Two Sides of Quantum-Based Modeling of Enzyme-Catalyzed Reactions: Mechanistic and Electronic Structure Aspects of the Hydrolysis by Glutamate Carboxypeptidase

We report the results of a computational study of the hydrolysis reaction mechanism of N-acetyl-l-aspartyl-l-glutamate (NAAG) catalyzed by glutamate carboxypeptidase II. Analysis of both mechanistic and electronic structure aspects of this multistep reaction is in the focus of this work. In these simulations, model systems are constructed using the relevant crystal structure of the mutated inactive enzyme. After selection of reaction coordinates, the Gibbs energy profiles of elementary steps of the reaction are computed using molecular dynamics simulations with ab initio type QM/MM potentials (QM/MM MD). Energies and forces in the large QM subsystem are estimated in the DFT(PBE0-D3/6-31G**) approximation. The established mechanism includes four elementary steps with the activation energy barriers not exceeding 7 kcal/mol. The models explain the role of point mutations in the enzyme observed in the experimental kinetic studies; namely, the Tyr552Ile substitution disturbs the “oxyanion hole”, and the Glu424Gln replacement increases the distance of the nucleophilic attack. Both issues diminish the substrate activation in the enzyme active site. To quantify the substrate activation, we apply the QTAIM-based approaches and the NBO analysis of dynamic features of the corresponding enzyme-substrate complexes. Analysis of the 2D Laplacian of electron density maps allows one to define structures with the electron density deconcentration on the substrate carbon atom, i.e., at the electrophilic site of reactants. The similar electronic structure element in the NBO approach is a lone vacancy on the carbonyl carbon atom in the reactive species. The electronic structure patterns revealed in the NBO and QTAIM-based analyses consistently clarify the reactivity issues in this system.

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Interpretation of neighboring group interactions in crystal structures. A solid state and quantum-chemical study of "incipient nucleophilic attack" in 2-diazonium benzoic acid and its benzoate

Canadian Journal of Chemistry ◽

10.1139/v96-135 ◽

1996 ◽

Vol 74 (6) ◽

pp. 1200-1214 ◽

Cited By ~ 14

Author(s):

Rainer Glaser ◽

Christopher J. Horan

Keyword(s):

Electronic Structure ◽

Electron Density ◽

Nucleophilic Attack ◽

Neighboring Group ◽

Group Interactions ◽

Diazonium Ions ◽

Attraction Model ◽

Density Analysis ◽

Bridging Attraction ◽

Electron Density Analysis

The concept of the Bürgi–Dunitz angle of attack on carbonyls is compatible with the electronic structure of carbonyls. However, it is argued here that the generalization asserted to describe the interaction of nucleophiles with diazonium ions is inappropriate. Distortions in crystal structures of diazonium ions with proximate nucleophiles were interpreted by an incipient nucleophilic attack (INA) on the formally positive-charged Nα. This "Nα attraction model" relies on the assumption that the formal charge in the most commonly used Lewis structure of diazonium ions represents actual charge. We proposed that the close approach of the proximate nucleophile to the diazonium group occurs to enhance attractive 1,3-(C,Nβ)-bridging interactions and despite repulsion between Nα and the proximate oxygen (Opr). The present study combines theoretical analysis of rotamers of 2-diazonium benzoic acid and its conjugate base with experimental results on the same system to provide compelling evidence that the more general conclusions drawn from analyses of neighboring group interactions in propenoic acid models are fully warranted. The crystallographic record is more fully consistent with the "1,3-bridging attraction model." Combined analysis of solid state and gas phase structures reveals the intrinsic features due to INA. Both electrostatic models can account for these features but with different postulates about the electron density distribution. While the structural analysis alone cannot distinguish between the alternative interpretations, the study of the electronic structure allows one to clearly differentiate between these competing interpretations. A method (ESI) for the quantitative evaluation of electrostatic neighboring group interactions has been devised and this ESI concept employs atomic electrical moments (charges, dipoles, and quadrupoles) determined via topological electron density analysis. The results of the ESI analysis support the 1,3-bridging attraction model and eliminate the Nα attraction model. Key words: electrostatic interactions, electron density analysis, atoms in molecules. X-ray crystallography, ab initio molecular orbital theory, incipient nucleophilic attack, bonding models, ESI analysis.

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Correlation of rates of uncatalyzed and hydroxide-ion catalyzed ketene hydration. A mechanistic application and solvent isotope effects on the uncatalyzed reaction

Canadian Journal of Chemistry ◽

10.1139/v00-032 ◽

2000 ◽

Vol 78 (4) ◽

pp. 508-515

Author(s):

John Andraos ◽

A Jerry Kresge

Keyword(s):

Carbon Atom ◽

Rate Constants ◽

Isotope Effects ◽

Nucleophilic Attack ◽

Carbonyl Carbon Atom ◽

Basic Solution ◽

Carbonyl Carbon ◽

Hydroxide Ion ◽

Solvent Isotope ◽

Solvent Isotope Effects

Rates of hydration of a number of ketenes were measured in neutral and basic solution using flash photolytic techniques, and rate constants for their uncatalyzed, kuc, and hydroxide-ion catalyzed, kHO, reactions were determined. These results, plus additional data from the literature, were found to provide the remarkably good correlation log kuc = -3.21 + 1.14 log kHO, which spans 10 orders of magnitude in reactivity and includes 31 ketenes. This good correlation implies that uncatalyzed and hydroxide-ion catalyzed ketene hydraton occur by similar reaction mechanisms, which for the hydroxide-ion catalyzed process is known to involve nucleophilic attack on the carbonyl carbon atom of the ketene. Rate constants for phenylhydroxyketene, on the other hand, do not fit this correlation, which suggests that the mechanistic assignment upon which these rate constants are based may not be correct. Solvent isotope effects on these uncatalyzed ketene hydrations are weak; most are less than kH/kD = 2. It is argued that these isotope effects are largely, if not entirely, secondary in nature and that they are consistent with both a reaction mechanism in which nucleophlic attack of a single water molecule on the ketene carbonyl carbon atom produces a zwitterionic intermediate and also a mechanism that avoids this intermediate by passing through a cyclic transition state involving several water molecules.Key words: ketene hydration, rate correlation, nucleophilic attack, solvent isotope effects, phenylhydroxyketene.

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Theoretical Study on Epoxide Ring-opening in CO2/Epoxide Copolymerization Catalyzed by Bifunctional Salen-Type Cobalt(III) Complexes: Influence of Stereoelectronic Factors

Catalysts ◽

10.3390/catal11030328 ◽

2021 ◽

Vol 11 (3) ◽

pp. 328

Author(s):

Karol Dyduch ◽

Aleksandra Roznowska ◽

Monika Srebro-Hooper ◽

Bun Yeoul Lee ◽

Artur Michalak

Keyword(s):

Carbon Atom ◽

Ring Opening ◽

Density Functional ◽

Model Systems ◽

Conformational Space ◽

Nucleophilic Attack ◽

Epoxide Ring ◽

Epoxide Ring Opening ◽

The Real ◽

Ring Opening Reaction

Propylene oxide (PO) binding and ring-opening reaction with the bifunctional CO2/epoxide copolymerization catalyst, based on the Co(III)-salcy complex including two quaternary ammonium salts with n-butyl substituents (N+-chains) were investigated by Density Functional Theory (DFT) calculations and compared with the model systems without the N+-chains. The importance of the different possible stereoisomers and the stereoselectivity of these processes for (S)- and (R)-enantiomers of PO were considered. To explore the conformational space for the real catalyst, a complex approach, developed previously was applied. The calculations for the model systems directly demonstrate that PO-ring opening proceeds preferentially in trans catalysts’ configuration and no participation of cis-β isomers is viable; nucleophilic attack at the methylene-carbon atom is preferred over that at methine-carbon atom. For the real bifunctional catalyst, with the (S,S)-configuration of cyclohexane, the results indicate a preference of (R)-PO ring-opening over (S)-PO ring-opening (ca. 6:5). Concerning stereoisomers resulting from the orientation of N+-chains in the real catalyst, different groups of structures participate in the ring-opening reaction for (R)-PO, and different for (S)-PO. The high population of nonreactive complexes of (R)-PO may be the key factor responsible for decreasing the activity of the analyzed catalyst in the epoxide ring-opening reaction.

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Electronic Property and Reactivity of (Hydroperoxo) Metal Compounds

Zeitschrift für Naturforschung C ◽

10.1515/znc-2001-1-222 ◽

2001 ◽

Vol 56 (1-2) ◽

pp. 144-153 ◽

Cited By ~ 3

Author(s):

Yuzo Nishida ◽

Satoshi Nishino

Keyword(s):

Carbon Atom ◽

Oxygen Atom ◽

Electron Density ◽

Metal Ion ◽

Coupling Reaction ◽

Metal Species ◽

Nucleophilic Attack ◽

Total Electron Density ◽

Total Electron ◽

Oxygen Atoms

Abstract DFT calculations were done for the (hydroperoxo)metal complexes with η1-coordination mode, where metal ions are Fe(III), Al(III), Cu(II) and Zn(II). Results shows that 1) the electron density at the two oxygen atoms of the hydroperoxide ion is highly dependent on the angle O-O-H in M-OOH species and the difference in electron density between the two oxygen atoms reaches a maximum at the angle O-O-H = 180°, 2) total electron density at the two oxygen atoms of the peroxide ion increases by approach of methane to the (hydro-peroxo)metal species in the cases of Fe(III) and Cu(II); on the other hand, significant decrease of the electron density on peroxide oxygen atoms was observed for the cases of Al(III) and Zn(II) compounds. These findings suggest that the (hydroperoxo)metal species acts as an electrophile in the former cases (M = Fe(III), Cu(II)) and as a nucleophile for the latter two compounds (M = Zn(II), Al(III)). The electrophilicity observed for the Fe(III) and Cu(II) complexes is attributed to the presence of unoccupied-or half-filled d-orbitals interacting with the hydroperoxide ion. 3) Two oxygen atoms of the (hydroperoxo)-com-pounds of Fe(III) and Cu(II) complexes exhibit quite different reactivity toward the substrate, such as methane. When methane approaches the oxygen atom which is coordinated to a metal ion, a strong decrease of electron density at the methane carbon atom occurs with concomitant increase of electron density at the peroxide oxygen atoms inducing its hetero-lytic O-O cleavage. When methane approaches the terminal oxygen atom, an oxidative coupling reaction occurs between peroxide ion and methane; at first a nucleophilic attack by the terminal electron-rich oxygen atom occurs at the carbon atom to induce C-O bond formation, and a subsequent oxidative electron transfer proceeds from substrate to the metal-peroxide species yielding CH3 -OOH, CH3OH, or other oxidized products. These results clearly demonstrate that the (hydroperoxo)-metal compound itself is a rather stable compound, and activation of the peroxide ion is induced by interaction with the substrate, and the products obtained by the oxygenation reaction are dependent on the chemical property of the sub strate, redox property of a metal ion, and stability of the compounds formed in the intermediate process.

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Relation Between Local Structure, Electric Dipole and Charge Carrier Dynamics in DHICA Melanin, a Model for Biocompatible Semiconductors

10.26434/chemrxiv.11323016 ◽

2019 ◽

Author(s):

Micaela Matta ◽

Alessandro Pezzella ◽

Alessandro Troisi

Keyword(s):

Electronic Structure ◽

Degrees Of Freedom ◽

Structural Model ◽

Computational Study ◽

Oxidative Polymerization ◽

Radical Scavenging ◽

Charge Carriers ◽

Electronic Charge ◽

Polymer Semiconductors ◽

Synthetic Pigments

<div><div><div><p>Eumelanins are a family of natural and synthetic pigments obtained by oxidative polymerization of their natural precursors: 5,6 dihydroxyindole and its 2-carboxy derivative (DHICA). The simultaneous presence of ionic and electronic charge carriers makes these pigments promising materials for applications in bioelectronics. In this computational study we build a structural model of DHICA melanin considering the interplay between its many degrees of freedom, then we examine the electronic structure of representative oligomers. We find that a non-vanishing dipole along the polymer chain sets this system apart from conventional polymer semiconductors, determining its electronic structure, reactivity toward oxidation and localization of the charge carriers. Our work sheds light on previously unnoticed features of DHICA melanin that not only fit well with its radical scavenging and photoprotective properties, but open new perspectives towards understanding and tuning charge transport in this class of materials.<br></p></div></div></div>

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Influence of Copper(I) Halides on the Reactivity of Aliphatic Carbodiimides

Chemistry Proceedings ◽

10.3390/ecsoc-24-08096 ◽

2020 ◽

Vol 3 (1) ◽

pp. 20

Author(s):

Valentina Ferraro ◽

Marco Bortoluzzi

Keyword(s):

Density Functional Theory ◽

Electronic Structure ◽

General Formula ◽

Electron Density ◽

Density Functional ◽

Functional Theory ◽

Fukui Functions ◽

Bond Lengths ◽

Linear Complexes ◽

Nitrogen Bond

The influence of copper(I) halides CuX (X = Cl, Br, I) on the electronic structure of N,N′-diisopropylcarbodiimide (DICDI) and N,N′-dicyclohexylcarbodiimide (DCC) was investigated by means of computational DFT (density functional theory) methods. The coordination of the considered carbodiimides occurs by one of the nitrogen atoms, with the formation of linear complexes having a general formula of [CuX(carbodiimide)]. Besides varying the carbon–nitrogen bond lengths, the thermodynamically favourable interaction with Cu(I) reduces the electron density on the carbodiimides and alters the energies of the (NCN)-centred, unoccupied orbitals. A small dependence of these effects on the choice of the halide was observable. The computed Fukui functions suggested negligible interaction of Cu(I) with incoming nucleophiles, and the reactivity of carbodiimides was altered by coordination mainly because of the increased electrophilicity of the {NCN} fragments.

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Understanding the reaction mechanism of the regioselective piperidinolysis of aryl 1-(2,4-dinitronaphthyl) ethers in DMSO: Kinetic and DFT studies

Progress in Reaction Kinetics and Mechanism ◽

10.1177/14686783211027446 ◽

2021 ◽

Vol 46 ◽

pp. 146867832110274

Author(s):

Yasmen M Moghazy ◽

Nagwa MM Hamada ◽

Magda F Fathalla ◽

Yasser R Elmarassi ◽

Ezzat A Hamed ◽

...

Keyword(s):

Carbon Atom ◽

Density Functional ◽

Function Analysis ◽

Density Functional Theory Method ◽

Activation Parameters ◽

Kinetic Studies ◽

Nucleophilic Attack ◽

Common Mechanism ◽

Slow Step ◽

Rate Determining Step

Reactions of aryl 1-(2,4-dinitronaphthyl) ethers with piperidine in dimethyl sulfoxide at 25oC resulted in substitution of the aryloxy group at the ipso carbon atom. The reaction was measured spectrophotochemically and the kinetic studies suggested that the titled reaction is accurately third order. The mechanism is began by fast nucleophilic attack of piperidine on C1 to form zwitterion intermediate (I) followed by deprotonation of zwitterion intermediate (I) to the Meisenheimer ion (II) in a slow step, that is, SB catalysis. The regular variation of activation parameters suggested that the reaction proceeded through a common mechanism. The Hammett equation using reaction constant σo values and Brønsted coefficient value showed that the reaction is poorly dependent on aryloxy substituent and the reaction was significantly associative and Meisenheimer intermediate-like. The mechanism of piperidinolysis has been theoretically investigated using density functional theory method using B3LYP/6-311G(d,p) computational level. The combination between experimental and computational studies predicts what mechanism is followed either through uncatalyzed or catalyzed reaction pathways, that is, SB and SB-GA. The global parameters of the reactants, the proposed activated complexes, and the local Fukui function analysis explained that C1 carbon atom is the most electrophilic center of ether. Also, kinetics and theoretical calculation of activation energies indicated that the mechanism of the piperidinolysis passed through a two-step mechanism and the proton transfer process was the rate determining step.

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