ONIOM Calculations Research Articles

Narrowband emission from fully-bridged triphenylamine derivatives: insights into effects of structure modification and pressure.

Triphenylamine derivatives with narrowband emission have attracted growing attention in purely organic thermally-activated fluorescence (TADF) materials owing to their enhanced color purity and flexible molecular design strategy. Combined time-dependent density functional theory (TD-DFT) and ONIOM (QM/MM) calculations indicate that the excellent planarity of the experimentally developed DQAO could result in gradually decreased intermolecular interactions in the aggregated state at ambient pressure and upon compression, which is unfavorable for suppressing structural relaxation and achieving narrowband emission in its non-doped practical application. Therefore, three structure-modified derivatives, DQAO-Cb, DQAO-Ph, and DQAO-PhCb, were theoretically designed by introducing the spherical o-carborane and dangling phenyl units positioned para to the N atom of the DQAO to provide additional geometrical distortion and steric hindrance. The explorations on the reported DQAO, OQAO, and SQAO found that small structural relaxations, suppressed low-frequency vibrations, and noticeable short-range charge-transfer (SR-CT) natures of DQAO and OQAO are responsible for their much narrower emission spectral full-width at half-maxima (FWHMs) compared to that of SQAO. Introducing the o-carborane unit directly at the para position of the N atom could result in additional scissoring and stretching vibrations of the corresponding DQAO-Cb while the presence of the phenyl unit in DQAO-Ph is beneficial for suppressing the high-frequency vibrations of the pristine DQAO. More importantly, the bridged phenyl unit incorporated in DQAO-PhCb is of particular importance to inhibit the undesired low-frequency scissoring and high-frequency stretching vibrations of the o-carborane unit, which is crucial to reduce the reorganization energy of DQAO-PhCb and achieve narrowband emission. Also, the phenyl unit in DQAO-Ph and DQAO-PhCb helps to shorten charge transfer distances and improve ISC and RISC processes. Since the o-carborane unit is an adopted building block to achieve piezochromic behaviors, the theoretically structure-modified DQAO-PhCb is expected to exhibit narrowband emission, TADF, and piezochromic features all together. Our findings will hopefully provide ideas for designing triphenylamine-based TADF emitters with narrowband emission and piezochromic behaviors.

Structural basis for inhibition of a GH116 β-glucosidase and its missense mutants by GBA2 inhibitors: Crystallographic and quantum chemical study

The crystal structure of the Thermoanaerobacterium xylanolyticum in glycoside hydrolase family 116 (TxGH116) β-glucosidase provides a structural model for human GBA2 glucosylceramidase, an enzyme defective in hereditary spastic paraplegia and a potential therapeutic target for treating Gaucher disease. To assess the therapeutic potential of known inhibitors, the X-ray structure of TxGH116 in complex with isofagomine (IFG) was determined at 2.0 Å resolution and showed the IFG bound in a relaxed chair conformation. The binding of IFG and 7 other iminosugar inhibitors to wild-type and mutant enzymes (Asp508His and Arg786His) mimicking GBA2 pathogenic variants was then evaluated computationally by two-layered ONIOM calculations (at the B3LYP:PM7 level). Calculations showed that six charged residues, Glu441, Asp452, His507, Asp593, Glu777, and Arg786 influence inhibitor binding most. His507, Glu777 and Arg786, form strong hydrogen bonds with the inhibitors (∼1.4−1.6 Å). Thus, the missense mutation of one of these residues in Arg786His has a greater effect on the interaction energies for all inhibitors compared to Asp508His. In line with the experimental data for the inhibitors that have been tested, the favorable interaction energy between the inhibitors and the TxGH116 protein followed the trend: isofagomine > 1-deoxynojirimycin > glucoimidazole > N-butyl-deoxynojirimycin ≈ N-nonyl-deoxynojirimycin > conduritol B epoxide ≈ azepane 1 > azepane 2. The obtained structural and energetic properties and comparison to the GBA2 model can lead to understanding of structural requirement for inhibitor binding in GH116 to aid the design of high potency GBA2 inhibitors.

A systematic mechanistic survey on the reactions between OH radical and CH3OH on ice.

A systematic mechanistic survey was performed for the CH3OH + OH reaction on ice. ONIOM(ωB97X-D/Def2-TZVP:AMOEBA09) calculations suggested a range of binding energies for the CH2OH radical (0.29-0.69 eV) and CH3OH (0.15-0.72 eV) molecule on hexagonal water ice (Ih) and amorphous solid water (ASW). Computed average binding energies of CH2OH radical (0.49 eV) and CH3OH (0.41 eV) are relatively stronger compared to the CH3O radical binding energies (0.32 eV, Sameera et al., J. Phy. Chem. A, 2021, 125, 387-393). Thus, the CH3OH molecule, CH2OH and CH3O radicals can adsorb on ice, where the binding energies follow the order CH2OH > CH3OH > CH3O. The multi-component artificial force-induced reaction (MC-AFIR) method systematically determined the reaction mechanisms for the CH3OH + OH reaction on ice, where two reaction paths, giving rise to CH2OH and CH3O radicals, were confirmed. A range of reaction barriers, employing the ωB97X-D/Def2-TZVP level of theory, was found for each reaction (0.03-0.11 eV for CH2OH radical formation, and 0.03-0.44 eV for CH3O radical formation). Based on the lowest energy reaction paths, we suspect that both reactions operate on ice. The computed data in this study evidence that the nature of the binding site or the reaction site has a significant effect on the computed binding energies or reaction barriers. Thus, the outcomes of the present study will be very useful for the computational astrochemistry community to determine reliable binding energies and reaction barriers on ice.

Nonoxidative Couplings of Methane to Form Ethylene Catalyzed by Coinage Metal-Containing ZSM-5 Zeolites: A Theoretical Study

DFT-based ONIOM calculations were employed to investigate the potential energy surfaces (PESs) for the conversion of methane to ethylene by a ZSM-5 zeolite containing a single coinage metal atom whose formal charge is +1 (M-ZSM-5). According to the ONIOM calculations, two methanes are activated by M-ZSM-5 to form ethylene and H2 via ethane. The mechanisms consist of the following elementary steps: activation of a C–H bond of two methanes by M-ZSM-5 to form CH3–M–CH3, a C–C bond formation in CH3–M–CH3 to form ethane and M-ZSM-5, and sequential activation of two C–H ethane bonds by the regenerated M-ZSM-5 to form ethylene. Depending on the metal cations, various active sites appear, reflecting whether Brønsted acid sites (BASs) are formed after the alkane C–H activation. Three types of active sites are present in Cu- and Ag-ZSM-5: metal cations, methyl-metal (M–CH3) species, and BASs. In contrast, the active sites in Au-ZSM-5 consist of Au cations or H–Au–alkyl species. Looking at their PESs, we found two energy-demanding steps: the second methane activation to form CH3–M–CH3 for all M-ZSM-5 and the second C–H bond activation of ethane by BASs (M = Cu and Ag). We compared their activation energies to find that Cu- and Au-ZSM-5 are catalysts that are more suitable for forming ethylene from methane and ethane, respectively.

MDO: A Computational Protocol for Prediction of Flexible Enzyme-Ligand Binding Mode.

Developing a method for use in computer aided drug design Background: Predicting the structure of enzyme-ligand binding mode is essential for understanding the properties, functions, and mechanisms of the bio-complex, but is rather difficult due to the enormous sampling space involved. Accurate prediction of enzyme-ligand binding mode conformation. A new computational protocol, MDO, is proposed for finding the structure of ligand binding pose. MDO consists of sampling enzyme sidechain conformations via molecular dynamics simulation of enzyme-ligand system and clustering of the enzyme configurations, sampling ligand binding poses via molecular docking and clustering of the ligand conformations, and the optimal ligand binding pose prediction via geometry optimization and ranking by the ONIOM method. MDO is tested on 15 enzyme-ligand complexes with known accurate structures. The success rate of MDO predictions, with RMSD < 2 Å, is 67%, substantially higher than the 40% success rate of conventional methods. The MDO success rate can be increased to 83% if the ONIOM calculations are applied only for the starting poses with ligands inside the binding cavities. The MDO protocol provides high quality enzyme-ligand binding mode prediction with reasonable computational cost. The MDO protocol is recommended for use in the structure-based drug design.

Do certain imidazolium-based ionic liquid ion pairs/mordenite capture H2S by conformational traps? An ONIOM-DFT study

We present detailed ONIOM(ωB97X-D:PM6) calculations for the formation mechanism of novel composites combining protonic mordenites (H-MOR) with various ionic liquids: 1,3-dimethyl-imidazolium chloride [MMIm]Cl, 1-ethyl-3-methyl-imidazolium chloride [EMIm]Cl; 1-methyl-3-propyl-imidazolium chloride [PMIm]Cl; 1-butyl-3-methyl-imidazolium chloride [BMIm]Cl, 1-(2-hydroxyethyl)-3-methyl-imidazolium chloride [HEMIm]Cl, 1,3-dimethyl-1,3,2-diazasilolium chloride [MMSiN]Cl, and 1,3-dimethyl-1,3-diphospholium chloride [MMPP]Cl. The most feasible [M]-MOR formation mechanism ([M] + = [MMIm] + , [EMIm] + , [PMIm] + , [BMIm] + , [HEMIm] + , [MMSiN] + [MMPP] + ) involves an ion exchange at the T4O10 position favoring the isolation of a minimal number of [M] + isomers (i.e., conformational traps). The interaction of these [M]-MOR composites with pollutant gases has afterward been evaluated. Among the studied sytems, [EMIm]-MOR and [HEMIm]-MOR present electronic and steric conditions for potential applications in gas separation, capture, and storage (H 2 and H 2 S). The H-MOR framework exhibits two structural conformers with the [HEMIm] + cation in the confined space. Both, the MOR-T4O10-[HEMIm] and MOR-T4O10-[HEMIm] HB conformers, interconvert by a dynamic equilibrium with a transition state MOR-T4O10-TS1 acting as a conformational switch ( - ) that selectively recognizes and captures H 2 S through a plier-like conformation. • In silico design of novel composites combining Ionic Liquids with mordenite (MOR) was examined. • A composites formation mechanism that involves the ion exchange of H + by Imidazolium-based Ionic Liquid cation on T4O10 position in H-MOR. • The existence of conformational traps within the mordenite framework was demonstrated. • A new molecular H 2 S recognition/capture mechanism using [HEMIm]-MOR composite was proposed.

Insights into the Interaction between Polyphenols and β-Lactoglobulin through Molecular Docking, MD Simulation, and QM/MM Approaches

In this work, we have explored the interaction of three different polyphenols with the food protein β-lactoglobulin. Antioxidant activities of polyphenols are influenced by complexation with the protein. However, studies have shown that polyphenols after complexation with the protein can be more beneficial due to enhanced antioxidant activities. We have carried out molecular docking, molecular dynamics (MD) simulation, and quantum mechanics/molecular mechanics (QM/MM) studies on the three different protein–polyphenol complexes. We have found from molecular docking studies that apigenin binds in the internal cavity, luteolin binds at the mouth of the cavity, and eriodictyol binds outside the cavity of the protein. Docking studies have also provided binding free energy and inhibition constant values that showed that eriodictyol and apigenin exhibit better binding interactions with the protein than luteolin. For eriodictyol and luteolin, van der Waals, hydrophobic, and hydrogen bonding interactions are the main interacting forces, whereas for apigenin, hydrophobic and van der Waals interactions play major roles. We have calculated the root mean square deviation (RMSD), root mean square fluctuations (RMSF), solvent-accessible surface area (SASA), interaction energies, and hydrogen bonds of the protein–polyphenol complexes. Results show that the protein–eriodictyol complex is more stable than the other complexes. We have performed ONIOM calculations to study the antioxidant properties of the polyphenols. We have found that apigenin and luteolin act as better antioxidants than eriodictyol does on complexation with the protein, which is consistent with the results obtained from MD simulations.

Systematic Functional and Computational Analysis of Glucose-Binding Residues in Glycoside Hydrolase Family GH116

Glycoside hydrolases (GH) bind tightly to the sugar moiety at the glycosidic bond being hydrolyzed to stabilize its transition state conformation. We endeavored to assess the importance of glucose-binding residues in GH family 116 (GH116) β-glucosidases, which include human β-glucosylceramidase 2 (GBA2), by mutagenesis followed by kinetic characterization, X-ray crystallography, and ONIOM calculations on Thermoanaerobacterium xylanolyticum TxGH116, the structural model for GH116 enzymes. Mutations of residues that bind at the glucose C3OH and C4OH caused 27–196-fold increases in KM for p-nitrophenyl-β-D-glucoside, and significant decreases in the kcat, up to 5000-fold. At the C6OH binding residues, mutations of E777 decreased the kcat/KM by over 60,000-fold, while R786 mutants increased both the KM (40-fold) and kcat (2–4-fold). The crystal structures of R786A and R786K suggested a larger entrance to the active site could facilitate their faster rates. ONIOM binding energy calculations identified D452, H507, E777, and R786, along with the catalytic residues E441 and D593, as strong electrostatic contributors to glucose binding with predicted interaction energies &gt; 15 kcal mol−1, consistent with the effects of the D452, H507, E777 and R786 mutations on enzyme kinetics. The relative importance of GH116 active site residues in substrate binding and catalysis identified in this work improves the prospects for the design of inhibitors for GBA2 and the engineering of GH116 enzymes for hydrolytic and synthetic applications.

Direct SN2 or SN2X Manifold─Mechanistic Study of Ion-Pair-Catalyzed Carbon(sp3)-Carbon(sp3) Bond Formation.

Density functional theory (DFT) is used in this work to predict the mechanism for constructing congested quaternary-quaternary carbon(sp3)-carbon(sp3) bonds in a pentanidium-catalyzed substitution reaction. Computational mechanistic studies were carried out to investigate the proposed SN2X manifold, which consists of two primary elementary steps: halogen atom transfer (XAT) and subsequent SN2. For the first calculated model on original experimental substrates, XAT reaction barriers were more kinetically competitive than an SN2 pathway and connect to thermodynamically stable intermediates. Extensive computational screening modeling was then done on various substrate combinations designed to study the steric influence and to understand the mechanistic rationale, and calculations reveal that sterically congested substrates prefer the SN2X manifold over SN2. Different halides as leaving groups were also screened, and it was found that the reactivity increases in the order of I > Br > Cl > F, in agreement with the strength of C-X bonds. However, DFT modeling suggests that chlorides can be a viable substrate for the SN2X process, which should be further explored experimentally. ONIOM calculations on the full catalyst model predicted the correct stereochemical outcome, and further catalyst screening with cationic Me4N+ and K+ predicted that pentanidium is still the choice for SN2X C-C bond formation.

Prediction of Gas‐Phase Acidities of Strong Brønsted Acids by ONIOM Method

AbstractThe gas‐phase acidities of very strong neutral Brønsted acids are estimated based on Gaussian theory and two‐layer ONIOM calculations. Although the calculated gas‐phase acidities using Gaussian theory are in excellent agreement with the experimental values, these high‐level calculations are limited to small molecules because of their high computational cost. ONIOM calculation with the smallest model system, where only the acid center is placed in the high layer, gives relatively poor results. In contrast, ONIOM calculation with a model system expanded to neighbor atoms or the next neighbor atoms of the acid center gives estimates of gas‐phase acidities with practically useful accuracy.

QM and QM/MM study on inhibition mechanism of polyphenolic compounds as non-classical inhibitors of α-human carbonic anhydrase (II)

Phenolic and polyphenolic compounds are distributed in plant tissues as a secondary metabolite which are compromised in multiple and imperative physiological phenomena. Herein, inhibition mechanism of human carbonic anhydrase isoform II, hCAII, with seven phenolic compounds including phenol, catechol, resorcinol, 4-methyl catechol, vanillic acid, trans-cinnamic acid and ortho-coumaric acid has been investigated using quantum mechanical and ONIOM calculations. B3LYP-D3/6–311++G** method has been employed to calculate the electronic structure and electronic energy of different species through the reaction mechanism path. The model system of hCAVII has been used that includes the core of the catalytic center, Zn2+, binds to three histidine residues and a hydroxide ion or water molecule forming a first coordination shell. Thr199 and Glu106 were considered as neighboring residues to the ones binding zinc. All thermodynamic functions through the reaction path are evaluated in different phases. The calculated results indicate that all phenolic inhibitors do not directly interact with the zinc ion in the CA active center, and the presence of aromatic moieties was associated with more effective inhibition. In addition, the implicit and explicit solvent effect has been considered for water solvent using QM and ONIOM (QM/MM) calculations.

Interaction poses, intermolecular forces, dynamic preferences between flavonoids and maltosyl-β-cyclodextrin

Cyclodextrins (CDs) can improve the solubility and stability of flavonoids by forming supramolecular complexes. However, the detailed inclusion mechanism has not been fully elucidated. In this study, the binding ability of eight flavonoids with four common CDs (α-, β-, methyl-β-, γ-CD) was investigated. Then, the interaction characteristics of two flavonoids (Dihydromyricetin (DMY) and Naringenin) with M-β-CD were further explored by using phase solubility, ultraviolet, infrared, X-ray diffraction, differential scanning calorimetry, molecular docking and ONIOM calculations. The results indicated that the molecular volume of flavonoids and the cavity size of CDs have distinct effects on the host-guest interaction. DMY and Naringenin form stable supramolecular complexes with M-β-CD mainly through hydrophobic interactions and Van der Waals forces. In addition, the stability of the Naringenin/m-β-CD is higher than that of DMY/M-β-CD, which is consistent with the experimental stability constant. Both of the above flavonoids entered the large hole of the hydrophobic cavity of M-β-CD through one end of the B-ring, which has a significant contribution to the formation of the host-guest hydrogen bonds. Taken together, this study is helpful to further understand the interaction mechanism between CDs and guest molecules, expand the application of CDs, and promote the utilization of natural active compounds.

Interactive Regulation between Aliphatic Hydroxylation and Aromatic Hydroxylation of Thaxtomin D in TxtC: A Theoretical Investigation.

TxtC is an unusual bifunctional cytochrome P450 that is able to perform sequential aliphatic and aromatic hydroxylation of the diketopiperazine substrate thaxtomin D in two distinct sites to produce thaxtomin A. Though the X-ray structure of TxtC complexed with thaxtomin D revealed a binding mode for its aromatic hydroxylation, the preferential hydroxylation site is aliphatic C14. It is thus intriguing to unravel how TxtC accomplishes such two-step catalytic hydroxylation on distinct aliphatic and aromatic carbons and why the aliphatic site is preferred in the hydroxylation step. In this work, by employing molecular docking and molecular dynamics (MD) simulation, we revealed that thaxtomin D could adopt two different conformations in the TxtC active site, which were equal in energy with either the aromatic C20-H or aliphatic C14-H pointing toward the active Cpd I oxyferryl moiety. Further ONIOM calculations indicated that the energy barrier for the rate-limiting hydroxylation step on the aliphatic C14 site was 9.6 kcal/mol more favorable than that on the aromatic C20 site. The hydroxyl group on the monohydroxylated intermediate thaxtomin B C14 site formed hydrogen bonds with Ser280 and Thr385, which induced the l-Phe moiety to rotate around the Cβ-Cγ bond of the 4-nitrotryptophan moiety. Thus, it adopted an energetically favorable conformation with aromatic C20 adjacent to the oxyferryl moiety. In addition, the hydroxyl group induced solvent water molecules to enter the active site, which propelled thaxtomin B toward the heme plane and resulted in heme distortion. Based on this geometrical layout, the rate-limiting aromatic hydroxylation energy barrier decreased to 15.4 kcal/mol, which was comparable to that of the thaxtomin D aliphatic hydroxylation process. Our calculations indicated that heme distortion lowered the energy level of the lowest Cpd I α-vacant orbital, which promoted electron transfer in the rate-limiting thaxtomin B aromatic hydroxylation step in TxtC.

Remote Water‐Mediated Proton Transfer Triggers Inter‐Cu Electron Transfer: Nitrite Reduction Activation in Copper‐Containing Nitrite Reductase

AbstractThe copper‐containing nitrite reductase (CuNiR) catalyzes the biological conversion of nitrite to nitric oxide; key long‐range electron/proton transfers are involved in the catalysis. However, the details of the electron‐/proton‐transfer mechanism are still unknown. In particular, the driving force of the electron transfer from the type‐1 copper (T1Cu) site to the type‐2 copper (T2Cu) site is ambiguous. Here, we explored the two possible proton‐transfer channels, the high‐pH proton channel and the primary proton channel, by using two‐layered ONIOM calculations. Our calculation results reveal that the driving force for electron transfer from T1Cu to T2Cu comes from a remote water‐mediated triple‐proton‐coupled electron‐transfer mechanism. In the high‐pH proton channel, the water‐mediated triple‐proton transfer occurs from Glu113 to an intermediate water molecule, whereas in the primary channel, the transfer is from Lys128 to His260. Subsequently, the two channels employ another two or three distinct proton‐transfer steps to deliver the proton to the nitrite substrate at the T2Cu site. These findings explain the detailed proton‐/electron‐transfer mechanisms of copper‐containing nitrite reductase and could extend our understanding of the diverse proton‐coupled electron‐transfer mechanisms in complicated proteins.

Theoretical DFT study on metal–organic frameworks for hydrogen storage

The cluster approach has been applied to mimic metal–organic framework (MOF) structures formed by 1,4-benzenecarboxylate linkers and metal cation connectors. The geometry optimizations are carried out at B3LYP/6-31G* level followed by frequency calculations. It was found that the replacement of OBe46+ connectors with OMg46+ (or OZn46+) ones leads to an increase in both the unit-cell sizes and basicity of oxide sites making them more potential for molecular hydrogen storage applications. Within the selected secondary building units (larger cluster models), the above replacement does not lead to an alteration on conduction and valence bands as well as in the resulting bandgap values. Bottleneck point of these structures is due to the presence of the so-called “central bulk” fourfold coordinated tetrahedral oxide anion site. The latter can be efficiently removed via replacement to “distorted cubic core” by introducing ZnTi3O46+ or MgTi3O46+ connectors which can be further replaced by MgSi3O46+ units. The all threefold coordinated O3C sites formed act as potential adsorption sites for incoming hydrogen molecules. Two-layer ONIOM (MP2/6-31G*: HF/3-21G) calculations have shown that the binding energies of molecular hydrogen lie within 5.5 and 5.3 kJ/mol for the MOF structures with MgTi3O46+ and MgSi3O46+ connectors, respectively.

Insights into the Direct Oxidative Repair of Etheno Lesions: MD and QM/MM Study on the Substrate Scope of ALKBH2 and AlkB

E. coli AlkB and human ALKBH2 belong to the AlkB family enzymes, which contain several α-ketoglutarate (α-KG)/Fe(II)-dependent dioxygenases that repair alkylated DNA. Specifically, the AlkB enzymes catalyze decarboxylation of α-KG to generate a high-valent Fe(IV)-oxo species that oxidizes alkyl groups on DNA adducts. AlkB and ALKBH2 have been reported to differentially repair select etheno adducts, with preferences for 1,N6-ethenoadenine (1,N6-εA) and 3,N4-ethenocytosine (3,N4-εC) over 1,N2-ethenoguanine (1,N2-εG). However, N2,3-ethenoguanine (N2,3-εG), the most common etheno adduct, is not repaired by the AlkB enzymes. Unfortunately, a structural understanding of the differential activity of E. coli AlkB and human ALKBH2 is lacking due to challenges acquiring atomistic details for a range of substrates using experiments. This study uses both molecular dynamics (MD) simulations and ONIOM(QM:MM) calculations to determine how the active site changes upon binding each etheno adduct and characterizes the corresponding catalytic impacts. Our data reveal that the preferred etheno substrates (1,N6-εA and 3,N4-εC) form favorable interactions with catalytic residues that situate the lesion near the Fe(IV)-oxo species and permit efficient oxidation. In contrast, although the damage remains correctly aligned with respect to the Fe(IV)-oxo moiety, repair of 1,N2-εG is mitigated by increased solvation of the active site and a larger distance between Fe(IV)-oxo and the aberrant carbons. Binding of non-substrate N2,3-εG in the active site disrupts key DNA–enzyme interactions, and positions the aberrant carbon atoms even further from the Fe(IV)-oxo species, leading to prohibitively high barriers for oxidative catalysis. Overall, our calculations provide the first structural insight required to rationalize the experimentally-reported substrate specificities of AlkB and ALKBH2 and thereby highlight the roles of several active site residues in the repair of etheno adducts that directly correlates with available experimental data. These proposed catalytic strategies can likely be generalized to other α-KG/Fe(II)-dependent dioxygenases that play similar critical biological roles, including epigenetic and post-translational regulation.

Mechanistic insights of adenine promoted activity of low-molecule tyrosine phosphatase: An ONIOM study

The mechanistic role of adenine, which assists the catalytic activity of low-molecular weight phosphatases, has been investigated using ONIOM calculations. Results confirm the dephosphorylation step being the rate-limiting step. In the absence and presence of adenine, the energy barriers of the rate-limiting step are 16.0 kcal/mol and 14.3 kcal/mol respectively, in agreement with experimental data. The formation of the favorable hydrogen bond contributes to the decreasing of barrier energy, resulting in the optimized attacking angle of the nucleophile. These results support the notion that adenine disfavors the formation of adverse hydrogen bond, which enables more effective hydrolyzation of phosphoenzyme intermediate.

Mechanistic Insights into the Regio- and Stereoselectivities of Testosterone and Dihydrotestosterone Hydroxylation Catalyzed by CYP3A4 and CYP19A1.

The hydroxylation of nonreactive C−H bonds can be easily catalyzed by a variety of metalloenzymes, especially cytochrome P450s (P450s). The mechanism of P450 mediated hydroxylation has been intensively studied, both experimentally and theoretically. However, understanding the regio‐ and stereoselectivities of substrates hydroxylated by P450s remains a great challenge. Herein, we use a multi‐scale modeling approach to investigate the selectivity of testosterone (TES) and dihydrotestosterone (DHT) hydroxylation catalyzed by two important P450s, CYP3A4 and CYP19A1. For CYP3A4, two distinct binding modes for TES/DHT were predicted by dockings and molecular dynamics simulations, in which the experimentally identified sites of metabolism of TES/DHT can access to the catalytic center. The regio‐ and stereoselectivities of TES/DHT hydroxylation were further evaluated by quantum mechanical and ONIOM calculations. For CYP19A1, we found that sites 1β, 2β and 19 can access the catalytic center, with the intrinsic reactivity 2β>1β>19. However, our ONIOM calculations indicate that the hydroxylation is favored at site 19 for both TES and DHT, which is consistent with the experiments and reflects the importance of the catalytic environment in determining the selectivity. Our study unravels the mechanism underlying the selectivity of TES/DHT hydroxylation mediated by CYP3A4 and CYP19A1 and is helpful for understanding the selectivity of other substrates that are hydroxylated by P450s.

Using ONIOM calculations to investigate the abilities of simple and nitrogen, boron, sulfur‐doped carbon nanotubes in sensing of carbon monoxide

AbstractIn this work, geometries, stabilities, and electronic properties of the carbon monoxide (CO) molecule as an adsorbent in a simple carbon nanotube (CNT) and nitrogen (N), boron (B), sulfur (S)‐doped CNTs (NCNT, BCNT, and SCNT) with parallel and perpendicular configurations are fully considered using ONIOM, natural bond orbital, and quantum theory of atom in molecule (QTAIM) calculations. The adsorption energies (Ead) demonstrate that a CO molecule could be adsorbed on the surface of the simple CNT with parallel configuration and N‐doped CNT with perpendicular configuration in an exothermic process. QTAIM calculations showed the close‐shell (noncovalent) interactions between the CO molecule and CNT or N, B, S‐doped CNTs. In addition, the energy gap (Eg) values between the highest occupied molecular orbital and the lowest unoccupied molecular orbital are calculated. In accordance with the results of energy gap, simple and N‐doped CNTs could be used as CO sensors.

Conversion of methanol to dimethyl ether over silicoaluminophosphates: Isolated acid sites and the influence of silicon islands. A DFT-ONIOM study

Abstract ONIOM(DFT:PM3) calculations were analyzed here in order to examine if, and how the isolated Bronsted acid sites, the silicon islands and the pore diameter affect the activation energies in the dimethyl ether formation from methanol for a series of silicoaluminophosphate (SAPO) molecular sieves, SAPO-5, SAPO-11, SAPO-34 and SAPO-41. Three density functionals were employed: B3LYP, ωB97X and ωB97X-D. The results revealed that the CH3OH adsorption energy increases with the type of functional used, according to the trend B3LYP