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This paper systematically examines the performance of contemporary wavefunction and density functional theory methods to identify robust and cost-efficient methods for predicting gas-phase anion binding energies. This includes the local coupled cluster LNO-CCSD(T) and DLPNO-CCSD(T), as well as double-hybrid DSD-PBEP86-D3(BJ) and various hybrid functionals M06-2X, B3LYP-D3(BJ), ωB97M-V, and ωB97X-V. The focus is on dual-hydrogen-bonding anion receptors that are commonly found in supramolecular chemistry and organocatalysis, namely, (thio)ureas, deltamides, (thio)squaramides, and croconamides as well as the yet-to-be-explored rhodizonamides. Of the methods examined, M06-2X emerged as the overall best performing method as the other functionals including DSD-PBEP86-D3(BJ) and the local coupled cluster DLPNO-CCSD(T) method displayed systematic errors that increase with the degree of carbonylation of the receptors. Hybrid ONIOM models that employed semiempirical methods (PM7, GFN1-xTB, and GFN2-xTB) and "threefold"-corrected small-basis set potentials (HF-3c, B97-3c, and PBEh-3c) were explored, and the best models resulted in 50- to 500-fold reduction in CPU time compared to W1-local. These calculations provide important insight into the structure-binding relationships where there is a direct correlation between Brønsted acidity and anion binding affinity, though the strength of the correlation also depends on other factors such as hydrogen-bonding geometry and the geometrical distortion that the receptor needs to undergo to bind the anion.

Catalytic fields representing the topology of the optimal molecular environment charge distribution that reduces the activation barrier have been used to examine alternative reaction variants and to determine the role of conserved catalytic residues for two consecutive reactions catalyzed by the same enzyme. Until now, most experimental and conventional top-down theoretical studies employing QM/MM or ONIOM methods have focused on the role of enzyme electric fields acting on broken bonds of reactants. In contrast, our bottom-up approach dealing with a small reactant and transition-state model allows the analysis of the opposite effects: how the catalytic field resulting from the charge redistribution during the enzyme reaction acts on conserved amino acid residues and contributes to the reduction of the activation barrier. This approach has been applied to the family of histidyl tRNA synthetases involved in the translation of the genetic code into the protein amino acid sequence. Activation energy changes related to conserved charged amino acid residues for 12 histidyl tRNA synthetases from different biological species allowed to compare on equal footing the catalytic residues involved in ATP aminoacylation and tRNA charging reactions and to analyze different reaction mechanisms proposed in the literature. A scan of the library of atomic multipoles for amino acid side-chain rotamers within the catalytic field pointed out the change in the Glu83 conformation as the critical catalytic effect, providing, at low computational cost, insight into the electrostatic preorganization of the enzyme catalytic site at a level of detail that has not yet been accessible in conventional experimental or theoretical methods. This opens the way for rational reverse biocatalyst design at a very limited computational cost without resorting to empirical methods.

Peptide bond formation in living cells occurs at the peptidyl transferase center (PTC) of the large ribosomal subunit and involves the transfer of the peptidyl group from peptidyl-tRNA to aminoacyl-tRNA. Despite numerous kinetic and theoretical studies, many details of this reaction -such as whether it proceeds via a stepwise or concerted mechanism- remain unclear. In this study, we calculated the geometry and energy of the transition states and intermediates in peptide bond formation in the PTC environment using the ONIOM (our own n-layered integrated molecular orbital and molecular mechanics) method. The calculations indicated that the energy of the transition states of stepwise mechanisms are lower than those of concerted mechanisms and suggested that the reaction involves a neutral tetrahedral intermediate that is stabilized through the hydrogen-bonding network in the PTC environment. The results will lead to a better understanding of the mechanism of peptidyl transfer reaction, and resolve fundamental questions of the steps and molecular intermediates involved in peptide bond formation in the ribosome.

A multi-environment computational approach is proposed to study the modulation of the emission behavior of the triphenylamine (Z)-4-benzylidene-2-methyloxazol-5(4H)-one (TPA-BMO) molecule [Tang et al., J. Phys. Chem. C 119, 21875 (2015)]. We aim at (1) proposing a realistic description of the molecule in several environments (solution, aggregate, polymer matrix), (2) modelling its absorption and emission properties, and (3) providing a qualitative understanding of the experimental observations by highlighting the photophysical phenomena leading to the emission modulation. To this purpose, we rely on (TD-)DFT calculations and classical Molecular Dynamics simulations, but also on the hybrid ONIOM QM/QM' approach and the in situ chemical polymerization methodology. In low-polar solvents, the investigation of the potential energy surfaces and the modulation of the emission quantum yield can be attributed to possible photophysical energy dissipation caused by low-frequency vibrational modes. In the aggregate and in the polymer matrix, the emission modulation can be qualitatively interpreted in terms of the possible restriction of the intramolecular vibrations. For these two systems, our study highlights that a careful modelling of the environment is far from trivial but is fundamental to model the optical properties of the fluorophore.

SARS-CoV-2 Mpro, also known as the main protease or 3C-like protease, is a key enzyme involved in the replication process of the virus that is causing the COVID-19 pandemic. It is also the most promising antiviral drug target targeting SARS-CoV-2 virus. In this work, the catalytic mechanism of Mpro was studied using the full model of the enzyme and a computational QM/MM methodology with a 69/72-atoms QM region treated at DLPNO-CCSD(T)/CBS//B3LYP/6-31G(d,p):AMBER level and including the catalytic important oxyanion-hole residues. The transition state of each step was fully characterized and described together with the related reactants and products. The rate-limiting step of the catalytic process is the hydrolysis of the thioester-enzyme adduct, and the calculated barrier closely agrees with the available kinetic data. The calculated Gibbs free energy profile, together with the full atomistic detail of the structures involved in catalysis, can now serve as valuable models for the rational drug design of transition state analogs as new inhibitors targeting the SARS-CoV-2 virus. Graphic abstract Supplementary Information The online version contains supplementary material available at 10.1007/s11030-021-10259-7.

Mycobacterium tuberculosis cell wall is intricate and impermeable to many agents. A D, D-carboxypeptidase (DacB1) is one of the enzymes involved in the biosynthesis of cell wall peptidoglycan and catalyzes the terminal D-alanine cleavage from pentapeptide precursors. Catalytic activity and mechanism by which DacB1 functions is poorly understood. Herein, we investigated the acylation mechanism of DacB1 by β-lactams using a 6-membered ring transition state model that involves a catalytic water molecule in the reaction pathway. The full transition states (TS) optimization plus frequency were achieved using the ONIOM (B3LYP/6-31 + G(d): AMBER) method. Subsequently, the activation free energies were computed via single-point calculations on fully optimized structures using B3LYP/6-311++(d,p): AMBER and M06-2X/6-311++(d,p): AMBER with an electronic embedding scheme. The 6-membered ring transition state is an effective model to examine the inactivation of DacB1 via acylation by β-lactams antibiotics (imipenem, meropenem, and faropenem) in the presence of the catalytic water. The ΔG# values obtained suggest that the nucleophilic attack on the carbonyl carbon is the rate-limiting step with 13.62, 19.60 and 30.29 kcal mol−1 for Imi–DacB1, Mero–DacB1 and Faro–DacB1, respectively. The electrostatic potential (ESP) and natural bond orbital (NBO) analysis provided significant electronic details of the electron-rich region and charge delocalization, respectively, based on the concerted 6-membered ring transition state. The stabilization energies of charge transfer within the catalytic reaction pathway concurred with the obtained activation free energies. The outcomes of this study provide important molecular insight into the inactivation of D, D-carboxypeptidase by β-lactams. Communicated by Ramaswamy H. Sarma

On the basis of density functional theory (DFT) calculations within the framework of the ONIOM method, here we report a new bimolecular mechanism for understating dihydrogen activation using the β-diketiminate (BDI)-ligated Group 13 metal complexes. In parallel with the termolecular Lewis acid–base cooperative mechanism proposed previously (J. Catal., 2019, 373, 1–12), this bimolecular stepwise mechanism, consisting of the initial intramolecular 1,4′-addition of dihydrogen to the BDI-ligated gallium complex followed by the intermolecular 4′,4-H-shift, could be also employed to rationalize the experimental observation. On the other hand, mechanisms and activity difference between the BDI-supported Group 13 and 14 elements, as well as the solvent effect on the aspect of the dihydrogen activation were also comparatively investigated. Differing from the aluminum and gallium complexes, dihydrogen activation over the silylene or germylene carbene analogue tends to occur via the termolecular cooperative mechanism. However, silicon and germanium ligated BDI analogues are demonstrated to be less effective in dihydrogen activation, owing to the smaller atomic radius, the weaker hydride affinity and the larger nonbonded repulsion effect from the intrinsic lone-pair electrons. Moreover, it was found that solvent media have a moderate impact on dihydrogen activation. The non-polar solvent might be more beneficial for the H–H bond cleavage and the intermolecular proton migration in the gallium system.

The research aims to help reduce the enormous post-harvest losses of rice or bananas in Cote d’Ivoire. It focuses on the breakdown mechanism of their starch. This process contributes to their decay. This study wants to elucidate it; to do this, it analyzes the tetra or penta saccharide reactions with the water or dioxide carbon. It calculates the geometric, energetic and spectroscopic parameters at the ONIOM level (B3LYP/6-311++G [d, p]: AM1). These quantities allow establishing that oxygen represents the privileged hydrogen bond (HB) site for amylose with four or five D-glucose building blocks. They suggest and are respectively those of amylopectin when the latter consists of four and five D-glucose synthons. They prove that amylose deteriorates before it; the degradation of starch begins with its alteration into disaccharides. It continues with that of amylopectin into tri or tetra-saccharides with four or five building blocks.

In this paper, we employed first-principles methods and the QM/MM technique to study the thermally activated delayed fluorescence (TADF) phenomenon of a near-infrared molecule (PIPAQ) in vacuum, solution, and the aggregation state. Our calculated results show that (1) the cluster can decrease the energy gap between the first singlet excited state (S1) and the first triplet state (T1) compared with the monomer, furthermore, the T1 state and S1 state in the cluster are energetically closer to each other, which implies that the energy gap is smaller in comparison with that in solution and can promote the intersystem crossing (ISC) process due to the surrounding effect; (2) the optimally tuned range-separated functional is applicable to simulation of excited states and the outcomes are in good agreement with experimental values; (3) the reorganization energies associated with ISC and the reverse intersystem crossing (RISC) processes between the S1 and T1 states are sensitive to the calculated methods and the environments, and thus the following calculated ISC and RISC rates vary dramatically according to different reorganization energies; (4) all radiative and nonradiative rates are insensitive to temperature, but sensitive to environments, all the radiative rates increase in the cluster while the nonradiative rates decrease, which enhances the fluorescence quantum efficiency and agrees with the observed value. The above results demonstrate that the surrounding effects are very important for modulating the photophysical properties of the PIPAQ compound. Finally, this studied conclusion can give a helpful insight into the TADF mechanism for the title compounds, by which novel TADF materials with excellent performance could be rationally designed.

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.

The reaction for the formation of the xuxuarine Aα triterpene dimer in an aqueous medium was studied using the ONIOM/CPCM-X scheme at the ONIOM(M06-2X/6-31G(d,p):PM6) level of theory, along with the inclusion of one and two explicit water molecules. The results show that the geometry of the water molecules in the complex of reactants switches the mechanism from a one-step to a two-step hetero Diels–Alder (HDA) reaction. The reaction begins with a Michael addition assisted by water, which is the rate-limiting step. Then, nucleophilic addition–protonation involving nucleophilic attack at the positive carbon center of the carbonyl group takes place. The two-step mechanism has an activation free energy that is 4.7 kcal mol−1 lower than the one-step mechanism, providing evidence of an alternative two-step water-assisted reaction for the biogenic origin of triterpene dimers.

Binding energies of the CH3O radical on hexagonal water ice (Ih) and amorphous solid water (ASW) were calculated using the ONIOM(QM:MM) method. A range of binding energies is found (0.10-0.50 eV), and the average binding energy is 0.32 eV. The CH3O radical binding on the ASW surfaces is stronger than on the Ih surfaces. The computed binding energies from the ONIOM(wB97X-D/def2-TZVP:AMBER) and wB97X-D/def2-TZVP methods agree quite well. Therefore, the ONIOM(QM:MM) method is expected to give accurate binding energies at a low computational cost. Binding energies from the ONIOM(wB97X-D/def2-TZVP:AMBER) and ONIOM(wB97X-D/def2-TZVP:AMOEBA09) methods differ noticeably, indicating that the choice of force field matters. According to the energy decomposition analysis, the electrostatic interactions and Pauli repulsions between the CH3O radical and ice play a crucial role in the binding energy. This study gives quantitative insights into the CH3O radical binding on interstellar ices.

Esterification of citric acid (CA) with the primary alcohols and the hydroxyl groups of cellulose chain (n = 1-2) in parched condition were investigated by using density functional theory (DFT) method and a two-layer ONIOM approach. Geometry and energy of reactants, products, and transition state (TS) structures were optimized at B3LYP/6-311g (d, p) level and ONIOM (B3LYP/6-311g (d, p):PM3MM) level. The computational results show that the esterification occurs in the two main steps: the first step is the dehydration reaction of CA to form anhydrides of 5-membered ring and 6-membered ring and the second step is the ring opening reaction with the hydroxyl –OH groups to form the ester products. The energy barrier of dehydration reaction step is much higher than that of ring opening reaction step. Effect of substituent R in primary alcohol R-CH2OH (R: CH=CH2, CH2NHCH3, CH2OCH3, CH2Cl) and cellulose chain (1G, 2G) on the reactivity, which has negative inductive effect –I, is significant. The combination of calculation data and experiment data were applied to make findings more rigorous. The activation energy of CA was determined by using differential scanning calorimetry (DSC) and thermal gravimetric (TG) analysis to be E a exp = 47.8 kcal/mol; the experimental data favoured the dehydration reaction step of CA.

Conventional protein:ligand crystallographic refinement uses stereochemistry restraints coupled with a rudimentary energy functional to ensure the correct geometry of the model of the macromolecule—along with any bound ligand(s)—within the context of the experimental, X-ray density. These methods generally lack explicit terms for electrostatics, polarization, dispersion, hydrogen bonds, and other key interactions, and instead they use pre-determined parameters (e.g. bond lengths, angles, and torsions) to drive structural refinement. In order to address this deficiency and obtain a more complete and ultimately more accurate structure, we have developed an automated approach for macromolecular refinement based on a two layer, QM/MM (ONIOM) scheme as implemented within our DivCon Discovery Suite and "plugged in" to two mainstream crystallographic packages: PHENIX and BUSTER. This implementation is able to use one or more region layer(s), which is(are) characterized using linear-scaling, semi-empirical quantum mechanics, followed by a system layer which includes the balance of the model and which is described using a molecular mechanics functional. In this work, we applied our Phenix/DivCon refinement method—coupled with our XModeScore method for experimental tautomer/protomer state determination—to the characterization of structure sets relevant to structure-based drug design (SBDD). We then use these newly refined structures to show the impact of QM/MM X-ray refined structure on our understanding of function by exploring the influence of these improved structures on protein:ligand binding affinity prediction (and we likewise show how we use post-refinement scoring outliers to inform subsequent X-ray crystallographic efforts). Through this endeavor, we demonstrate a computational chemistry ↔ structural biology (X-ray crystallography) "feedback loop" which has utility in industrial and academic pharmaceutical research as well as other allied fields. Electronic supplementary material The online version of this article (10.1007/s10822-020-00354-6) contains supplementary material, which is available to authorized users.

In this study, we have considered the interaction of aromatic amino acids (AAAs), i.e., Phenylalanine (Phen), Histidine (His), Tyrosine (Tyr), and Tryptophan (Trp), with different Gallium Nitride Nanotubes (GaNNTs). For optimization, we have used molecular mechanics (MM) method for GaNNTs and density functional theory (DFT) for aromatic amino acids respectively. We have investigated the interaction between AAAs and GaNNTs using ONIOM methods. We have found that aromatic amino acids are well encapsulated inside the wall of the GaNNTs. For different structures of GaNNTs chiral (10, 5), (12, 6) and armchair (10, 10), (12, 12) it has been found that the adsorption energy (Eads) of all AAAs range from -24.058 to -60.907 kcal/mol.

The mechanism of oxidation of N-heterocycle phthalazine to phthalazin-1(2H)-one and its associated free energy profile, catalyzed by human aldehyde oxidase (hAOX1), was studied in atomistic detail ...

The solid-state structures of three H-bonded enol forms of 5-substituted 9-hydroxyphenalenones were investigated to accurately determine the H atom positions of the intramolecular hydrogen bond. For this purpose, single-crystal X-ray diffraction (SC-XRD) data were evaluated by invariom-model refinement. In addition, QM/MM computations of central molecules in their crystal environment show that results of an earlier standard independent atom model refinement, which pointed to the presence of a resonance-assisted hydrogen bond in unsubstituted 9-hydroxyphenalone, are misleading: in all our three and the earlier solid-state structures the lowest energy form is that of an asymmetric hydrogen bond (CS form). Apparent differences of results from SC-XRD and other analytical methods are explained.

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., Selective insertion: The results of a theoretical study on the selective hydroxylation of testosterone and dihydrotestosterone by CYP3A4 and CYP19A1 is reported (see scheme).

The cycloaddition of CO2 with epoxides catalyzed by ionic liquids (ILs) has been a widely ongoing studied hot topic over the years. Recent experimental research has shown that the protic ionic liquids (PILs) behave stronger hydrogen proton donating ability than aprotic ionic liquids (APILs), and can effectively catalyze the cycloaddition of CO2. Unfortunately, the mechanistic explanation remains primarily unraveled. Herein, a detailed simulation study on the cycloaddition reaction catalyzed by PIL ([HDBU][Mim]) in comparison with APIL ([MeDBU][Mim]) reaction catalysts was conducted, including the three-step route (ring-opening of PO (propylene oxide), insertion of CO2 and ring-closure of propylene carbonate (PC)) and two-step route (simultaneously ring-opening of PO and addition of CO2, and then ring-closure of PC). Based on the activation energy barrier of the rate-determining step, PIL preferentially activates PO as the optimal route for the reaction with the energy barrier of 23.2 kcal mol-1, while that of APIL is 31.2 kcal mol-1. The role of [HDBU]+ in the reaction was also explored and found that the direct formation of intermolecular hydrogen bond (H-bond) between [HDBU]+ and the reactants (PO + CO2) was unfavorable for the reaction, while the cooperation with the anion [Mim]- to assist indirectly was more conducive. To fully consider the reaction microenvironment of ILs, ONIOM calculation was used to study the solvent effect. At last, the above conclusions were further verified by the analysis of intermediates with charge, non-covalent interaction (NCI), and atoms in molecules (AIM) methods. The computational findings show that ILs studied in this work have dual functions of catalyst and solvent, enabling a microscopic understanding of the ILs catalyst for CO2 utilization as well as providing guidance for the rational design of more efficient ILs-based catalysts.

Heme is located in the active site of proteins and has diverse and important biological functions, such as electron transfer and oxygen transport and/or storage. The distortion of heme porphyrin is considered an important factor for the diverse functions of heme because it correlates with the physical properties of heme, such as oxygen affinity and redox potential. Therefore, clarification of the relationship between heme distortion and the protein environment is crucial in protein science. Here, we analyzed the fluctuation in heme distortion in the protein environment for hemoglobin and myoglobin using molecular dynamics (MD) simulations and quantum mechanical (QM) calculations. We also investigated the protein structures of hemoglobin and myoglobin stored in Protein Data Bank and found that heme is distorted along the doming mode, which correlates with its oxygen affinity, more prominently in the protein environment than in the isolated state, and the magnitude of distortion is different between hemoglobin and myoglobin. This tendency was also observed in the results of MD simulations and QM calculations. These results suggest that heme distortion is affected by its protein environment and fluctuates around its fitted conformation, leading to physical properties that are appropriate for protein functions.

The catalytic mechanism of Pdx2 was herein studied with atomic detail employing the computational ONIOM hybrid QM/MM methodology. Pdx2 employs a Cys-His-Glu catalytic triad to deaminate glutamine to glutamate and ammonia-the source of the nitrogen of pyridoxal 5'-phosphate(PLP). This enzyme is, therefore, a rate-limiting step in the PLP biosynthetic pathway of Malaria and Tuberculosis pathogens. For this reason,Pdx2 is considered a novel and promising drug target to treat these diseases. The results herein obtained show that the catalytic mechanism of Pdx2 occurs in six steps that can be divided into four stages: (i) activation of Cys87, (ii) deamination of glutamine with the formation of the glutamyl-thioester intermediate, (iii) hydrolysis of the formed intermediate, and (iv) enzymatic turnover. The kinetic data available in the literature(19.1-19.5 kcal mol-1) agrees very well with the calculated free energy barrier of the hydrolytic step(18.2 kcal.mol-1), which is the rate-limiting step of the catalytic process when substrate is readily available in the active site. This catalytic mechanism differs from other known amidases in three main points: i)it requires the activation of the nucleophile Cys87 to a thiolate; ii)the hydrolysis occurs in a single step and therefore does not require the formation of a second tetrahedral reaction intermediate, as it is proposed, and iii)Glu198 does not have a direct role in the catalytic process.

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 connects to thermodynamically stable intermediates. Extensive computational screening-modelling were then done on various substrate combinations designed to study 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 order of Br > Cl > F in agreement of the strength of C–X bonds. However, DFT modelling suggests that chlorides can be a viable substrate for the SN2X process which should be further explored experimentally. Finally, ONIOM calculations on the full catalyst model were carried out to rationalize the stereoselectivity which corroborates with experimental results.

The study of photoexcitations in molecular aggregates faces the twofold problem of the increased computational cost associated with excited states and the complexity of the interactions among the constituent monomers. A mechanistic investigation of these processes requires the analysis of the intermolecular interactions, the effect of the environment, and 3D arrangements or crystal packing on the excited states. A considerable number of techniques have been tailored to navigate these obstacles; however, they are usually restricted to in‐house codes and thus require a disproportionate effort to adopt by researchers approaching the field. Herein, we present the FRamewOrk for Molecular AGgregate Excitations (fromage), which implements a collection of such techniques in a Python library complemented with ready‐to‐use scripts. The program structure is presented and the principal features available to the user are described: geometrical analysis, exciton characterization, and a variety of ONIOM schemes. Each is illustrated by examples of diverse organic molecules in condensed phase settings. The program is available at https://github.com/Crespo-Otero-group/fromage., Accurately modeling the photoexcitations of molecular aggregates involves complementing excited state methodologies with auxiliary calculations. Due to the diversity of chemical and structural space in multimolecular complexes, these calculations require a high degree of adaptability which calls for the use of modular programming tools hitherto unavailable for the investigation of photochemical properties of molecular aggregates. The FRamewOrk for Molecular AGgregate Excitations (fromage), described herein, compiles geometry manipulation tools, exciton state characterization, and QM:QM′ models for geometry optimization.

The origin of aggregation-induced enhanced emission (AIEE) is investigated considering cyano-substituted 1,2-bis(pyridylphenyl)ethene (CNPPE) as an example. On the basis of ONIOM calculations using time-dependent density functional theory (TD-DFT), we found that pseudo-degeneracy of excimers formed in solid phase plays an important role in the appearance of AIEE. The electron density difference delocalized over molecules gives rise to small diagonal vibronic coupling constants (VCCs), which suggests that the internal conversion is more suppressed in the solid phase than in the solution phase. The reduction of the off-diagonal VCCs owing to the packing effect is elucidated by vibronic coupling density (VCD) analysis. Pseudo-degeneracy enables fluorescence from the high singlet excited states against Kasha's rule because the electron density difference and the overlap density between the excited states vanish. A Hubbard model of a pseudo-degenerate electronic system is constructed to explain the vanishing mechanism. We propose the following design principle for AIEE: a candidate molecule for AIEE should have pseudo-degenerate adiabatic electronic states in the aggregation phases originating from excimer formation.

The oxygen-dependent heme utilization degrading enzyme in Mycobacterium tuberculosis (MhuD) uniquely integrates monooxygenase and dioxygenase functions in a single active site. It cannot convert heme to biliverdin as canonical heme oxygenases but generates mycobilin without releasing carbon monoxide. Herein, by employing ONIOM calculations, we investigated the heme degradation mechanism of MhuD. Our calculations revealed that MhuD firstly follows a canonical monooxygenation mechanism to hydroxylate heme on the δ-meso carbon guided by the asparagine residue Asn7, which experiences a 21.2 kcal mol-1 energy barrier in the O-O cleavage rate-limiting step during the conversion process from ferric heme-hydroperoxy species to mycobilin. In the second degradation step, the ruffled conformation of oxoheme (oxoheme is the ferrous π radical complex formed by hydroxyheme experiencing deprotonation in the hydroxyl group and intramolecular electron transfer) imposed by the hydrophobic environment of the enzyme not only inhibits the continuing conversion of oxoheme to biliverdin but also endows the meso-carbons with radical characteristics, which turns the second degradation step to a dioxygenation reaction with 20.4 kcal mol-1 energy barrier. We further analysed the electronic structure change along the reaction process. Our calculation discovered that the ruffled structure of oxoheme is critical to the regiospecificity and even atom location selectivity, as well as the reaction mechanism of the degradation process.

Formation of cluster is a popular phenomenon for ionic liquids due to the strong interactions between cation and anion. It would definitely affect the intrinsic properties of ionic liquids and its catalytic activity. Taken the coupling reaction of carbon dioxide and propylene oxide as an example, the effect of quaternary ammonium ionic liquids cluster on its catalytic performance is investigated by combination of ONIOM and molecular dynamics simulations, including quaternary ammonium ionic liquid, hydroxyl functionalized quaternary ammonium ionic liquid, protic quaternary ammonium ionic liquid, and protic hydroxyl functionalized quaternary ammonium ionic liquid. The influence of electrostatic interaction and covalent and non-covalent interactions on the catalytic activity is analyzed by natural bond orbital, electron localization function, and atoms in molecules to explore the critical factors to control the catalytic activity.

The study presents a comprehensive vibrational analysis of N -(4- n -pentyl-oxybenzylidene)-4′- n -hexylaniline liquid crystal molecule. The vibrational observations are supported by potential energy distribution analysis performed by VEDA. The optimized structure and the total electron density surface mapped with electrostatic potential were computed at the B3LYP/6–31 G level. A thorough comparative analysis of discernible modes, chemical reactivity, charge distribution, electrical properties, charge transfer, and hyperpolarizability was attempted using semi-empirical, Hartree-Fock, density functional theory and ONIOM (our own n-layered integrated molecular orbital and molecular mechanics) computational methods for the mentioned molecule.

Three implicit solvation models, the conductor-like polarizable continuum model (C-PCM), the conductor-like screening model (COSMO), and universal implicit solvent model (SMD), combined with a hybrid two layer QM/QM approach (ONIOM), were utilized to calculate the pKa values, using a direct thermodynamic scheme, of a set of Group 10 transition metal (TM) hydrides in acetonitrile. To obtain the optimal combination of quantum methods for ONIOM calculations with implicit solvation models, the influence of factors, such as the choice of density functional and basis set, the atomic radii used to build a cavity in the solvent, and the size of the model system in an ONIOM scheme, was examined. Additionally, the impact of Grimme's empirical dispersion correction and exact exchange was also investigated. The results were calibrated by experimental data. This investigation provides insight about effective models for the prediction of thermodynamic properties of TM-containing complexes with bulky ligands. © 2019 Wiley Periodicals, Inc.

The supermolecule approach has been used to model molecules embedded in a solid argon matrix. The interaction between the guest and the host atoms in the first solvation shell (FSS) are evaluated using density functional calculations while that beyond the FSS is incorporated using ONIOM calculations to extend the results of our previous study [F. Ito, J. Chem. Phys. 133 (2010) 214502]. The vibrational spectra of a formic acid dimer (FAD) in an Ar matrix was simulated using (FAD)-Arn clusters (n = 94–1095). Structural relaxation in the first solvation shell is crucial to quantitatively reproduce the matrix shifts of fundamental bands, according to calculations at the B971/6-31++G(3df,3pd) level. Moreover, the influence of the outer Ar atoms is negligible.

Six coordination complexes: {[H2NMe2][Co(CHO2)3]}n (1), [Co(bpy)(CHO2)2]n (2), [Cu(dmf)(CHO2)2]2 (3), {[H2NMe2][Cu(CHO2)3]}n (4), [H2NMe2]4[Fe4O2(dmf)4(SO4)6] (5) and [Co3(bpy)(SO4)3]n (6) have been efficaciously synthesized using solvothermal techniques and slow evaporation. Two compounds (5 and 6) containing the sulfate anion (SO42−) with iron (III) and cobalt (II) had never been described in the Cambridge Structural Database. In all complexes, the transition metal is hexacoordinated with a distorted octahedral geometry and displays a three-dimensional supramolecular architecture through hydrogen bonding interactions [N H⋯O]. Formate (CHO2−) and sulfate (SO42−) anions were very important to the assembly of the three-dimensional MOFs and can be regarded as the template for all structures. All metal-organic complexes were identified by single-crystal X-ray diffraction, elemental composition and Fourier-transform infrared spectroscopy. In this paper, we propose the PM7 and ONIOM calculations as two effective methods in the determination of hydrogen storage. The weight percentage (wt %) of the hydrogen stored in the small cavities of the PCPs studied were: (1) 1.03 wt %, (4) 1.01 wt %, (6) 0.28 wt %.

The mechanism for the cycloaddition of carbon dioxide and epoxides catalyzed by ionic liquids has been elucidated in lots of theoretical literature. It is well known that the calculated barrier height could not be compared with the activation energy. However, it is expected that the sequence of activity estimated by barrier height could be consistent with the experimental result. Actually, the calculated results are not accurate enough to be reliable. One of possible reasons is attributed to the improper treatment for the solvent effect. The solvent effect induced by ionic liquids is not carefully considered or neglected at all in most of previous theoretical studies. In this work, ionic liquids are really included in the catalytic system to consider the solvent effect by the ONIOM method along with the molecular dynamics simulations. When the solvent effect is considered, the theoretical reliability is greatly improved. More important, this model is suitable not only for non-protic ionic liquids but also for protic ones and not only for imidazolium ionic liquids but also for pyrazolium ionic liquids. The solvent effect aroused by epoxides is also considered by the same model.

We present a study on an indolo[3,2-b]carbazole derived macromolecule viz; ICZP5 formed through Suzuki coupling reaction. The synthesized polymer exhibits good thermal and photophysical properties. The semiconducting nature of the polymer has been confirmed by cyclic voltammetric and current-voltage analyses. Its ground-state optimized structure has been achieved by DFT/B3LYP/6-31G* calculations. ONIOM method has been used for the optimization of its dimer and tetramer structures. A well- organized ICZP5 immobilized filter paper strip has subsequently been designed which could sense Hg2+ under UV light; as a solid state sensor. Moreover, for the development of automated chemical systems and molecular scale computers, a reversible INHIBIT logic gate has been put forward which extends the scope of the designed polymer. The theoretical calculations on the sensing mechanism have also been highlighted.

The interaction of CO2, CO, H2O, N2, N2O and O2 with the isoreticular metal-organic frameworks [Co(bdc)(pz)]n and [Co(bdc)(bpy)]n was studied. The ONIOM (M06/6-31G(d)HF/6-31G(d)) was applied to determine the structural and thermodynamic changes produced by the interaction among these small molecules and the framework structures. All the calculated adsorption energies are in the range of van der Waals non-covalent interactions, both influenced by dipole-quadrupole and quadruple-quadrupole electrostatic forces as well as confinement effect due to the different cavity sizes. The Δ H ads values obtained for the adsorption of CO2, CO and N2O suggest that [Co(bdc)(pz)]n and [Co(bdc)(bpy)]n framework structures are potential materials for the capture of these gases at standard conditions, which [Co(bdc)(bpy)]n exhibits greater adsorptive selectivity of post-combustion CO2, with a CO2/N2 energy ratio around 150% higher than [Co(bdc)(pz)]n.

In this work, the supramolecular host-guest interaction of the prodrug Olsalazine (OLZ) and β-Cyclodextrin (β-CD) was examined experimentally and computationally. Experimentally, employing the UV–Vis spectroscopic method in aqueous media at various pH's, results obtained using the Benesi-Hilderbrand approach demonstrated that OLZ can form supramolecular inclusion complex with β-CD with stoichiometric ratio of 1:1. Furthermore, these results revealed that the formation of OLZ: β-CD complexes exhibited insignificant pH dependency in the range 5–8 with an average binding constant (Kb) of approximately 1 × 103 M−1. Computationally, geometry optimization of 1:1 OLZ: β-CD complexes was performed employing the ONIOM (DFT((ωB97XB)/6–31 + G(d)),SQM(PM3)) approach. Obtained results demonstrated that OLZ: β-CD complex is stabilized by the formation of intermolecular hydrogen bonds with an average length of approximately 1.8 A. Additionally, the stability of OLZ: β-CD complex was demonstrated employing ADMP molecular dynamic simulations over a timeframe of 500 fs. The molecularity of the supramolecular host-guest interaction between OLZ and β-CD is presented and interpreted in the essence of TD-DFT and molecular orbitals analyses.

Molecular dynamics simulation performed by the DFT/ONIOM method and X-ray photoemission spectroscopy (XPS) data were employed for studying the adsorbate-adsorbent interaction system in diesel desulfurization over Ag/MCM-41 produced from beach sand silica (MPI). The morphology and structure of the materials were characterized via powder X-ray diffraction (XRD), scanning transmission electron microscopy (STEM) and field emission scanning electron microscopy (FESEM) together with energy dispersive spectrometry (EDS) analysis. The results proved a high dispersion of different Ag nanodomains onto MCM-41 and their chemical interaction with support and sulfur compounds by π-complexation. The best fit of kinetic and equilibrium data to pseudo-second order (R2 > 0.99) and Langmuir models (R2 > 0.98), respectively, demonstrate the occurrence of chemisorptive/catalytic interactions with organosulfur compounds, as seen in the XPS results. Its adsorption capacity (qm = 31.25 mgS/g) was 10 times higher than that obtained for pure MCM-41 and double the qm for Ag/MCM-41(C) adsorbent from commercial silica. The computational modeling approach provided valuable insight towards molecular level understanding of the mechanism in aromatic S-compounds adsorption over functionalized MCM-41 and the role of Ag species in this process.

Residual oils and fats are promising renewable sources for the production of liquid fuels and the synthesis of various chemicals with significant life cycle and large-scale economic advantages over other biomass sources. Thus, oleic acid esterification was investigated on zeolites type FAU and sulfuric acid by kinetic, spectroscopic assessments and theoretical calculations using a hybrid ONIOM scheme. In the catalytic tests, the solid catalyst with the highest Si/Al (H-Y-80) ratio showed the highest catalytic activity for esterification (92% conversion) as compared to H-Y-5.2 (66% conversion), Na-Y (15% conversion) and homogeneous acid catalysis (89% conversion). The catalytic activity between different acid catalysts is discussed. It was observed that the acidity of the active sites and the hydrophobicity resulting from the Si/Al molar ratio influence the esterification conversion. Theoretical calcultations predicts that the voluminous confined space of the FAU zeolite perfectly accommodates the oleic acid molecule in the adsorption step (Eads = − 25.5 kJ mol−1) and the van der Waals interactions of the zeolite walls with the aliphatic chain help to accommodate the bulky molecule between the supercages. Experimental and theoretical results confirm that H-Y-80 zeolite applied in the esterification reaction can be an efficient catalyst in processes involving conversion of unsaturated fatty acids.

1,3,5-triisopropylbenzene (TIPB) has been employed as a model compound for evaluation of kinetics, diffusion, and deactivation of Y-zeolite during fluidized catalytic cracking. Given the wide experimental information regarding the TIPB cracking, this molecule has been selected for the thermodynamic evaluation of different cracking reactions taking into account the stability of proposed products and possible carbonium intermediates using molecular modeling by means of ONIOM method implemented in Gaussian 09. Computational results indicate that, although some products seem to be favored by Gibbs energy values, and relatively low enthalpy requirements, they are not main products in the real distribution given the instability of formed carbonium intermediates.

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.

Orientador: Nelson Henrique Morgon Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica Mestrado Físico-Química Mestre em Química

Alzheimer's disease is a progressive nervous system disorder linked to the presence of extracellular senile plaques. Extracellular senile plaques are mostly made up of 40-42 residues of amino acid-containing polypeptides known as \(\beta\)-peptides. The Theory of Chemical Reactivity, MEDT (Molecular Electron Density Theory), and Conceptual DFT were used to find descriptors that allowed QM:MM calculations with the ONIOM methodology to predict the sites of reactivity of the Alzheimer amyloid \(\beta\)-peptides A\(\beta\)40 and A\(\beta\)42.

Natural halogenated phenolic compounds are unique bioactive structures which share features and physicochemical properties with thyroid hormones, who are essential regulators of neurological development and metabolism processes. Also, these structures can be used as natural antioxidants to minimize the diseases related to oxidative stress. In this work, the binding affinity of 32 natural and synthetic halogenated bisphenols were investigated on thyroid hormone receptor-β (THR-β) using the molecular docking, MM/GBSA, molecular dynamics, and a rigorous three-layer ONIOM ((M06-2X/6-31G*:PM6:AMBER) calculation. The desirable potency is observed for binding of selected compounds to THR-β. The Met313, Asn331, and His435 are the main interacting residues in the binding cavity which involved in the hydrogen and halogen bond interactions with the ligands. The most potent candidate on binding to the active site of THR-β is presented with respect to the results of mentioned calculations. Moreover, the antioxidant activity of compounds has been investigated using the quantum mechanical calculations. The electrostatic potential surfaces illustrate well the antioxidant capacity of compounds. The halogen substituents increase the antioxidant activity of the most stable conformers. The position and number of OH groups are crucial factors which affect the activity, whereas two adjacent hydroxyl groups enhance the antioxidant activity of selected compounds. Communicated by Ramaswamy H. Sarma

Nicotine oxidoreductase (NicA2) is a monoamine oxidase (MAO)-based flavoenzyme that catalyzes the oxidation of S-nicotine into N-methylmyosmine. Due to its nanomolar binding affinity toward nicotine, it is seen as an ideal candidate for the treatment of nicotine addiction. Based on the crystal structure of the substrate-bound enzyme, hydrophobic interactions mainly govern the binding of the substrate in the active site through Trp108, Trp364, Trp427, and Leu217 residues. In addition, Tyr308 forms H-bonding with the pyridyl nitrogen of the substrate. Experimental and computational studies support the hydride transfer mechanism for MAO-based enzymes. In this mechanism, a hydride ion transfers from the substrate to the flavin cofactor. In this study, computational models involving the ONIOM method were formulated to study the hydride transfer mechanism based on the crystal structure of the enzyme-substrate complex. The geometry and energetics of the hydride transfer mechanism were analyzed, and the roles of active site residues were highlighted.

Biomolecules with metal ion(s) (e.g., metalloproteins) play many important biological roles. However, accurate structural determination of metalloproteins, particularly those containing transition metal ion(s), is challenging due to their complicated electronic structure, complex bonding of metal ions, and high number of conformations in biomolecules. Quantum refinement, which was proposed to combine crystallographic data with computational chemistry methods by several groups, can improve the local structures of some proteins. In this study, a quantum refinement method combining several multiscale computational schemes with experimental (X-ray diffraction) information was developed for metalloproteins. Various quantum refinement approaches using different ONIOM (our own N-layered integrated molecular orbital and molecular mechanics) combinations of quantum mechanics (QM), semiempirical (SE), and molecular mechanics (MM) methods were conducted to assess the performance and reliability on the refined local structure in two metalloproteins. The structures for two (Cu- or Zn-containing) metalloproteins were refined by combining two-layer ONIOM2(QM1/QM2) and ONIOM2(QM/MM) and three-layer ONIOM3(QM1/QM2/MM) schemes with experimental data. The accuracy of the quantum-refined metal binding sites was also examined and compared in these multiscale quantum refinement calculations. ONIOM3(QM/SE/MM) schemes were found to give good results with lower computational costs and were proposed to be a good choice for the multiscale computational scheme for quantum refinement calculations of metal binding site(s) in metalloproteins with high efficiency. Additionally, a two-center ONIOM approach was employed to speed up the quantum refinement calculations for the Zn metalloprotein with two remote active sites/ligands. Moreover, a recent quantum-embedding wavefunction-in-density functional theory (WF-in-DFT) method was also adopted as the high-level method in unprecedented ONIOM2(CCSD-in-B3LYP/MM) and ONIOM3(CCSD-in-B3LYP/SE/MM) calculations, which can be regarded as novel pseudo-three- and pseudo-four-layer ONIOM methods, respectively, to refine the key Zn binding site at the coupled-cluster singles and doubles (CCSD) level. These refined results indicate that multiscale quantum refinement schemes can be used to improve the structural accuracy obtained for local metal binding site(s) in metalloproteins with high efficiency.

We present a weighted-graph-theoretic approach to adaptively compute contributions from many-body approximations for smooth and accurate post-Hartree-Fock (pHF) ab initio molecular dynamics (AIMD) of highly fluxional chemical systems. This approach is ONIOM-like, where the full system is treated at a computationally feasible quality of treatment (density functional theory (DFT) for the size of systems considered in this publication), which is then improved through a perturbative correction that captures local many-body interactions up to a certain order within a higher level of theory (post-Hartree-Fock in this publication) described through graph-theoretic techniques. Due to the fluxional and dynamical nature of the systems studied here, these graphical representations evolve during dynamics. As a result, energetic "hops" appear as the graphical representation deforms with the evolution of the chemical and physical properties of the system. In this paper, we introduce dynamically weighted, linear combinations of graphs, where the transition between graphical representations is smoothly achieved by considering a range of neighboring graphical representations at a given instant during dynamics. We compare these trajectories with those obtained from a set of trajectories where the range of local many-body interactions considered is increased, sometimes to the maximum available limit, which yields conservative trajectories as the order of interactions is increased. The weighted-graph approach presents improved dynamics trajectories while only using lower-order many-body interaction terms. The methods are compared by computing dynamical properties through time-correlation functions and structural distribution functions. In all cases, the weighted-graph approach provides accurate results at a lower cost.

A multi-scale and multi-environment computational approach is proposed to study of the modulation of the emission behavior of the triphenylamine (Z)-4-benzylidene-2-methyloxazol-5(4H)-one (TPA-BMO) molecule [Tang et al., J. Phys. Chem. C,119, 21875 (2015)]. Going from (TD-)DFT calculations to classical Molecular Dynamics simulations through the hybrid ONIOM QM/QM’ approach and the in situ chemical polymerization methodology, we have rationalized distinct photophysical phenomena: (1) in low-polar solvents, a polarity-dependent solvatochromic effect as well as a modulation of the emission quantum yield, attributed to possible photophysical energy dissipation caused by low-frequency vibrational modes, (2) in the aggregate, a subtle competition between an excitonic coupling and a restriction of the intramolecular vibrations leading to an Aggregation-Induced Emission behavior, and (3) in the polymer matrix, an antagonist effect between the loss of global flexibility and the presence of vibrational modes similar to those observed in solution, explaining a similar emissive behavior within the polymer.

The uptake of atmospheric gaseous oxidant such as O3 or the ROx (OH, HO2, RO2) family, have a strong impact on the oxidative capacity of the atmosphere. [1], [2] Last decade, few studies have been carried out on the uptake of such compounds on atmospheric aerosol. However, the large variety of organic compounds provides uptake coefficients with a wide range of order of magnitude. [3], [4] Furthermore, the uptake resulting from the combination of different processes (mass accommodation, bulk diffusion, reactivity), the detailed understanding of such a process is not always accessible through experiments. Theoretical tools such as quantum mechanics (QM) combined with Molecular Mechanics (MM) is one way to investigate separately the different processes.The ONIOM hybrid QM/MM method [5] allows to study the reactivity of few molecules in a large system. In our group, a methodology using this computational method have been developed in order to estimate the reactive uptake of gaseous compounds onto organic aerosol particles. In this presentation, reactive uptake of HO2 and O3 onto glutaric acid and oleic acid aerosols respectively will be discussed. Comparisons will be addressed with gas phase theoretical reaction rates and with experimental data.We acknowledge support by the French government through the Program “Investissement d'avenir” through the Labex CaPPA (contract ANR-11-LABX-0005-01) and I-SITE ULNE project OVERSEE (contract ANR-16-IDEX-0004), CPER CLIMIBIO (European Regional Development Fund, Hauts de France council, French Ministry of Higher Education and Research) and French national supercomputing facilities (grants DARI x2016081859 and A0050801859). References[1] H. L. Macintyre and M. J. Evans, “Parameterisation and impact of aerosol uptake of HO2 on a global tropospheric model,” Atmos. Chem. Phys., vol. 11, no. 21, pp. 10965–10974, Nov. 2011, doi: 10.5194/acp-11-10965-2011.[2] M. Zeng and K. R. Wilson, “Efficient Coupling of Reaction Pathways of Criegee Intermediates and Free Radicals in the Heterogeneous Ozonolysis of Alkenes,” The Journal of Physical Chemistry Letters, Jul. 2020, doi: 10.1021/acs.jpclett.0c01823.[3] P. S. J. Lakey, I. J. George, L. K. Whalley, M. T. Baeza-Romero, and D. E. Heard, “Measurements of the HO2 Uptake Coefficients onto Single Component Organic Aerosols,” Environ. Sci. Technol., vol. 49, no. 8, pp. 4878–4885, Apr. 2015, doi: 10.1021/acs.est.5b00948.[4] M. Mendez, N. Visez, S. Gosselin, V. Crenn, V. Riffault, and D. Petitprez, “Reactive and Nonreactive Ozone Uptake during Aging of Oleic Acid Particles,” J. Phys. Chem. A, vol. 118, no. 40, pp. 9471–9481, Oct. 2014, doi: 10.1021/jp503572c.[5] L. W. Chung et al., “The ONIOM Method and Its Applications,” Chem. Rev., vol. 115, no. 12, pp. 5678–5796, Jun. 2015, doi: 10.1021/cr5004419.

L-6-Hydroxynicotine oxidase (LHNO) is a member of monoamine oxidase (MAO) family and catalyzes conversion of (S)-6-hydroxynicotine to 6-hydroxypseudooxynicotine during bacterial degradation of nicotine. Recent studies indicated that the enzyme catalyzes oxidation of carbon-nitrogen bond instead of previously proposed carbon-carbon bond. Based on kinetics and mutagenesis studies, Asn166, Tyr311, and Lys287 as well as an active site water molecule have roles in the catalysis of the enzyme. A number of studies including experimental and computational methods support hydride transfer mechanism in MAO family as a common mechanism in which a hydride ion transfer from amine substrate to flavin cofactor is the rate-limiting step. In this study, we formulated computational models to study the hydride transfer mechanism using crystal structure of enzyme-substrate complex. The calculations involved ONIOM and DFT methods, and we evaluated the geometry and energetics of the hydride transfer process while probing the roles of active site residues. Based on the calculations involving hydride, radical, and polar mechanisms, it was concluded that hydride transfer mechanism is the only viable mechanism for LHNO.