaufbau determinants are generally spin-contaminated. Here, we describe a general approach for spin-coupling interactions of open-shell molecules, making use of multistate density functional theory (MSDFT). In particular, the effective exchange integrals that determine spin coupling are obtained by enforcing the multiplet degeneracy of the S+1 state in the MS = S manifold. Consequently, they are consistent with the energy of the high-spin state that is adequately treated by Kohn-Sham density functional theory (DFT) and, thereby, free of double counting of correlation. The method was applied to core excitations of open-shell molecules and compared with those by spin-adapted time-dependent DFT. An excellent agreement with experiment was found employing the BLYP functional and aug-cc-pCVQZ basis set. Overall, MSDFT provides an effective combination of the strengths of DFT and wave function theory to achieve efficiency and accuracy.
ABSTRACT
Studies on the optical properties of donor-bridge-acceptor (DBA) materials in their radical anion state are rare but important. Such investigations can help to extend the application of DBA materials to opto-electrochemical devices and no longer limit them to optical physics research. In this work, a series of new DBA materials, TACzs, for overcoming this limitation are reported. All TACzs show strong intramolecular charge transfer (ICT) in their photoexcited states, leading to noticeable solvatochromism. Besides, the electronic structures of their radical anions show great variability, displaying different absorption spectra and diverse colors. Moreover, the potential application of TACzs as electrochromic and electro-fluorochromic materials are discussed. This work demonstrates that manipulating the π bridge between the donor and acceptor in the DBA system is an effective pathway not only to tailor the ICT properties of materials in their neutral state, but also to tune the absorption characteristics of their radical anion state, which makes them very promising for applications in electroluminescent and electrochemical devices.
ABSTRACT
It is now well established that the spin-adapted time-dependent density functional theory [X-TD-DFT; Li and Liu, J. Chem. Phys. 135, 194106 (2011)] for low-lying excited states of open-shell systems has very much the same accuracy as the conventional TD-DFT for low-lying excited states of closed-shell systems. In particular, this has been achieved without computational overhead over the unrestricted TD-DFT (U-TD-DFT) that usually produces heavily spin-contaminated excited states. It is shown here that the analytic energy gradients of X-TD-DFT can be obtained by just slight modifications of those of U-TD-DFT running with restricted open-shell Kohn-Sham orbitals. As such, X-TD-DFT also has no overhead over U-TD-DFT in the calculation of energy gradients of excited states of open-shell systems. Although only a few prototypical open-shell molecules are considered as showcases, it can definitely be said that X-TD-DFT can replace U-TD-DFT for geometry optimization and dynamics simulation of excited states of open-shell systems.
ABSTRACT
AIMS: The purpose of this study was to investigate the protective effects of puerarin and elucidate the underlying mechanisms of puerarin in myocardial ischemia/reperfusion (MI/R) injury. MAIN METHODS: C57BL/6 mice were exposed to puerarin (100 mg/kg) with or without the SIRT1 inhibitor nicotinamide (500 mg/kg) and then subjected to MI/R operation. Myocardial infarct size, serum creatine kinase-MB (CK-MB) activity, apoptotic cell death, and cardiac structure and function were examined to evaluate MI/R injury. RT-PCR and western blotting were used to determine the inflammatory response and inflammasome activation, as well as activation of SIRT1/NF-κB pathway. RESULTS: Puerarin significantly reduced myocardial infarct size, serum CK-MB activity, and apoptotic cell death, and improved cardiac structural damage and dysfunction. Moreover, puerarin notably decreased the mRNA and protein levels of TNF-α, IL-6, and IL-1ß, indicating that puerarin attenuated MI/R-induced inflammation. Furthermore, puerarin markedly decreased the protein levels of Ac-NF-κB, NLRP3, cleaved caspase-1, cleaved IL-1ß, and cleaved IL-18 and increased the protein level of SIRT1. More importantly, the SIRT1 inhibitor nicotinamide prevented these puerarin-induced cardioprotective effects and regulation of the SIRT1/NF-κB pathway, as well as the NLRP3 inflammasome activation. CONCLUSION: Puerarin protected against MI/R injury by inhibiting inflammatory responses probably via the SIRT1/NF-κB pathway, and inhibition of the NLRP3 inflammasome was also involved in puerarin-induced cardioprotective effects. These results suggest that puerarin may be a novel candidate for the treatment of ischemic heart disease.
Subject(s)
Cardiotonic Agents/pharmacology , Inflammation/metabolism , Isoflavones/pharmacology , Myocardial Reperfusion Injury/prevention & control , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Signal Transduction/drug effects , Animals , Cardiotonic Agents/administration & dosage , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Heart/drug effects , Inflammasomes/antagonists & inhibitors , Inflammasomes/drug effects , Inflammation/etiology , Male , Mice, Inbred C57BL , Myocardial Reperfusion Injury/blood , Myocardial Reperfusion Injury/complications , Myocardial Reperfusion Injury/pathology , Myocardium/metabolism , Myocardium/pathology , NF-kappa B p50 Subunit/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Niacinamide/administration & dosage , Niacinamide/pharmacology , Sirtuin 1/metabolismABSTRACT
Neonicotinoid insecticide (NEO) concentrations in ambient fine particulate matter (PM2.5) and daily exposure via inhalation were investigated during spring and fall in an urban area in Beijing and in urban and rural areas of Zhengzhou, Henan Province, China. Four NEOs, including imidacloprid, acetamiprid, thiamethoxam and clothianidin, were assessed using a QuEChERS (quick, easy, cheap, effective, rugged, safe) extraction procedure coupled to liquid chromatography-tandem mass spectrometry. Of 64 PM2.5 samples, 100% contained at least two NEOs (imidacloprid and acetamiprid). Imidacloprid was detected at the highest levels, ranging from 4.33 to 1.13 × 102 pg m-3. A relative potency factor method that considered different toxicities was used to integrate the four NEO concentrations. The total NEO concentrations in air in the Zhengzhou rural area (mean: 80.86 pg m-3) were higher than those in urban areas. Differences between seasons were not significant (p > 0.05). The highest value for the total average daily dose via inhalation of four NEOs (ADDinh,total), 91.0 pg kg-1 day-1, was found in rural children <6 years old. The ADDinh,total of rural residents was significantly higher than that of urban residents when there was no intensive pesticide application. Although the ADDinh,total values were below the current chronic reference dose, when possible joint toxicity and the increasing use of NEOs are considered, a potential health risk via inhalation is evident. We believe this study is the first to characterize NEO levels in fine particulate matter and to evaluate inhalation exposure in urban and rural residents under nonoccupational scenarios in China. It will enhance our understanding of exposure to NEOs and provide a basis for risk management decisions.
Subject(s)
Air Pollutants , Insecticides , Air Pollutants/analysis , Air Pollutants/toxicity , Beijing , Child , China , Humans , Insecticides/analysis , Insecticides/toxicity , Neonicotinoids/toxicity , Particulate Matter/toxicityABSTRACT
The selectivity of halogenation versus hydroxylation in α-KG de-pendent halogenases is vital to their function and has been widely studied, particularly using the halogenase SyrB2 as a model. WelO5, a new member of α-KG dependent halogenases, catalyzes the chlorination of 12-epi-fischerindole U in the welwitindolinone biosynthetic pathway. Herein, we give a detailed insight into the selectivity of WelO5 through combined quantum mechanical/molecular mechanical (QM/MM) calculations for the whole catalytic cycle. O2 activation leads to a Fe(iv)[double bond, length as m-dash]O moiety which adopts an equatorial conformation (in the plane consisting of His164, chloride and Fe atom), in contrast to axial conformation (perpendicular to the plane). Key to the conformational selectivity is a serine residue (Ser189) in the equatorial plane, that brings the precursor of the Fe(iv)[double bond, length as m-dash]O intermediate (a Fe(ii)-peracid complex) to the equatorial conformation through hydrogen bonding. Hydrogen abstraction of the substrate by the equatorial Fe(iv)[double bond, length as m-dash]O leads to a five-coordinated HO-Fe(iii)-Cl complex, where the hydroxyl ligand is still equatorial and thus relatively far from the substrate radical in the axial direction compared to the chloride ligand. This smoothly explains the extremely high selectivity of chlorination in WelO5 and provides a microscopic explanation for the experimental finding that S189A WelO5 ceases to display any chlorination selectivity versus hydroxylation. Notably, although Ser189 is vital for the selectivity of the enzyme, it is not part of the substrate binding pocket. Therefore, WelO5 serves as an excellent example how chemoselectivity can be achieved in directed evolution without the tedious redesign of the substrate binding pocket.
Subject(s)
Enzymes/metabolism , Nonheme Iron Proteins/metabolism , Halogenation , Hydroxylation , Nonheme Iron Proteins/chemistry , Substrate SpecificityABSTRACT
The BDF (Beijing Density Functional) program package is in the first place a platform for theoretical and methodological developments, standing out particularly in relativistic quantum chemical methods for chemistry and physics of atoms, molecules, and periodic solids containing heavy elements. These include the whole spectrum of relativistic Hamiltonians and their combinations with density functional theory for the electronic structure of ground states as well as time-dependent and static density functional linear response theories for electronically excited states and electric/magnetic properties. However, not to be confused by its name, BDF nowadays comprises also of standard and novel wave function-based correlation methods for the ground and excited states of strongly correlated systems of electrons [e.g., multireference configuration interaction, static-dynamic-static configuration interaction, static-dynamic-static second-order perturbation theory, n-electron valence second-order perturbation theory, iterative configuration interaction (iCI), iCI with selection plus PT2, and equation-of-motion coupled-cluster]. Additional features of BDF include a maximum occupation method for finding excited states of Hartree-Fock/Kohn-Sham (HF/KS) equations, a very efficient localization of HF/KS and complete active space self-consistent field orbitals, and a unique solver for exterior and interior roots of large matrix eigenvalue problems.
ABSTRACT
A heterobimetallic complex, (TPFC)Sn-Co(TAP) (TPFC = 5,10,15-tris(pentafluorophenyl)corrole, TAP = 5,10,15,20-tetrakis(p-methoxyphenyl)porphyrin), was synthesized. The complex featured a Sn-Co bond with a bond dissociation enthalpy (BDE) of 30.2 ± 0.9 kcal mol-1 and a bond dissociation Gibbs free energy (BDFE) of 21.0 ± 0.2 kcal mol-1, which underwent homolysis to produce the (TPFC)Sn radical and (TAP)CoII under either heat or visible light irradiation. The novel tin radical (TPFC)Sn, being the first four-coordinate tin radical observed at room temperature, was studied spectroscopically and computationally. (TPFC)Sn-Co(TAP) promoted the oligomerization of aryl alkynes to give the insertion products (TPFC)Sn-(CH[double bond, length as m-dash]C(Ar)) n -Co(TAP) (n = 1, 2, or 3) as well as 1,3,5-triarylbenzenes. Mechanistic studies revealed a radical chain mechanism involving the (TPFC)Sn radical as the key intermediate.