Mechanism of chemical reactions in the active site of aspartate N-acetyltransferase NAT8L revealed by molecular modeling

The results of a computational study of the synthesis of a key brain metabolite, N-acetyl-l-aspartate, catalyzed by aspartate N-acetyltransferase, encoded by the NAT8L gene, are reported. The reaction Gibbs energy profiles were computed using molecular dynamics simulations with interaction potentials estimated on-the-fly by the quantum mechanics/molecular mechanics QM(PBE0/6-31G**)/MM(CHARMM) approach. The revealed reaction mechanism includes four elementary steps with corresponding activation energies not exceeding 14 kcal mol^?1     

Quantum chemical modeling of enzymatic reactions: The case of histone lysine methyltransferase

Quantum chemical cluster models of enzyme active sites are today an important and powerful tool in the study of various aspects of enzymatic reactivity. This methodology has been applied to a wide spectrum of reactions and many important mechanistic problems have been solved. Herein, we report a systematic study of the reaction mechanism of the histone lysine methyltransferase (HKMT) SET7/9 enzyme, which catalyzes the methylation of the N‐terminal histone tail of the chromatin structure. In this study, HKMT SET7/9 serves as a representative case to examine the modeling approach for the important class of methyl transfer enzymes. Active site models of different sizes are used to evaluate the methodology. In particular, the dependence of the calculated energies on the model size, the influence of the dielectric medium, and the particular choice of the dielectric constant are discussed. In addition, we examine the validity of some technical aspects, such as geometry optimization in solvent or with a large basis set, and the use of different density functional methods. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010     

Tailor-made hexaethylene glycolic ionic liquids as organic catalysts for specific chemical reactions

Hexaethylene glycol substituted imidazolium based ionic liquids (hexaEGILs) were designed and prepared well-tailored to a specific organic reaction using alkali-metal fluorides (MFs) as multifunctional organic catalysts. These hexaEGIL catalysts could significantly enhance the reactivity of MF, even KF. Furthermore, the hexaEGIL systems showed tremendous efficiency in the nucleophilic fluorination of base-sensitive substrates.     

The intertwined physics of active chemical reactions and phase separation

Phase separation is the thermodynamic process that explains how droplets form in multicomponent fluids. These droplets can provide controlled compartments to localize chemical reactions, and reactions can also affect the droplets' dynamics. This review focuses on the tight interplay between phase separation and chemical reactions, which originates from thermodynamic constraints. In particular, simple mass action kinetics cannot describe chemical reactions since phase separation requires non-ideal fluids. Instead, thermodynamics implies that passive chemical reactions reduce the complexity of phase diagrams and provide only limited control over the system's behavior. However, driven chemical reactions, which use external energy input to create spatial fluxes, can circumvent thermodynamic constraints. Such active systems can suppress typical droplet coarsening, control droplet size, and localize droplets. This review provides an extensible framework for describing active chemical reactions in phase separating systems, which forms a basis for improving control in technical applications and understanding self-organized structures in biological cells.     

Quantum chemical modeling of enzyme active sites and reaction mechanisms

Density functional methods, in particular the B3LYP functional, together with the explosive enhancement of computational power, have in the last 5 years or so made it possible to model enzyme active sites and reaction mechanisms in a quite realistic way. Many mechanistic problems have indeed been addressed and solved. This review gives a brief account of the methods and models used to study enzyme active sites and their reaction mechanisms using quantum chemical methods. Examples are given from our recent work in this field. Future perspectives of the field are discussed.     

Technical aspects of quantum chemical modeling of enzymatic reactions: the case of phosphotriesterase

Quantum chemical methods are today a powerful tool in the study of enzymatic reaction mechanisms. In this paper we evaluate the adequacy of some of the technical approximations frequently used in the modeling of enzyme reactions with high level methods. These include the choice of basis set for geometry optimizations and energy evaluation, the choice of dielectric constant to model the enzyme surrounding, and the effects of locking the centers of truncation. As a test case, we choose the phosphotriesterase enzyme, which is a binuclear zinc enzyme that catalyzes the hydrolysis of organophosphate triesters.     

Kinetic Monte Carlo modeling of chemical reactions coupled with heat transfer

In this paper, we describe two types of effective events for describing heat transfer in a kinetic Monte Carlo (KMC) simulation that may involve stochastic chemical reactions. Simulations employing these events are referred to as KMC-TBT and KMC-PHE. In KMC-TBT, heat transfer is modeled as the stochastic transfer of "thermal bits" between adjacent grid points. In KMC-PHE, heat transfer is modeled by integrating the Poisson heat equation for a short time. Either approach is capable of capturing the time dependent system behavior exactly. Both KMC-PHE and KMC-TBT are validated by simulating pure heat transfer in a rod and a square and modeling a heated desorption problem where exact numerical results are available. KMC-PHE is much faster than KMC-TBT and is used to study the endothermic desorption of a lattice gas. Interesting findings from this study are reported.     

The state-to-state-to-state model for direct chemical reactions: application to D+H2-->HD+H

A simple theoretical model is developed to predict the state-to-state dynamics of direct chemical reactions. Motivated by traditional ideas from transition state theory, expressions are derived for the reactive S matrix that may be computed using the local transition state dynamics. The key approximation involves the use of quantum bottleneck states to represent the near separable dynamics taking place near the transition state. Explicit expressions for the S matrix are obtained using a Franck-Condon treatment for the inelastic coupling between internal states of the collision complex. It is demonstrated that the energetic thresholds for various initial reagent states of the D+H(2) reaction can be understood in terms of our theory. Specifically, the helicity of the reagent states are found to correlate directly to the symmetry of the quantum bottleneck states, which thus possess very different thresholds. Furthermore, the rotational product state distributions for D+H(2) are found to be associated with interfering pathways through the quantum bottleneck states.     

Heavy atom tunneling in chemical reactions: study of H + LiF collisions

The H+LiF(X (1)sigma(+),upsilon=0-2,j=0)-->HF(X (1)sigma(+),upsilon',j')+Li(2S) bimolecular process is investigated by means of quantum scattering calculations on the chemically accurate X 2A' LiHF potential energy surface of Aguado et al. [A. Aguado, M. Paniagua, C. Sanz, and J. Roncero, J. Chem. Phys. 119, 10088 (2003)]. Calculations have been performed for zero total angular momentum for translational energies from 10(-7) to 10(-1) eV. Initial-state selected reaction probabilities and cross sections are characterized by resonances originating from the decay of metastable states of the H...F-Li and Li...F-H van der Waals complexes. Extensive assignment of the resonances has been carried out by performing quasibound states calculations in the entrance and exit channel wells. Chemical reactivity is found to be significantly enhanced by vibrational excitation at low temperatures, although reactivity appears much less favorable than nonreactive processes due to the inefficient tunneling of the relatively heavy fluorine atom strongly bound in van der Waals complexes.     

Concerted cycloaddition reactions: a study using the parabolic model and quantum chemical modeling

Concerted cycloaddition reactions were studied by the method of intersecting parabolas (M3IP) and quantum chemical calculations. Experimental data were processed within the framework of the M3IP method and an algorithm for calculating the activation energies (E) and rate constants (k) for reactions from the enthalpies of reactions was developed. The parameters E and k for twelve cycloaddition reactions not studied previously were calculated. Factors affecting the activation energies were established and evaluated; these include the enthalpy of reaction, substituents, and the molecular structure of reactants. Quantum chemical modeling and topological analysis of transition states (TS) of six concerted cycloaddition reactions were performed. Depending on structure of the starting olefins, the TS of reactions can have either a symmetric or asymmetric geometry. This influences their electronic structures, the energies of chemical bonds, and the activation energies of reactions. A comparison of the activation energy values obtained from the M3IP and DFT(B3lyp/6-311++G** ) calculations revealed good agreement between them.     

Cold and ultracold chemical reactions of F+HCl and F+DCl

We report quantum dynamics calculations of F((2)P)+HCl(v,j)-->HF(v('),j('))+Cl((2)P) and F+DCl(v,j)-->DF(v('),j('))+Cl reactions at cold and ultracold temperatures. The effect of rotational and vibrational excitations of the HCl molecule on the reactivity is investigated. It is found that, in the ultracold regime, vibrational excitation of the HCl molecule from v=0 to v=2 enhances the reactivity by four orders of magnitude. The rotational excitation from j=0 to j=1 decreases the reactivity while the rotational excitation from j=0 to j=2 increases the reactivity. The overall effect of rotational excitation was found to be much smaller than vibrational excitation. The reactivity of the F+DCl system is significantly lower than that of the F+HCl case indicating the importance of quantum tunneling at low energies. For both reactions, Feshbach resonances corresponding to Fcdots, three dots, centered HCl or Fcdots, three dots, centeredDCl triatomic states occur at low energies. We also explored the validity of the coupled-states approximation for cold collisions taking the F+HCl(v=0,j=0) reaction as an illustrative example. It is found that the coupled-states approximation is generally valid for the background scattering even at low energies but it is inadequate to accurately describe the rich resonances in the energy dependence of the cross section resulting from the decay of van der Waals complexes. It is further shown that the coupled-states approximation cannot be used for scattering in the Wigner threshold regime when the molecule is initially in a rotationally excited level.     

Potential energy surfaces for simple chemical reactions: Li + F2 → LiF + F

A potential energy surface is calculated for the Li + F₂ → LiF + F reaction using an ab initio multistructure valence-bond approach. The orthogonalized Moffit (OM) method is employed to apply a correction for the large errors made by the ab initio calculation in representing the F⁻ ion relative to the F atom. The OM method predicts the potential surface to be of the highly “attractive” or “early downhill” type and to possess a potential energy well with respect to dissociation to the products LiF + F. The attributes of the surface predicted by the OM method are compared with those suggested by experiment and used in trajectory calculations for analogous systems.     

Single-atom catalysis for organic reactions

Metal-based catalysis, including homogeneous and heterogeneous catalysis, plays a significant role in the modern chemical industry. Heterogeneous catalysis is widely used due to the high efficiency, easy catalyst separation and recycling. However, the metal-utilization efficiency for conventional heterogeneous catalysts needs further improvement compared to homogeneous catalyst. To tackle this, the pursing of heterogenizing homogeneous catalysts has always been attractive but challenging. As a recently emerging class of catalytic material, single-atom catalysts (SACs) are expected to bridge homogeneous and heterogeneous catalytic process in organic reactions and have arguably become the most active new frontier in catalysis field. In this review, a brief introduction and development history of single-atom catalysis and SACs involved organic reactions are documented. In addition, recent advances in SACs and their practical applications in organic reactions such as oxidation, reduction, addition, coupling reaction, and other organic reactions are thoroughly reviewed. To understand structure-property relationships of single-atom catalysis in organic reactions, active sites or coordination structure, metal atom-utilization efficiency (e.g., turnover frequency, TOF calculated based on active metal) and catalytic performance (e.g., conversion and selectivity) of SACs are comprehensively summarized. Furthermore, the application limitations, development trends, future challenges and perspective of SAC for organic reaction are discussed.     

Multicomponent coupling reactions for organic synthesis: chemoselective reactions with amide-aldehyde mixtures

The acid-catalyzed condensation chemistry of simple amides and aldehydes provides a highly prolific source of diverse reactants for irreversible follow-up reactions. Amide-aldehyde mixtures have been successfully employed in multicomponent syntheses of N-acyl alpha-amino acids (via palladium-catalyzed amidocarbonylation) and various cyclohexene, cyclohexadiene, and benzene derivatives (via the amide-aldehyde-dienophile (AAD) reaction).     

The chemical profile of active fraction of Kalimeris indica and its quantitative analysis

Kalimeris indica (L) Sch-Bip is a medicinal plant used by the Miao ethnic group in the Guizhou province of China. It is widely used as a fresh vegetable to treat colds, diarrhea and gastric ulcers. However, few studies have been conducted on the mechanism of its effect on colds, and its quality control. The anticomplement and antitussive activities of different polar extracts of K. indica were evaluated. Fifty-nine compounds, mainly including phenols and flavonoids, were identified in K. indica extract by ultra-high-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry. A method was established through ultra-high-performance liquid chromatography with a photodiode array to simultaneously determine the anticomplement and antitussive activity of five compounds in K. indica combining chemical identification with chemometrics for discrimination and quality assessment. Also, 3,5-dicaffeoylquinic acid and 4,5-dicaffeoylquinic acid exhibited significantly higher anticomplementary activity than the other three compounds. The quantitative data were further analyzed by principal component analysis and orthogonal partial least-squares discriminant analysis. Heatmap visualization was conducted to clarify the distribution of the major compounds in different geographical origins. Screening pharmacological activities by a combination of chemometrics and chemical identification might be an effective method for the quality control of K. indica.