Computational Kinetic Modeling of the Catalytic Cycle of Glutathione

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Computational Kinetic Modeling of the Catalytic Cycle of Glutathione Peroxidase Nanomimic: Effect of Nucleophilicity of Thiols on the Catalytic Activity Ramesh Kheirabadi, Mohammad Izadyar, and Mohammad Reza Housaindokht J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.7b09929 • Publication Date (Web): 07 Dec 2017 Downloaded from http://pubs.acs.org on December 9, 2017

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The Journal of Physical Chemistry

Computational Kinetic Modeling of the Catalytic Cycle of Glutathione Peroxidase Nanomimic: Effect of Nucleophilicity of Thiols on the Catalytic Activity Ramesh Kheirabadia, Mohammad Izadyarb*, Mohammad Reza Housaindokhtb a

Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, International Campus, Mashhad, Iran b

Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran [email protected] Telefax: ++985138795457

ABSTRACT The catalytic cycle of a new derivative of ebselen, 1, was elucidated via three steps by the density functional theory and solvent-assisted proton exchange procedure involving indirect proton exchange through a hydrogen-bonded transfer network. Different behaviors of the aromatic and aliphatic thiols were investigated in the reduction of selenoxide (step 2→3) and selenurane (step 3→1) based on their nucleophilicity. The reduction of selenoxide in the presence of thiophenol (ΔG≠=15.9 kcal.mol-1) is faster than methanethiol (ΔG≠=29.3 kcal.mol-1), and methanethiol makes the reduction of selenoxide unspontaneous and kinetically unfavorable (ΔG=2.8 kcal.mol-1). The nucleophilic attack may be enhanced by using the thiophenol backbone at the selenium center to lower the energy barrier of the selenoxide reduction (ΔG≠=15.9 kcal.mol-1). On the 1 ACS Paragon Plus Environment

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basis of the turnover frequency calculations, during the catalytic cycle, the rate of the reaction was analyzed and discussed. Low values of the electron density and Laplacian at the transition states are the evidences of the covalent O-H and O-O bonds rupture the in the presence of methanethiol and thiophenol. The nature of the critical bond points was characterized, using the quantum theory of atoms in molecules, based on the electron location function and localized orbital locator values. Finally, the charge transfer process at the rate-determining step was investigated based on the natural bond orbital analysis. 1- INTRODUCTION In the last decades, the biological consistency of the characterized element, selenium, has been considerably designated in contrast with the toxic and beneficial effects.1 Although selenium plays the essential roles in the animal species and many bacteria,2 in 2011, selenazolidine and its relation with KashinBeck disease was studied in order to demonstrate that the selenium-containing proteins are composed of selenium as a beneficial trace element for humans and mammalian.3 In fact, selenium-enriched yeast and garlic were discovered as a crucial ingredient in our diet and inorganic selenium compounds, such as sodium 2 ACS Paragon Plus Environment

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selenite, restore the GPx activity.4 Many organoselenium compounds have been prepared to be used as antioxidant, anti-infective and antitumor agents5 and also enzyme inhibitors such as cytokine inducers.6 The first distinguished selenoprotein GPx1 is composed of five amino acids to protect their environment, biologically, against the oxidative stress through a catalytic process through the peroxides reduction. However, it mitigates the toxicity of the hydroperoxides through the reduction of hydrogen peroxide to water or similar compounds via a three-step catalytic mechanism.7 The commonly accepted catalytic cycle of the GPx is illustrated in Scheme 1.8 In the first step, the selenol part of the GPx is oxidized to selenenic acid and the peroxide is reduced to water. GSH is converted to the selenenylsulfide and H2O in the second step. In the third step, thioldisulfide, GSSG, is produced through the reduction of GSH, followed by the regeneration of selenol enzyme. Since GPx shows an original antioxidant activity in vivo, it cannot be substituted by other selenoproteins.9 The fundamental role of the mineral selenium and the selenocysteine incorporated in GPx during the translation has encouraged the researchers to synthesize numerous small molecules with GPx-like antioxidant

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activity.10 These mimics obviously point out to the catalytic properties, substrate-specific and low toxicity.

Scheme 1. Catalytic mechanism of the GPx enzyme

The new generation of the GPx mimics are classified into the three main groups: cyclic selenenylamides (Ebselen: 2-phenyl-1,2-benzisoselenazol3(2H)-one), organodiselenides (DMBS: N,N-dimethylbenzylamine-2-selenol ) and aryl/alkyl monoselenides which are depicted in Scheme 2.11-14 The first proposed nontoxic scavenger of the reactive oxygen and nitrogen species is ebselen, which has been synthesized more than 30 years ago.15 In 2011, the mechanism of ebselen as a GPx-mimic in the catalytic cycle was studied, theoretically, by the proposed density functional theory-solvent assisted 4 ACS Paragon Plus Environment

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proton exchange (DFT-SAPE) model.16 On the basis of the obtained results, it was concluded that a realistic interpretation of the redox mechanism of ebselen is provided via the SAPE modeling.

Scheme 2. Chemical structures of the new generations of the GPx mimics

Explicit water molecules provide an indirect pathway for proton shuttle, showing the role of bulk water in the solution phase as the proton transfer procedure.17 One of these processes is the microsolvation technique as the solvent assisted proton exchange model which designs the explicit solvation effects.18 For example, in a research, the oxidation reaction of the ebselen was 5 ACS Paragon Plus Environment


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considered by the SAPE-DFT modeling of the oxygen atom transfer to show an acceptable rate constant in comparison with the experimental results.19 The reduction mechanism of GPx mimic oxidation with thiols was studied by Heverly-Coulson and Boyd in 2012.12 According to their research, DMBS as a GPx mimic reduces the peroxides via a three-step catalytic mechanism in the presence of the thiol and thiolate. Thiol was considered in the proposed mechanism as the nucleophile and two molecules of water were applied as the solvent in the proton shuttle process. On the basis of the obtained results, neither methanethiol nor thiophenol has a significant effect on the energy barriers. Bayse and Ortwine, theoretically modeled the GPx-like selectivity of the seleninate by the DFT–SAPE approach in 2013.20 In this research, Seleninate which is produced by oxidation of the ω-hydroxyalkyl selenides, is more efficient than ebselen. According to the proposed models, Seleninate as a catalyst is regenerated by the selenenylsulfide.21-22 In order to analyze the mimetic aspects of the seleninate, its performance was examined via the ROS scavenging mechanism. For this purpose, several catalytic pathways were designed to determine the most probable intermediates and transition states


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(TSs). On the basis of the DFT-SAPE results, its catalytic activity was confirmed.23 In 2015, the oxidation of the selenocysteine was investigated in the GPx catalytic cycle.7 The active site was theoretically modeled to validate the mechanism aspects and the efficiency of the GPx mimic. The destruction of the redox center is prohibited by the selenenylamide route due to selenium elimination or over-oxidation. In the previous work, we have employed the quantum chemistry methods as an important tool to inquire the catalytic activity of the new GPx mimic (selenenamide) which was synthesized from the ebselen and related compounds. 24

DFT-SAPE model, natural bond orbital (NBO) and quantum theory of atoms

in molecules (QTAIM) analyses were applied to demonstrate the indirect effect of the hydrogen transfer and the nature of bond formation and cleavage, respectively. Furthermore, the kinetic and mechanistic aspects of the proposed catalytic cycle of the GPx mimic and rate-determining step were investigated through a four-step mechanism. Considering the most recent researches on the enzyme mimics shows a great interest to the reactions of the amid-based organoselenium compounds.25 7 ACS Paragon Plus Environment


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Although DMBS exhibited a poor antioxidant and low mimetic activities,12 it is possible to design new molecular structures containing both the Se−N covalent bond and the amine group. In this work, we consider the effects of different thiols as the substitute on the catalytic activity of new GPx nano mimic 1 (Figure 1). For this purpose, the molecular mechanisms were calculated by the DFT method from the energetic point of view to characterize the intermediates and TSs on the reaction pathways, relevant mechanism steps and rate-determining step (RDS).

2- COMPUTATIONAL DETAILS Geometry optimization and vibrational frequency calculations were performed by using the Gaussian 0926 at the M06-2X/6-31+G(d,p) level of theory which is an appropriate functional for organoselenium systems.27-29 The structures of the TSs were located by the Schlegel’s synchronous transit-guided quasi-Newton method (STQN) and their accuracy was checked via the intrinsic reaction coordinate (IRC) calculations.30,31 Thermodynamic parameters were obtained at the M06-2X/ 6-31+G (d,p) level within the zero-point vibrational energy, thermal and entropy corrections 8 ACS Paragon Plus Environment

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which are based on the harmonic oscillator approximation and solvation corrections at 298.15 K and 1 atm. Microsolvation technique as the solvent assisted proton exchange network was distinguished for designing the explicit solvation effects by two or three water molecules (dielectric constant of 78.36) which were applied in the conductor-like polarizable continuum model (CPCM).32-33 Additionally, there may be favorable free energies contribution due to an increased entropy which is modeled by the explicit solvent, because the entropy of the solvent is difficult to be modeled, implicitly.34. To include more accurate theoretical data, single point energies were obtained for all of the studied structures by using the mPW1PW91/6311++G(d,p) level of theory.35-36 The mPW1PW91 functional provides the best agreement with the several tested post-HF methods such as MP2 and this functional is accurate in the benchmarks of the thermochemical and kinetic parameters of the experimental data.37 On the basis of the relative energies of the catalytic cycle, state energies (E-representation) were generated by the computational study instead of the rate constants (k-representation) in an experimental study. The “state energy” is 9 ACS Paragon Plus Environment


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defined by the turnover frequency (TOF). TOF is evaluated by the energetic span model which are used to demonstrate several catalytic cycles of the organometallic reactions. Accurate TOF (turnover frequency) was evaluated based on equation 1:38 TOF =

KB T h

e

−δE⁄ RT

(1)

Where kB and h are the Boltzmann and Planck constants, respectively. R is the gas constant (1.98 cal. mol-1. K-1) and T is the absolute temperature (298.15 K). δE is the energetic span as the energy difference between the TDI (TOFdetermining intermediate) and the TDTS (TOF-determining transition state) which is calculated by equation 2.39 TTDTS - ITDI δE =

if TDTS appears after TDI (2)

TTDTS - ITDI + ΔGt

if TDTS appears before TDI

TTDTS is the energy at the highest transition state, ITDI means the energy at the lowest intermediate state and ΔGt is the reaction Gibbs energy during the catalytic cycle. On the basis of the QTAIM analysis, the topological properties such as electron densities, kinetic and potential energy densities by AIM2000


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software package,40-41 electron location function (ELF)42-47 and localized orbital locator (LOL)48-49 were calculated by Multi WFN 3.1.50 Also, NBO method was applied to evaluate the electronic charge distribution into the atomic and molecular orbitals.51 Additionally, the secondorder perturbation energies (E2) of the donor-acceptor interactions at the RDS of the methanethiol and thiophenol were calculated to investigate the stability of the structures during the reaction proceeding. E(2) = qi

(Fij ) 2

(3)

εj − εi

Where qi is the orbital occupancy, εi, εj show the diagonal elements and Fi,j represents the off-diagonal NBO Fock matrix element.52 3- RESULTS AND DISCUSSION The catalytic activity of mimic 1 in the presence of various thiols is depicted in Figure 1. To investigate the influence of the aliphatic and aromatic substituent effects on the catalytic activity of the mimic 1, methanethiol and thiophenol were considered. According to Figure 1, mimic 1 is regenerated via two intermediates of selenoxide 2 and selenurane 3 which were trapped in vitro.53 11 ACS Paragon Plus Environment


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Figure 1. Proposed catalytic cycle for the new GPx mimic 1, R = Ph, CH3.

The proposed mechanism, Figure 1, is composed of three main steps of the oxidation/reduction processes: the oxidation/reduction of 1 (step 1), the intermediate conversion (step 2), and the regeneration of the mimic 1 (step 3). Two and three water molecules (SAPE microsolvent model) are used to build a stable indirect proton exchange network as the hydrogen-bonded network in the proposed catalytic cycle. This technique makes a synchronous process of proton shuttle because water molecules play a key role in the limitation of heavy atom linkage/breakage. 12 ACS Paragon Plus Environment

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- Oxidation of 1 (Step 1 → 2). Although the oxidation reaction of ebselen was considered via a two-step hydrogen transfer mechanism,54 the oxidation of selenol zwitterion was investigated by the protons via a single-step process.55 On the basis of the obtained data, a single-step hydrogen transfer via SN2 reaction was considered as the most probable path to complete the oxidation of 1. In the experimental studies, it was suggested that the selenocysteine residue in the GPx enzyme, directly enters into the catalytic process of hydroperoxide reduction .56-58 In the first step, the reaction of 1 with H2O2, the oxidative stress conditions, has been designed by Fisher and Dereu59 to acquire selenoxide 2. In hydrogen peroxide structure, the O-O bond is broken to alleviate the formation of the Se=O bond in the selenoxide. It is noteworthy that, in the first step, the peroxide bond is broken which is followed by the proton transfer, yielding the O....H bond. The calculated bond lengths of the Se=O are 3.36Å, 2.17Å, 1.77Å in the reactant, TS and product, respectively, confirming the formation of selenoxide 2. The Gibbs energy change of this step (Figure 2a, Figure 3a) shows an 13 ACS Paragon Plus Environment


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exothermic nature, -44.1 kcal·mol-1, and the activation energy of the oxidation of 1 is 26.8 kcal.mol-1. Although the calculated activation energy is higher than the experimental data for the GPx (14.9 kcal.mol-1)60, it significantly overestimates the reaction barrier of the GPx1 more than 10.0 kcal mol-1, but the activation energy of the oxidation of 1 (26.8 kcal.mol-1) is in good agreement with the hybrid QM/MM calculations on the first redox step of the Bovine GPx (26.3 kcal.mol-1).27 - Reduction of selenoxide 2 in the presence of thiols (Step 2 → 3). It is well worth mentioning that selenylsulfide formation (E-Se-SG) through the seleno-sulfide linkage has been experimentally observed.61 Hence, on the basis of the experimental data, the reduction mechanism of selenoxide 2 was modeled in the presence of thiols. The H-transfer process from the thiol proceeds through a concerted four-center TS, in which three-hydrogen atom transfer is related to: 1) From the thiol to water molecule, 2) from the water molecule to the oxygen atom of the second water molecule, 3) from the second water molecule to the oxygen atom of selenoxide which is followed by the Se−S bond formation, yielding selenurane and also three water molecules. This model of proton shuttle 14 ACS Paragon Plus Environment

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is possible through the incorporation of the protic solvent that plays an important role in the thiolic hydrogen atom transfer to the oxygen atom of selenoxide. On the basis of the computational studies of Coulson and Boyd, two water molecules are necessary for hydrogen transfers.62 An effective process of the proton shuttle is not possible through a single water molecule, because a single water molecule is not sufficiently flexible to accept a hydrogen bond from the thiol. Accordingly, adding a second water molecule produces a chain in the reactant complex, which accepts a hydrogen bond from the thiol and donates it to the hydroxyl group. The optimized structures of the stationary points on the reaction paths are depicted in Figures 2 and 3 in the presence of methanethiol and thiophenol, respectively. In these figures, the reaction of the selenoxide 2 with the methanethiol and thiophenol has been considered in some parts of the Figures 2b and 3b, respectively. On the basis of the proposed mechanism, the hydrogen atom of the thiols is transferred to the oxygen atom of selenoxide 2 in the presence of the explicit water molecules to produce selenurane and three water molecules, which are necessary and sufficient for a normal chain of the proton transfer. 15 ACS Paragon Plus Environment

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Figure 2. Optimized stationary states on the reaction pathways within the imaginary vibrational frequencies (in parentheses) of the TSs in the presence of methanethiol. 16 ACS Paragon Plus Environment

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Figure 3. Optimized stationary states on the reaction pathways within the imaginary vibrational frequencies (in parentheses) of the TSs in the presence of thiophenol. 17 ACS Paragon Plus Environment


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This behavior can be explained based on the research reported by Wang and coworkers on the Se-N bond cleavage.63 They investigated the effects of the implicit water as the solvent on the Se-N bond splitting and concluded that the sulfur atom of the thiols is bonded to the selenium atom, without any hydrogen transfer. Since the hydrogen transfer is an important step in the proposed mechanism, using the explicit solvent molecules is not only necessary to describe comprehensively the H-transfer path, but also is suitable for completion of the catalytic cycle.

- Reduction of 3 (Selenurane) by thiols (Step 3 → 1). The final step of the catalytic cycle of 1 as the GPx mimic is considered by the reduction of thiols with selenurane in a concerted manner. Thiol acts as a nucleophile and hydrogen transfer occurs through a chain of three water molecules from the thiol to the hydroxyl group of selenium as a leaving group at the TS 31. The sulfur atom of the selenurane is linked to the sulfur atom of the thiol via the collinear interaction which is followed by the production of disulfide and water (see Figures 2c and 3c). The regeneration of 1 through the reduction of selenurane with methanethiol is 2.5 kcal.mol-1 more stable than 18 ACS Paragon Plus Environment

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thiophenol (Table 1). Furthermore, the nucleophilic attack to the sulfur atom in selenurane is an exothermic reaction. Calculated Gibbs energies of -29.3 kcal.mol-1 and -26.8 kcal.mol-1 by methanethiol and thiophenol, respectively, show that this step of total reaction (3 →1) is thermodynamically favorable. The comparison of the S-S bond length in disulfide formation in the presence of methanethiol is 1.4 Å less than thiophenol, confirming that step 3→1 is more probable in methanethiol.

- Structural and Energy Analysis. Calculated thermodynamic parameters for three steps of the catalytic cycle of 1 are represented in Table 1. According to Table 1, Gibbs energy for the reduction of hydrogen peroxide in the proposed mimic 1 is -44.1 kcal.mol-1 with an activation Gibbs energy of 26.8 kcal.mol-1. A positive value of ΔG (2→3) in the presence of methanethiol indicates that this step of the proposed mechanism is not spontaneous. Since this value is on the border line of the spontaneous and non-spontaneous reaction, it may be changed by an increment in the applied theoretical level of the calculation.



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Table 1. Calculated thermodynamic and activation parameters (kcal.mol-1) for the studied step of the proposed catalytic cycle of mimic 1. Reaction

Methanethiol

Thiophenol

pathway

ΔH≠

ΔH

ΔG≠

ΔG

ΔE≠

ΔE*

ΔH≠

ΔH

ΔG≠

ΔG

ΔE≠

ΔE*

1→2

25.5

-44.6

26.8

-44.1

18.4

-43.3

25.5

-44.6

26.8

-44.1

18.4

-43.3

2→3

26.6

1.8

29.3

2.8

29.6

-0.5

12.7

-1.2

15.9

-0.5

8.7

-4.6

3→1

4.5

-26.5

5.5

-29.3

9.3

-28.5

5.8

-21.6

8.9

-26.8

9.7

-26.1

*Single point energies were calculated by mPW1PW91/6-311++G(d,p). A lower barrier in the presence of thiophenol is likely due to its lower pKa, which enhances the reactivity. Also, the phenol ring of thiophenol stabilizes the TS23 through the resonance effects which is absent in the case of methanthiol. Therefore, the nucleophilic attack may be enhanced by using the thiophenol (phSH) backbone at the selenium center that decreases the lower energy barrier of the selenoxide reduction. To obtain a more accuracy in the theoretical data, high level of the computational theory and larger 6-311++G(d,p) basis set were chosen, based on the fact that all mechanisms in the catalytic cycle of the mimic 1 are spontaneous in the presence of the thiols, which is according to the experimental data. The optimized structures were reconsidered from the energy viewpoint at the 20 ACS Paragon Plus Environment

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mPW1PW91/6-311++G(d,p) level. According to Table 1, a value of -0.5 kcal.mol-1 as the reaction energy, at this higher level of theory, shows that this step of the proposed mechanism is thermodynamically favorable in the presence of methanethiol. Theoretical trends of the thermodynamic stability of the studied products in three steps are as follows: (1→2) ˃ (3→1) ˃ (2→3). Kinetic studies on the reaction paths show that the highest activation Gibbs energy in the presence of methanethiol is related to step 2→3, having a value of 29.3 kcal.mol-1, which shows that this step is the RDS, in agreement with the experimental data.65 There is a similar discussion for the reaction in the presence of thiophenol. In this case, step 1→2 is the RDS with an activation energy of 26.8 kcal.mol -1, which is not according to methanethiol. Kinetic studies shows that thiophenol, with a lower activation energy at the RDS, accelerates the catalytic reaction of 1 more than methanethiol. Moreover, a reported lower pKa for the thiophenol makes it proper leaving groups in these types of reactions.66 Relative Gibbs energy changes as a function of the reaction progressin the presence of the methanthiol and thiophenol is



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depctide in Figure 4 as the potential energy diagram (PED). On the basis of the PED, it is confirmed that the most stable intermediate is selenoxide (P2). Since methanethiol and thiophenol are involved in step 2→3 of the catalytic mechanism, the obtained activation energies in step 1→2 are equal which is in contrast to steps 2→3 and 3→1. Moreover, TS23 and TS12 are the most important critical structures on the PED, showing the RDS of the reaction in two cases.

Figure 4. Potential energy diagram (PED) of the proposed mechanism; the reactants Gibbs energy in each step has been considered in the presence of thiols as the reference, for more clarity.

-Accurate TOF Calculation 22 ACS Paragon Plus Environment

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Turnover frequency is used in the theoretical studies to make a relation between the theoretically calculated energy representation (E-representation) and the rate constant (k-representation) in the experimental studies.67 TOFdetermining transition state and the TOF-determining intermediate have been innovated in the catalytic cycles by equation 1. Meanwhile, δE is the energetic span to make the kinetic assessment possible through a specific computationally calculated catalytic cycle. In Figure 5, TDTS and TDI are illustrated by the energy profile of the modeled catalytic cycle of 1 in the presence of the methanthiol and thiolphenol.

Figure 5. Energy diagram of the proposed catalytic cycle to demonstrate the TOF transition states (TDTS) and TOF determining intermediate (TDI) in the presence of thiols.



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Figure 5 shows that in the presence of the methanethiol, TDTS appears after the TDI, which means that δE value (δE= TTDTS – ITDI) is 72.9 kcal.mol-1 and the corresponding TOF is equal to 3.7 × 1013 s-1. An opposite behavior is observed in the case of thiophenol, TDI appears after TDTS, which means that δE (δE= TTDTS – ITDI + ΔGt) is 35.6 kcal.mol-1 and TOF= 3.9 × 1013 s-1. Hawkes and coworkers indicated that a smaller energetic span (δE) showed a faster reaction.68,69 As a result, the catalytic cycle of the mimic 1 in the presence of thiophenol is faster than methanethiol, according to the previous analyses. - Topological Analysis The proton transfer process between the methanethiol and selenoxide in the reduction of selenoxide (2→3) and the oxidation of 1 (1→2) in the presence of thiophenol, which are introduced as the rate determining step, were studied in the framework of the QTAIM. Electron density, ρ(r), and Laplacian of the electron density, L(r), were evaluated at the bond critical points (BCPs). Additionally, the bond ellipticity at the BCPs, 𝜀 = (𝜆1/𝜆2) – 1, which estimated the anisotropy of the curvature of the electron density in the direction perpendicular to the bond, was calculated. This molecular descriptor is sensitive to the bond cleavage and formation.70,71 In the mathematical equation of the 24 ACS Paragon Plus Environment

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ellipticity, 𝜆1 and 𝜆2 are the values of the negative curvature of the electron density. The dimensionless ratios of the potential to the kinetic energy density, ǀV(r)ǀ/G(r), were calculated in order to determine the nature of bond formation and cleavage at the corresponding TSs in the RDSs.

Table 3. Topological properties of the BCPs in the RDS steps in the presence of methanthiol and thiophenol. Methanethiol Stepa 2→3

ρ(r)

ǀV(r)ǀ / G(r)

L(r)

ɛ

R

Ts

R

Ts

R

Ts

R

Ts

Se1-S6

0.000

0.015

0.000

-0.098

0.000

0.897

1.010

0.159

S6-H7

0.215

0.097

0.149

-0.016

4.693

2.556

0.058

0.174

H7-O4

0.000

0.188

0.000

0.143

0.000

3.702

0.126

0.024

O4-H3

0.331

0.260

0.513

0.324

9.457

6.537

0.019

0.022

H3-O8

0.031

0.079

-0.025

-0.033

1

1.428

0.047

0.011

O8-H10

0.032

0.017

0.489

0.164

9.119

5.072

0.020

0.023

H10-O2

0.041

0.095

-0.031

-0.013

1.009

1.809

0.051

0.004

Stepb

Thiophenol

1→2 Se1-O2

0.000

0.085

0.000

-0.031

0.000

1.372

0.143

0.062

O2-O4

0.306

0.103

0.045

-0.086

2.213

1.075

0.029

0.042

O2-H3

0.348

0.043

0.516

-0.022

9.384

1.347

0.026

0.043

O4-H3

0.000

0.103

0.000

-0.086

0.000

1.076

0.033

0.026

For atom numbering see a) Figure 2b, b) Figure 3a.



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A low value of the electron density and positive sign of the Laplacian are evidences for bond rupture of the O4-H3, O8-H10 at the TS23. On the other hand, the change of the Laplacian sign from the positive values in the reactant to negative values in the TS23 indicates a decrease in the charge density confirming the S6-H7, O4-H3 and O8-H10 bonds cleavage. The electron density increment of the Se1-S6, H7-O4, H3-O8 and H10-O2 bonds shows the corresponding bond formation. Moreover, an increase in the sigma bond character of the Se1-S6 and H10O2, from the reactant to TS23, has been specified by a decrease in the ellipticity values. A small value of 0.011 au. for the ellipticity character of the H3-O8 bond shows an advanced sigma character within a little distortion. Theoretical ratios of the ǀV(r)ǀ/G(r) at the BCPs are different, which confirms that they are different in chemical nature. On the basis of the electron densities and Laplacian values of the critical bonds in Table 3, it is confirmed that the O2-O4 and O2-H3 bonds are broken, while Se1-O2 and O4-H3 bonds are formed at the TS12. These changes are according to the electron density depletion/increment and Laplacian increment/depletion at the TS12, respectively. 26 ACS Paragon Plus Environment

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A depletion in the ellipticity values of the Se1-O2 and O2–H3 bonds from the reactant to the TS12 indicates a less distortion of the electron density and strong sigma bond. In the reactant, O2-O4 and O2-H3 bonds are the strong covalent bonds, while this character decreases at the TS confirming the bond rupture. However, Se1-O2 and O2-H3 bonds represent a middle covalent character at the TS12 which is an evidence for the corresponding bond formation. Furthermore, the analysis of electron location function and localized orbital locator of the Se1-S6 and S6-H7 bonds at the TS23, in the presence of the methanethiol, and Se1-O2 and O2-H3 bonds at TS12, in the presence of thiophenol, were shown in Figures 6 and 7, respectively. According to Figure 6, the lowest values of the ELF and LOL in the reactant regions between the Se and S atoms confirm the electrostatic interactions at the BCP, whereas higher values at the TS display the bond formation. Similarly, in Figure 7, the lowest values of the ELF and LOL in the reactant regions, between the Se and O atoms, indicate the electrostatic interactions at the BCP, while the corresponding high values at the TS regions



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confirm the bond formation. These results are in agreement with the previous analyses.

Figure 6. Electron location function and localized orbital locater of the Se···S-H bonds in presence of methanethiol at the TS23.

Figure 7. Electron location function and localized orbital locater of the Se···O-H bonds in presence of thiophenol at the TS12. 28 ACS Paragon Plus Environment

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- NBO Analysis Donor-acceptor interaction energies were calculated at the TSs in the presence of methanethiol and thiophenol. These calculations show the effects of different thiols on the stabilization energies of the corresponding TSs, using the second order perturbation energies, E(2). Moreover, natural charges were calculated to describe the charge transfer process at the TSs. Main frontier orbital interactions of the TS23 and TS12 in the presence of methanthiol and thiophenol are reported in Table 4, respectively. In Table 4, the largest stabilization energies are related to the lpO8 O4

and lpSe1

σ*O2-H3 in the reactant in the presence of methanthiol and

thiophenol, respectively. The stabilization energies of the σSe1-O2 and lpO4

σ*H3-

σ*O8-H10

σ*Se1-O2 are the maximum values at the corresponding TSs, which

are according to the bond formation/cleavage at the TSs. The calculated sum of the main stabilization energies for the TSs are 51.67 kcal.mol −1 and 18.04 kcal.mol−1 in the presence of methanthiol and thiophenol, respectively, while the corresponding values for the reactants are, 36.67 kcal.mol−1 and 15.44 kcal.mol−1. The comparison of these stabilization energies shows that a higher 29 ACS Paragon Plus Environment


Page 30 of 44

nucleophilicity value of methanthiol affects the overall energy of the donor−acceptor interactions. Table 4. Significant natural bond orbital interactions at the TSs of the proposed mechanism and stabilization energies E(2) (kcal.mol-1) in presence of methanethiol at thiophenol. Donor

Acceptor

E(2), (kcal.mol-1)

Methanthiol

Reactant

TS23

lpSe1

σ*S7-H8

1.04

lpS6

σ*O2-Se1

8.81

lpO8

σ*H3-O4

16.82

σO4-H3

σ*H10-O8

3.04

lpO8

σ*O4-H3

3.55

σN-Se1

σ*Se1-S6

15.81

σSe1-O2

σ*O8-H10

16.60

lpS6

σ*H7-O4

16.59

lpS6

σ*Se1-N

6.08

Thiophenol

Reactant

TS12

lpSe1

σ*O2-H3

12.1

lpO2

σ*O4-H5

1.94

lpO4

σ*O2-H3

1.40

lpO2

σ*Se1-O2

6.18

lpO4

σ*Se1-O2

6.88

σO2-H3

lpO4

1.68

σO16-H17

σ*Se1-O14

3.3


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In order to have an insight into the charge transfer during the reaction, the change in the atomic charges of the atoms involved at the center of the TSs was evaluated and reported in Table S1. According to Table S1 and on the basis of the charge evolution or depletion on the Se1, S6, O4, O2 and H3 atoms at the TS23 and TS12, the corresponding chemical bond formation and cleavage are confirmed. Additionally, the global electron density transfer (GEDT) values of 0.03e and -0.06e in the presence of methanethiol and thiophenol were obtained, respectively. These values are according to the electronic charge increment at the TS23 in the presence of methanethiol and electronic charge depletion at the TS12 in the presence of thiophenol. 4- CONCLUSION In this research, a kinetic thermodynamic study on the designed glutathione peroxidase nano mimic 1 was done by the DFT-SAPE model. The mechanism of action of the proposed GPx-mimic 1 was analyzed by a three-step catalytic cycle in which the effects of the methanethiol and thiophenol were considered as the nucleophiles. A higher nucleophilicity of the thiophenol than methanethiol reduces the energy barrier in the catalytic reaction. The 31 ACS Paragon Plus Environment


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significance of the dispersion interactions in the thermodynamic and kinetic studies of the proposed mechanism was considered via the mPW1PW91 functional, confirming a favorable nature of the catalytic reaction, thermodynamically. To describe the kinetic aspects of the reaction, comprehensively, energetic span model (δE) was used to evaluate the turnover frequency through which TDTS and TDI parameters were analyzed and discussed. On the basis of the location of the TDTS and TDI on the PED, the catalytic reaction of mimic 1 in the presence of thiophenol is faster than methanethiol. These analyzes show that the phenyl ring of the thiophenol is able to enrich the antioxidant activity of the new GPx-mimic 1. Moreover, QTAIM and NBO analyses were applied for investigation of the possible effects of the different thiols on the topological parameters and donor-acceptor interactions, respectively, at the TSs in the rate determining steps. Finally, the comparison of the theoretical results on the GPx mimic 1 and the experimental thermodynamic results on the glutathione peroxidase shows that mimic 1 is good enough to simulate the enzymatic behavior. Also, the


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comparison of the various GPx mimics which investigated theoretically, indicates that the proposed GPx mimic 1 is an efficient catalyst. Supporting Information Natural atomic charges calculated by the NBO method for the reactant and TSs at the RDS in the presence of methanethiol and thiophenol at the M06-2X/6 31+G(d,p) level of the theory; Cartesian coordinates of the studied compounds in the catalytic cycle of the GPX mimic 1 in water.

ACKNOWLEDGEMENT Research Council of Ferdowsi University of Mashhad, international Campus is acknowledged for financial supports (Grant No. 3/38560). REFERENCES: 1- Bodnar, M.; Konieczka, P.; Namiesnik, J. Polycyclic Aromatic Hydrocarbons and Digestive Tract Cancers: A Perspective. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2012, 30, 225-252. 2- Nogueira, C.W.; Rocha, J. B. Toxicology and Pharmacology of Selenium: Emphasis on Synthetic Organoselenium Compounds. Arch Toxicol. 2011, 85, 1313–1359. 33 ACS Paragon Plus Environment


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Computational Kinetic Modeling of the Catalytic Cycle of Glutathione

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