Synergistic Charge Transfer Effect in Ferrous Heme-CO Bonding within Cytochrome P450.

We conducted ab initio valence bond (VB) calculations employing the valence bond self-consistent field (VBSCF) and breathing orbital valence bond (BOVB) methods to investigate the nature of the coordination bonding between ferrous heme and carbon monoxide (CO) within cytochrome P450. These calculations revealed the significant influence exerted by both proximal and equatorial ligands on the π-backdonation effect from the heme to the CO. Moreover, our VB calculations unveiled a phenomenon of synergistic charge transfer (sCT). In the case of ferrous heme-CO bonding, the significant stabilization in this sCT arises from cooperative resonance between the VB structures associated with σ donation and π backdonation. Unlike many other ligands, CO possesses the unique ability to establish two mutually perpendicular π-backdonation orbital interaction pairs, leading to an intensified stabilization attributed to σ-π resonance. Furthermore, while of a smaller energy magnitude, sCT due to one π-π pair is also present, contributing to the differential stabilization of ferrous heme-CO bonding.

Nickel-Catalyzed Enantioconvergent Allenylic Amination of Allenols Activated by Hydrogen-Bonding Interaction with Methanol.

The ubiquitous nature of amines in drug compounds, bioactive molecules and natural products has fueled intense interest in their synthesis. Herein, we introduce a nickel-catalyzed enantioconvergent allenylic amination of methanol-activated allenols. This protocol affords a diverse array of functionalized allenylic amines in high yields and with excellent enantioselectivities. The synthetic potential of this method is demonstrated by employing bioactive amines as nucleophiles and conducting gram-scale reactions. Furthermore, mechanistic investigations and DFT calculations elucidate the role of methanol as an activator in the nickel-catalyzed reaction, facilitating the oxidative addition of the C-O bond of allenols through hydrogen-bonding interactions. The remarkable outcomes arise from a rapid racemization of allenols enabled by the nickel catalyst and from highly enantioselective dynamic kinetic asymmetric transformation of η3-alkadienylnickel intermediates.

Atom Transfer Radical Coupling Enables Highly Enantioselective Carbo-Oxygenation of Alkenes with Hydrocarbons.

The selective functionalization of C(sp3)-H bonds has emerged as a transformative approach for streamlining synthetic routes, offering remarkable efficiency in the preparation and modification of complex organic molecules. However, the direct enantioselective transformation of hydrocarbons to medicinally valuable chiral molecules remains a significant challenge that has yet to be addressed. In this study, we adopt an atom transfer radical coupling (ATRC) strategy to achieve the asymmetric functionalization of C(sp3)-H bonds in hydrocarbons. This approach involves intermolecular H atom transfer (HAT) between a hydrocarbon and an alkoxy radical, leading to the formation of a carbon-centered radical. The resulting radical adds to alkenes, generating a new radical species that is intercepted by a chiral copper-mediated C-O bond coupling. By employing this method, we can directly access valuable chiral lactones bearing a quaternary stereocenter with high efficiency and excellent enantioselectivity. Importantly, ATRC exhibits great potential as a versatile platform for achieving stereoselective transformations of hydrocarbons.

Spectral features of the ferrous-CO complex in cytochrome P450: a revisit using TDDFT calculations.

There are different views in the literature regarding how to interpret the observed spectral features of the ferrous-CO complexes in cytochrome P450 enzymes (P450s). In this work, we applied density functional theory (DFT) and time-dependent DFT (TDDFT) calculations at the B3LYP-D3BJ/def2-TZVP level with a CPCM correction to the ferrous-CO models of P450s as well as of proteins that contain a histidine-ligated heme. Our results support the notion derived from a previously reported iterative extended Hückel calculation that the involvement of the sulfur lone-pair orbital (S(nz)) of the axial cysteine ligand in the electronic excitations gives rise to a spectral anomaly. The Q and the shorter-wavelength Soret (B') peaks are primarily due to the electronic transitions from the a2u- and S(nz)-type molecular orbitals (MOs), generated via an orbital interaction of fragment orbitals, to the near-degenerate eg-type π* MOs, respectively. The transitions from the a1u-type MO to the eg-type MOs contribute most to the longer wavelength Soret (B) peaks. Both a2u- and S(nz)-type MOs contribute to the B peaks, but the contribution of the latter is greater. When the axial ligand is histidine, the Q and Soret peaks originate essentially from the excitations from the a2u- and a1u-type MOs to the eg-type MOs. The transitions from the b2u-type MOs to the eg-type MOs play the most significant role in the N peaks of such ferrous-CO complexes. Here, the b2u-type MOs have a large contribution from the imidazole π orbital.

Bidirectional Charge Transfer at the Heme Iron in Reversible and Quasi-irreversible Cytochrome P450 Inhibition.

The coordination bonding between inhibitor ligands and heme iron plays a critical role in disrupting the essential catalytic functions of cytochrome P450 enzymes (P450s). Despite its intrinsic importance and consequential implications for human health, our current understanding of coordination bonding in P450 inhibition remains limited. To address this knowledge gap, we conducted a systematic theoretical analysis of the complexes between a ferric or a ferrous heme model and representative inhibitor ligands. Specifically, we evaluated the charge-transfer (CT) effect within these complexes by employing a series of theoretical methods based on density functional theory (DFT). Through a comprehensive analysis, we unveiled the relative significance of ligand-to-heme forward CT in the ferric and ferrous complexes of reversible inhibitors. In contrast, backward CT dominates over forward CT in the ferrous heme complexes of quasi-irreversible inhibitors. Further analysis using the compact frontier orbital method underscores the elevated electron-accepting abilities of quasi-irreversible inhibitors for π backdonation, which greatly amplifies their binding affinity for the ferrous heme. This study sheds light on the intricate mechanisms underlying P450 inhibition and provides valuable insights for future inhibitor design and development.

Mechanism of Selective Aromatic Hydroxylation in the Metabolic Transformation of Paclitaxel Catalyzed by Human CYP3A4.

Paclitaxel (PTX) is heralded as one of the most successful natural-product drugs for the treatment of refractory cancers. In humans, the hepatic metabolic transformation of PTX is primarily mediated by two cytochrome P450 enzymes (P450s): CYP3A4 and CYP2C8. The impact of P450 metabolism on the anticancer effectiveness of PTX is significant. However, the precise mechanism underlying selective P450-catalyzed reactions in PTX metabolism remains elusive. To address this knowledge gap, we conducted molecular docking and molecular dynamics simulations using multiple crystal structures of CYP3A4, which originally contained other ligands. These methods enabled us to determine the most plausible binding structure of PTX within the enzyme. By further employing hybrid quantum mechanics and molecular mechanics calculations, we successfully identified two primary pathways for the reaction between compound I (Cpd I) of CYP3A4 and PTX. One of these pathways involves the formation of an epoxide, while the other proceeds through a ketone intermediate.

The Bonding Nature of Fe-CO Complexes in Heme Proteins.

Although carbon monoxide (CO) has been known to bind to the ferrous heme in cytochrome P450 enzymes (P450s) since the earliest days of P450 research, details on the nature of the ferrous-CO bonding remain elusive. This study employed dispersion-corrected density functional theory (DFT) calculations and DFT-based theoretical analyses to investigate the complexes between CO and a thiolate- or imidazole-ligated heme that contains ferric or ferrous iron. Traditionally, the ferrous-CO bonding in heme systems has been interpreted qualitatively in terms of σ donation and π backdonation. Complementary occupied-virtual orbital pair (COVP) analysis yielded one orbital pair for σ donation and two for π backdonation together with the specific magnitude of their energetic contributions. The charge-transfer effect for these three orbital pairs has nearly the same energetic significance in the ferrous-CO complexes. Therefore, in total, the π-backdonation effect is much greater than the σ-donation effect. In contrast, the σ-donation effect is more significant in the ferric-CO complex because of the less efficient π backdonation. The nature of ferric-CO and ferrous-CO bonding was further scrutinized using the generalized Kohn-Sham energy decomposition analysis (GKS-EDA) scheme, whose results highlighted the significance of various effects in enhancing the Fe-CO bonding for the thiolate- and imidazole-ligated heme groups. In particular, the intrinsic repulsion effect plays a crucial role in promoting the preferential binding of CO toward the ferrous heme and in determining the geometry of the complexes.

Cooperativity in Shape-Persistent Bis-(Zn-salphen) Catalysts for Efficient Cyclic Carbonate Synthesis under Mild Conditions.

A series of conformationally rigid (Zn-salphen)2 complexes with a planar bridging component (xanthene or dibenzofuran) are described. Conformational changes for these assemblies are essentially limited to the axial rotation of the Zn-salphen moieties; however, such geometric constraints crucially permit the subtle tuning of the intermetallic separation and geometry to potentially enhance catalytic activity (and cooperative effects). The complexes have been investigated as catalysts in conjunction with nBu4NI for the coupling of CO2 with epoxides. Selected dibenzofuran derivatives are significantly more active for the production of cyclic carbonate than their mononuclear analogues under identical conditions and concentrations of Zn sites. High initial turnover frequencies (up to 29 000 h-1; 14 500 h-1 per Zn, using 10 bar of CO2 at 95 °C) and excellent efficiencies under mild conditions (1 bar of CO2 at 55 °C) have been achieved. Kinetic studies using in situ (ReactIR) spectroscopy and density functional theory calculations have been performed, which reveal the existence of an intramolecular rate component and a preference for the cooperative pathway as well as transition states that depict the Zn sites operating in tandem. Taken together, these results provide strong evidence of cooperative reactivity in these Zn2 catalysts.

Ultrafast Luminescent Light-Up Guest Detection Based on the Lock of the Host Molecular Vibration.

Light-up luminescence sensors have been employed in real-time in situ visual detection of target molecules including volatile organic compounds (VOCs). However, currently employed light-up sensors, which are generally based on the aggregation-induced emission (AIE) or solvent-induced energy transfer effect, exhibit limited sensitivity for light-up detection and poor recycling performances thereby significantly hindering their industrial applications. Inspired by the low-temperature enhanced luminescence phenomenon, we herein propose and show that a guest-lock-induced luminescence enhancement mechanism can be used to realize the ultrafast light-up detection of target VOCs. Through introduction of chlorinated hydrocarbons to lock the molecular vibrations within a designed [Cu4I4]-based metal-organic framework (MOF), luminescence intensity could be enhanced significantly at room temperature. This guest-lock-induced luminescence enhancement is brought about by weak supramolecular interactions between the host framework and the guest molecules, allowing highly sensitive and specific detection of the guest vapor with ultrafast response time (<1 s). Single-crystal X-ray diffraction (SCXRD) analysis of guest molecules-loaded MOFs and density functional theory (DFT) calculations were employed to investigate the host-guest interactions involved in this phenomenon. Moreover, the above MOF sensor successfully achieved real-time detection of a toxic chloroaromatic molecule, chlorobenzene. The guest-lock-induced light-up mechanism opens up a route to discovering high-performance ultrafast light-up luminescent sensors for real-time detection applications.

C-H oxidation enhancement on a gold nanoisland by atomic-undercoordination induced polarization.

C-H activation is of great significance in the chemical industry while an effective solvent-free catalyst is highly desired. This work shows that a gold nanoisland which was inert in the bulk is effective for C-H activation reactions. We investigated the C-H activation of toluene on an Au nanoisland (58 atoms) using relativistic density functional theory (DFT). We found that (i) the bonds between under-coordinated gold atoms (corner site) shrink spontaneously and become stronger; (ii) the valence charges of corner atoms are polarized to the upper edge of the valence band (near the Fermi level), indicating the electron donation ability in the catalytic process; (iii) during C-H oxidation, the indirect path (O2 dissociation and O-H bonding) and direct path (O2-H bonding) were considered. The Au-O2 complex is active enough to abstract a hydrogen atom directly from toluene, with a barrier that is 6.8 kcal mol-1 lower than that of the indirect path; and (iv) a transfer of up to ∼0.8 electrons from gold to O2 occurs. Moreover, hybridization between delocalized gold orbitals and oxygen p-orbitals leads to the stabilization of the singlet spin state of Au58O. Our results suggest that undercoordination-charge-polarization are key factors for the C-H oxidation catalyzed by an Au nanoisland.

Direct Atomic-Level Imaging of Zeolites: Oxygen, Sodium in Na-LTA and Iron in Fe-MFI.

Zeolites are becoming more versatile in their chemical functions through rational design of their frameworks. Therefore, direct imaging of all atoms at the atomic scale, basic units (Si, Al, and O), heteroatoms in the framework, and extra-framework cations, is needed. TEM provides local information at the atomic level, but the serious problem of electron-beam damage needs to be overcome. Herein, all framework atoms, including oxygen and most of the extra-framework Na cations, are successfully observed in one of the most electron-beam-sensitive and lowest framework density zeolites, Na-LTA. Zeolite performance, for instance in catalysis, is highly dependent on the location of incorporated heteroatoms. Fe single atomic sites in the MFI framework have been imaged for the first time. The approach presented here, combining image analysis, electron diffraction, and DFT calculations, can provide essential structural keys for tuning catalytically active sites at the atomic level.

Host-Guest Complexation Using Pillar[5]arene Crystals: Crystal-Structure Dependent Uptake, Release, and Molecular Dynamics of an Alkane Guest.

Host-guest complexation has been mainly investigated in solution, and it is unclear how guest molecules access the assembled structures of host and dynamics of guest molecules in the crystal state. In this study, we studied the uptake, release, and molecular dynamics of n-hexane vapor in the crystal state of pillar[5]arenes bearing different substituents. Pillar[5]arene bearing 10 ethyl groups yielded a crystal structure of herringbone-type 1:1 complexes with n-hexane, whereas pillar[5]arene with 10 allyl groups formed 1:1 complexes featuring a one-dimensional (1D) channel structure. For pillar[5]arene bearing 10 benzyl groups, one molecule of n-hexane was located in the cavity of pillar[5]arene, and another n-hexane molecule was located outside of the cavity between two pillar[5]arenes. The substituent-dependent differences in molecular arrangement influenced the uptake, release, and molecular dynamics of the n-hexane guest. The substituent effects were not observed in host-guest chemistry in solution, and these features are unique for the crystal state host-guest chemistry of pillar[5]arenes.

Copper-Catalyzed Asymmetric Arylation of N-Heteroaryl Aldimines: Elementary Step of a 1,4-Insertion.

Copper complexes of monodentate phosphoramidites efficiently promote asymmetric arylation of N-azaaryl aldimines with arylboroxines. DFT calculations and experiments support an elementary step of 1,4-insertion in the reaction pathway, a step in which an aryl-copper species adds directly across four atoms of C=N-C=N in the N-azaaryl aldimines.

Zwitterionic Inorganic Benzene Valence Isomer with σ-Bonding between Two π-Orbitals.

Despite the large number of plausible isomers of benzene (C6H6), only four valence isomers [(CH)6] have been experimentally detected, all of which are nonionic and possess skeletal frameworks built from localized C-C bonds. Herein, we present the isolation of a diazatetraborabenzene analogue of a hypothetical zwitterionic valence isomer of benzene. Therein, two electrons are delocalized over the four boron atoms in the six-membered B4N2 ring, which is a result of the σ-bonding interaction between two odd-electron B-B π-orbitals. Simple treatment with a crown ether leads to the formation of a paramagnetic potassium-doped radical ion pair that exhibits a thermally populated triplet character.

Ferrihydrite Particle Encapsulated within a Molecular Organic Cage.

Metal oxides with sizes of a few nanometers show variable crystal and electronic structures depending on their dimensions, and the synthesis of metal oxide particles with a desired size is a key technology in materials science. Although discrete metal oxide particles with an average diameter ( d) smaller than 2 nm are expected to show size-specific properties, such ultrasmall metal oxide particles are significantly limited in number. In nature, on the other hand, nanosized ferrihydrite (Fh), which is ferric oxyhydroxide, occurs as a result of biomineralization in ferritin, an iron storage protein cage. Here we describe the synthesis of Fh particles using a covalent molecular organic cage (MOC) derived from 8 + 12 cyclocondensation of triaminocyclohexane with a diformylphenol derivative. At the initial reaction stage, eight iron ions accumulated at the metal binding sites in the cage cavity, and Fh particles ( d = 1.9 ± 0.3 nm) encapsulated within the cage (Fh@MOC) formed with a quite narrow size distribution. The formation process of the Fh particle in the organic cage resembles the biomineralization process in the natural iron storage protein, and the present method could be applicable to the synthesis of other metal oxide particles. Fh@MOC is soluble in common organic solvents and shows substantial redox activity in MeCN.

Analytical hessian fitting schemes for efficient determination of force-constant parameters in molecular mechanics.

Building upon our recently developed partial Hessian fitting (PHF) method (Wang et al., J. Comput. Chem. 2016, 37, 2349), we formulated and implemented two other rapid force-field parameterization schemes called full Hessian fitting (FHF) and internal Hessian fitting (IHF), and comparisons were made among these three parameterization schemes to assess their performance. FHF minimizes deviation between the Hessian matrices in Cartesian coordinates computed by quantum mechanics (QM) and molecular mechanics (MM), to determine the best possible MM force-constant parameters. While PHF requires step-by-step fittings of 3 × 3 partial Hessian matrices, FHF compares the lower triangular part of the QM and MM Hessian matrices, which allows simultaneous determination of all force-constant parameters. In addition to this simple FHF scheme, IHF was developed such that it considers the Hessian matrices in redundant internal coordinates, where all possible internal coordinates that arise from the user-defined interatomic connectivity are utilized. The results show that IHF performs best overall, followed by PHF and then FHF. Python-based programing codes were developed to automate various tedious steps involved in the parameterization processes. © 2017 Wiley Periodicals, Inc.

Revisiting the catalytic mechanism of Mo-Cu carbon monoxide dehydrogenase using QM/MM and DFT calculations.

Previous density functional theory (DFT) studies have shown that the release of the produced carbon dioxide (CO2) from an active-site cluster is a thermodynamically or kinetically difficult step in the enzymatic carbon monoxide (CO) oxidation catalyzed by Mo-Cu carbon monoxide dehydrogenase (Mo-Cu CODH). To better understand the effect of the protein environment on this difficult CO2 release step as well as other reaction steps, we applied hybrid quantum mechanics and molecular mechanics (QM/MM) calculations to the Mo-Cu CODH enzyme. The results show that in the first step, the equatorial Mo[double bond, length as m-dash]O group in the active-site cluster attacks the nearby CO molecule bound to the Cu site. Afterward, a stable thiocarbonate intermediate is formed in which the CO2 molecule is embedded and the copper-S(µ-sulfido) bond is broken. A free CO2 molecule, i.e., the final product, is then released from the active-site cluster, not directly from the thiocarbonate intermediate but via a previously formed intermediate that also contains CO2 but retains the Cu-S(µ-sulfido) bond. In contrast to the previous DFT results, the calculated barrier for this process was low in our QM/MM calculations. An additional QM/MM analysis of the barrier height showed that the effect of the protein environment on this barrier lowering is not very large. We found that the reason for the low barrier obtained by QM/MM is that the barrier for CO2 release is already not high at the DFT level. These results allow us to conclude that the CO oxidation reaction passes through the formation of a thiocarbonate intermediate, and that the subsequent CO2 release is kinetically not difficult. Nevertheless, the protein environment has an important role to play in making the latter process thermodynamically favored. No low-barrier pathway for the product release could be obtained for the reaction of n-butylisocyanide, which is consistent with the experimental fact that n-butylisocyanide inhibits Mo-Cu CODH.

Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-ß assembly.

Neurodegeneration correlates with Alzheimer's disease (AD) symptoms, but the molecular identities of pathogenic amyloid ß-protein (Aß) oligomers and their targets, leading to neurodegeneration, remain unclear. Amylospheroids (ASPD) are AD patient-derived 10- to 15-nm spherical Aß oligomers that cause selective degeneration of mature neurons. Here, we show that the ASPD target is neuron-specific Na(+)/K(+)-ATPase α3 subunit (NAKα3). ASPD-binding to NAKα3 impaired NAKα3-specific activity, activated N-type voltage-gated calcium channels, and caused mitochondrial calcium dyshomeostasis, tau abnormalities, and neurodegeneration. NMR and molecular modeling studies suggested that spherical ASPD contain N-terminal-Aß-derived "thorns" responsible for target binding, which are distinct from low molecular-weight oligomers and dodecamers. The fourth extracellular loop (Ex4) region of NAKα3 encompassing Asn(879) and Trp(880) is essential for ASPD-NAKα3 interaction, because tetrapeptides mimicking this Ex4 region bound to the ASPD surface and blocked ASPD neurotoxicity. Our findings open up new possibilities for knowledge-based design of peptidomimetics that inhibit neurodegeneration in AD by blocking aberrant ASPD-NAKα3 interaction.

Facile Activation of Homoatomic σ Bonds in White Phosphorus and Diborane by a Diboraallene.

Metal-free activation of homoatomic E-E σ bonds (E=P, B) in white phosphorus (P4 ) and bis(catecholato)diboron (B2 cat2 ) with a 1,2-diboraallene 1 is reported. The 1:1 and 1:2 reactions of P4 with 1 afford Bn P4 cages (2: n=2, 3: n=4), whereas a stoichiometric mixture of 1 and B2 cat2 undergoes homonuclear catenation through the addition of the B-B σ bond of B2 cat2 across the B=B double bond of 1 (i.e. diboration), which leads to the formation of a tetraborane (4) featuring a B4 chain.

Palladium-Catalyzed para-Selective Alkylation of Electron-Deficient Arenes.

Intermolecular alkylations of electron-deficient arenes proceed with good para selectivity. Palladium catalysts were used to generate nucleophilic alkyl radicals from alkyl halides, which then directly add onto the arenes. The arene scope and the site of alkylation are opposite to those of classical Friedel-Crafts alkylations, which prefer electron-rich systems.