Computational Modeling of the Catalytic Cycle of Glutathione

Subscriber access provided by UNIV TORONTO

Article

Computational Modelling of the Catalytic Cycle of Glutathione Peroxidase Nano Mimic Ramesh Kheirabadi, and Mohammad Izadyar J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.6b11437 • Publication Date (Web): 07 Dec 2016 Downloaded from http://pubs.acs.org on December 12, 2016

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

The Journal of Physical Chemistry A is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 24

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

Computational Modelling of the Catalytic Cycle of Glutathione Peroxidase Nano Mimic Ramesh Kheirabadia, Mohammad Izadyar*b a

Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, International Campus, Mashhad, Iran

b

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

ABSTRACT To elucidate the role of a derivative of ebselen as a mimic of the antioxidant selenoenzyme glutathione peroxidase, density functional theory and solvent-assisted proton exchange (SAPE) were applied to model the reaction mechanism in a catalytic cycle. This mimic plays the role of glutathione peroxidase through a four-step catalytic cycle. The first step is described the oxidation of 1 in the presence of hydrogen peroxide, while selenoxide is reduced by methanthiol at the second step. In the third step of the reaction, the reduction of selenenylsulfide occurs by methanthiol and the selenenic acid is dehydrated at the final step. Based on the kinetic parameters, step 4 is the rate determining step (RDS) of the reaction. The bond strength of the atoms involved in the RDS, are discussed with the quantum theory of atoms in molecules (QTAIM). Low value of electron density, ρ(r), and positive Laplacian values are the evidences for the covalent nature of the hydrogen bonds rupture (O30-H31, O33-H34). A change in the sign of the Laplacian, L(r), from the positive value in the reactant to a negative character at the transition state indicates the depletion of the charge density, confirming the N5-H10 and O11-Se1 bond breaking. The analysis of electron location function (ELF) and localized orbital locator (LOL) of the Se1-N5 and Se1-O11 bonds have been done by multi-WFN program. A high value of ELF and LOL at the transition state regions between the Se, N and O atoms display the bond formation. Finally, the main donor-acceptor interaction energies were analysis using the natural bond orbital analysis for investigation of their stabilization effects on the critical bonds at the RDS.

1 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 24

1. INTRODUCTION The biochemistry of selenium is of the utmost importance by discovering of selenocystine which is a cysteine analogue with a selenium-containing selenol group. Glutathione peroxidase-1 (GPx1) is a kind of selenoprotein which protects cells against oxidative damage.1 The selenocysteine residue (Sec) and glutathione (GSH) are used as the reducing substrates by organic hydroperoxidase.2 In the last decades, the possible mimics of the glutathione peroxidase have been explored by the synthesis and application of the organoselenium compounds having low molecular weight.3,4 Hence, the most of the aromatic glutathione peroxidase-1 mimics have been made by organoselenium compounds.5,6 Moreover, many organoselenides such as therapeutic agents play a mimetic role as an antioxidant of selenium-based glutathione peroxidase (GPx).7 Antioxidant system is the glutathione peroxidase that defense against the reducing hydrogen peroxide and other harmful organic hydroperoxides, which use glutathione as the substrate.8 Orian et.al investigated the catalytic activity of the selenoenzymes to verify the mechanistic aspects of the GPx catalysis and its efficiency. 9 Based on the obtained data, they concluded that due to selenium over-oxidation or its elimination, the destruction of the redox center is prohibited. This behavior is important in the fine-tuning activity of the GPx.10 Scheme 1 shows the effect of Selenol (E-SeH) on the hydroperoxides which this alcohol molecule plays an active role in the reduction of hydroperoxides, yielding selenenic acid (E-SeOH). The selenosulfide (Enz-Se-SG) attacks to the second molecule of glutathione (GSH) regenerating the active site of the enzyme. According to the catalytic cycle, disulfide and water have been produced within two equivalents of glutathione and the corresponding alcohol through hydroperoxides reduction.11,12


Page 3 of 24

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Scheme 1. Catalytic mechanism of the GPx enzyme. The properties of the organoselenium-based glutathione peroxidase mimics are considered by designing the effective chemopreventatives and computational chemistry tools.13 Nevertheless, the aqueous phase proton exchange pathways caused the special circumstance for modeling the mechanisms of the GPx compounds. Small GPx mimics, which belong to a series of heterocyclic compounds, have the Se···N/O intramolecular interactions or Se–N/O linkages.14 Ebselen (2-phenyl-1,2-benziso selenazol-3(2H)-one) is the first synthetic mimic of glutathione peroxidase which is of interest for anti-inflammatory properties.15 Various types of the GPx mimics have been discovered based on ebselen containing selenium and their chemical structures are shown in Scheme 2.16-19 Stable organoselenium compounds have been considered by weak intermolecular interactions (Se···N/O) to modulate the glutathione peroxidase activity. 20,21 Approximately, all of the GPx mimics have incorporated nitrogen atom in the vicinity of the selenium to generate the covalent interactions of Se-N type and noncovalent interactions. Previous studies showed that the activity of the GPx mimics22,23 are enhanced by the noncovalent interactions between the selenium and N-containing group.24



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 24

Scheme 2. Chemical structures of some glutathione peroxidase mimics. Bayse studied the gas-phase SAPE models to represent the role of the solvent in proton exchange through the oxidation of Cys to the sulfenic acid. His studies showed an agreement between the SAPE models and experimental data on the reaction of sulfenic acid and certain protein environments.25 SAPE procedure was also used by Bayse group as the network of explicit solvent molecules to facilitate the proton transfer reaction.26 In the micro solvent SAPE model, the heavy atom proton donor/acceptor is connected to a number of solvent molecules by building a hydrogen-bonding network to supply a direct proton shuttle pathway.27 The mechanisms of the catalytic cycle activity of the GPx mimic such as ebselen have been investigated theoretically28 by Pearson and Boyd in 2008 and experimentally12 by Bhabak and Mugesh in 2010. They experimentally showed that a nitro group in the ortho position to the selenium atom inhibited the nucleophile attack to the selenium atom. Therefore, the employing of the SAPE procedure reduces the barrier of the reaction which was predicted, theoretically29. Hybrid QM/MM calculations on the first redox step of the catalytic cycle of Bovine glutathione peroxidase, GPx1, was studied by Kona and Fabian in 2011.30 They modeled the first reduction step of the bovine GPx1 based on the density functional theory (DFT) methods and then discussed on the accuracies in 4 ACS Paragon Plus Environment

Page 5 of 24

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


the prediction of the reaction barriers calculated with B3LYP, MPW1PW91, MPW1K, BB1K, M05-2X, M06-2X, and M06 functionals. Their studies indicated that the most accurate prediction of the selenium reactivity, is obtained by the MPW1PW91 and B3LYP functionals. Also, they could explain the QM calculations on the redox reaction of the selenocysteine without the assistance of the proton with a higher reaction barrier. In 2015, Kumakura et.al31 considered the glutathione peroxidase activity by investigation of the ring size and polar functional group effects, experimentally. They synthesized various series of the cyclic selenides and compared their activities as the GPx mimics by changing the substituent groups in the different solvents. Methanol as a solvent by affecting the reducing ability of the selenides enhanced their activities. Behera and Panda studied the effect of chelate ring and rigidity on the Se…N interactions.32 They reported the results of the intramolecular Se…N nonbonding interactions in a series of aryl chalcogenides substituted in the ortho position. Their investigations showed that the strength of these interactions is extremely related to the Se…N distance. Also, this interaction was analyzed by the quantum theory of atoms and molecules (QTAIM) and natural bond orbital (NBO) procedures. In 2016, Wolters and Orian18 reviewed quantum chemistry literature focused on quantum chemistry studies of the peroxidase activity of organic selenides. Boyd and coworkers reported that the reaction barrier for the direct oxidation of the organoselenium mimics approximately have a correlation with the charge of selenium in the isolated reactant molecule28,33. In the previous work, by using the quantum chemistry methods as an important support tool to inquire the structural and electronic properties of the selenol zwitterion, the role of the enzyme mimics and its catalytic activity were investigated.34 we demonstrated the theoretical modeling of the catalytic behavior of the selenol zwitterion as the mimic of the GPX. The DFT-SAPE model in the presence of water molecules were applied to show reasonably, the medium effect on the hydrogen transfer during the reaction. 5 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 24

Three steps were considered for the selenol zwitterion activity. Based on the NBO and QTAIM analyses, the nature of bond formation and cleavage at the TS of the RDS were discussed. In the recent decades, many experimental and theoretical studies have been reported the first mimic of enzyme GPx (Ebselen). But, a poor antioxidant and low mimetic activity of ebselen was reported. Therefore, a new generation of ebselen was studied based on the selenium such as the DMBS, a combination of selenium and the amine group.35 Based on the activity of this compound and our experiences, we decided to study the mechanism of action of the heterocyclic mimic based on the Se, containing the Se-N covalent bond within an improved amide-based group. Our aim here, is a comprehensive theoretical study on the catalytic activity of the new generation of the GPX, nanomimic 1, via the DFT method. For this purpose, the investigation of the molecular mechanism from the energetic point of view within the evaluation of the topological properties and donor-acceptor interactions are of a great importance, which are discussed in the following sections.

2. COMPUTATIONAL DETAILS All geometry optimizations and single-point energy calculations were done via Gaussian 09.36 Since, it has been reported that B3LYP functional shows an authentic anticipation of the organoselenium geometries and energetics,37 optimizations and frequency calculations were done using the B3LYP/631+G(d,p) level of the theory.38-39 Frequency calculations were executed to give an estimation of the zero point vibrational energies (ZPVEs) likewise their accompanying thermochemical parameters and justification of the transition state (TS) structures. Schlegel’s synchronous transit-guided quasi-Newton method (STQN) was considered to distinguish the TS structures40 and the validity of the proposed reaction paths was confirmed by intrinsic reaction coordinate (IRC) procedure.41


Page 7 of 24

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


In the SAPE networks, two or three water molecules were considered for accounting the solvation effects,42 also to include the solvent effects on the probable reactions, conductor-like polarizable continuum model (CPCM) was applied.43,44 In order to have more accurate data, dispersion interactions have been evaluated in energy calculations by using the single point energies at the mPW1PW91-6-311++G (d,p) level of the theory.45,46 Topological properties such as electron densities, kinetic and potential energy densities,47 electron location function (ELF)48-54 and localized orbital locator (LOL)55,56 were evaluated using the QTAIM procedure by Multi WFN 3.1.57 Finally, the electronic charge distributions into the atomic and molecular orbitals were examined by using the NBO method.58 Accordingly, the stability of the structures during the reaction proceeding were investigated by the second-order perturbation energies, E2, of the donor-acceptor interactions at the RDS.

3. RESULTS and DISCUSSION In order to investigate the catalytic activity of the proposed GPx mimic, the catalytic cycle of mimic 1 has been depicted in Figure 1. This figure shows the regeneration of 1 from the selenoxide 2 by two equivalents of methanthiol. Selenenylsulfide 3 and selenenic acid 4 are considered as the intermediates in the reaction pathway which have been detected in vitro conditions.61 The proposed mechanism in Figure 1 was modeled by DFT-SAPE approach in which hydrogen peroxide and methanthiol were considered. There are three main steps in the oxidation/reduction process which as follows: a) Oxidation/ Reduction of 1 b) Catalytic cycle of GPx mimic c) Regeneration of 1. In the SAPE microsolvent model, three water molecules as the hydrogen bonded network, were considered to build a stable indirect proton exchange network in the catalytic cycle. In this model, the proton shuttle is a synchronous process because heavy atom linkage/breakage is limited by the number of water molecules.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 24

O Me Me

N

Me

H2O

CH3SH

Se

2

O

H2O2

H2O O

O

Me

Me Me Me

N

HN

Me

Me Se

SCH3

Se

3

1 -H2O

O

O

CH3SH

Me Me

HN

Me

H2O

Se

4

OH

Figure 1. Proposed catalytic cycle of the new GPx mimic 1

3-1. THE OXIDATION of 1 (step

)

Based on the Pearson report on the ebselen, the oxidation reaction occurs through a two-step hydrogen transfer mechanism.28 However, the experimental kinetic studies have illustrated that the real ebselen system is completed by protons via a single-step process.59 Accordingly, the oxidation of complex 1 is done through a single-step as depicted in Figure 2a. Fisher and Dereu60 designed the reaction of 1 under the oxidative stress conditions in the presence of H2O2, yielding the selenoxide 2. The O-O bond of the hydrogen peroxide is broken to facilitate the reaction proceeding through the S=O bond formation in the selenoxide. There is a remarkable point that there is not any H…O bond in this stage, because the proton shifting occurs after the peroxide bond cleavage. Gibbs energy change for this step is -50.13 kcal.mol-1 with an exothermic nature, for the oxidation of 1, and a free energy barrier of 13.06 kcal.mol-1. 8 ACS Paragon Plus Environment

Page 9 of 24

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


3-2. THE REDUCTION of SELENOXIDE 2 with METHANTHIOL (step 2→3) According to the proposed mechanism, a concerted H-transfer of the thiol makes it possible to Se-S bond be formed. The six-center transition state is formed under a lot of strains in which the protic solvent molecules are used as a proton shuttle which transfer the thiolic hydrogen to the amide group, Figure 2b. The reaction of selenoxide and methanthiol was modeled, theoretically under the conditions of the explicit and implicit water molecules as the solvent. In the implicit procedure, the sulfur atom of the thiol is bonded to the selenium without the thiolic hydrogen transferring to the amide leaving group,22 while the solvent molecules under the explicit conditions are added to the reactant as the proton shuttle. For this purpose, three water molecules have been considered to complete the chain of the proton transfer. In this procedure, a concerted transition state is obtained by the following proton transfer processes from: thiol to water, water to water, water to water and finally, water to amide. According to Table S1, the Se-N bond length increases during the reaction and TS23 is formed by the nitrogen atom linked to the SAPE network. The calculated activation barrier of 20.65 kcal.mol-1 for this synchronous reaction (step 2→3) is according to the SN2 reactions.17 Moreover, the ring-opening process by methanthiol reduction is a spontaneous exothermic reaction, ΔG= -9.11 kcal.mol-1.

3-3. THE REDUCTION of 3 (SELENENYLSULFIDE) by METHANTHIOL (step 3→4) The third step of the catalytic cycle of the GPx mimic is the reduction of selenenylsulfide. In the presence of methanthiol, which acts as a nucleophile, water molecules generate a chain for the thiolic Htransfer from the methanthiol to the oxygen atom of the selenoxide, according to Figure 2c. The length of the S-S bond, Table S1, between the selenenylsulfide and methanthiol is an evidence for weak interactions in the reactant. Nevertheless, a high interaction between the Se and S atoms in the reactant and Se-S bond cleavage in the product is probable.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

Page 10 of 24

a)

b)

c)

d)

Figure 2. The optimized stationary states on the reaction pathways, atom numbering and the imaginary vibrational frequencies of the TSs. 10 ACS Paragon Plus Environment

Page 11 of 24

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


In this step, the Se…..O interaction in the selenenylsulfide is important which passes through a saddle point by an activation energy of 19.87 kcal.mol-1. This step, 3→4, is thermodynamically favorable, ΔG=-8.24 kcal.mol-1.

3-4. THE DEHYDRATION of the SELENENIC ACID (step 4→1) According to Figure 2d, four water molecules as the SAPE network are necessary to complete a chain for the proton shuttle from the amide to selenenic acid. The SAPE model confirms substantially a low energy barrier in comparison to the direct proton transfer. In this step, 4→1, the Se-N bond formation is of a great importance which is obtained by the N-H and Se-OH bond cleavage at the TS41, in a concerted pathway followed by a water molecule release. Although, this step is thermodynamically favorable, ΔG= 5.07 kcal.mol-1, but it is a kinetic control process with an activation energy value of 30.10 kcal.mol-1. This is the highest barrier energy in all of the studied steps.

3-5. STRUCTURAL and ENERGY ANALYSIS After optimization of the structures, geometrical parameters of the important bonds were reported for the reactants, TSs and products in Table S1 in all steps of the proposed mechanism. Comparison between the interatomic distances on the stationary points of the reaction in the different steps show the critical changes in each step of the reaction. For example, the bond cleavage of the S 14-H15, O16-H18 and N5Se1 in step 2, Se1-S14, S28-H29 in step 3, Se1-O11, H10-N5 and H34-O33 in step 4 are the critical bond splitting during the reaction. On the other hand, the bond formation of the Se1-O7 in step 1, Se1-S14 and H15-O16 in step 2, S14-S28, H29-O34 in step 3 and O11-H34, N5-Se1 and O33-H31 in step 4 are of more importance.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 24

Thermodynamic and activation parameters for the proposed steps were calculated and reported in Table 1. Based on the calculated activation Gibbs energies, step 4→1 is the rate determining step from the energy point of view, while step 1→2 is the most favorable step, thermodynamically. In order to improve the accuracy of the obtained data within the inclusion of the dispersion interactions in energy calculations, single point energies were computed at the MPW1PW91/6-311++G(d,p) level and reported in Table 1. According to the obtained data by two functionals, the probable RDS and the most stable products, obtained by different functionals are the same. In order to have a pictorial knowledge of the relative energies of the studied paths in the catalytic cycle, relative Gibbs energies of the reactant, TSs and products as a function of the reaction coordinate were depicted in Figure 3. From the kinetic point of view, steps (2→3) and (3→4) have nearly equal barrier energy, while step (4→1) shows the highest activation energy. Theoretical trend in the saddle point energy is as follows: (1→2) ˃ (2→3) ˃ (3→4) ˃ (4→1). Table 1. Calculated thermodynamic and activation parameters (kcal.mol-1) of the proposed catalytic cycle. ΔE

ΔH

ΔG

ΔE≠

ΔH≠

ΔG≠

Step 1→2

-48.86

-56.16

-50.13

16.97

7.11

13.06

Step 2→3

-15.32

-12.65

-9.11

14.51

13.95

20.65

Step 3→4

-19.98

-11.43

-8.42

9.91

11.83

19.87

Step 4→1

-2.00

-4.72

-5.07

32.47

26.01

30.10


Page 13 of 24

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 3. Potential energy diagram (PED) of the proposed mechanism, the reactants Gibbs energy in each step has been considered as the reference, for more clarity.

3-6. QTAIM ANALYSIS Since QTAIM procedure is a unique method for evaluation of the critical bond nature at the RDS, the proton transfer reaction between the amide and the hydroxyl groups of the selenenic acid, step (4→1), was investigated by the framework of the QTAIM. For this purpose, electron density ρ(r), Laplacian of the electron density, L(r), and the ratio of ǀV(r)ǀ/G(r) at the bond critical points (BCP) were computed to quantify the nature of the bond rupture/formation.62



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 24

Table 2. Topological properties of the BCPs. ρ(r)

Step

ǀV(r)ǀ/G(r)

L(r)

4→1

R

Ts

R

Ts

R

Ts

Se1-N5*

0.000

0.098

0.000

-0.030

0.000

1.550

N5-H10

0.345

0.067

0.465

-0.021

11.117

1.432

H10-O30

0.000

0.263

0.000

0.313

0.000

6.500

O30-H31

0.327

0.250

0.472

0.293

8.757

6.200

H31-O33

0.042

0.082

-0.030

-0.029

1.000

1.464

O33-H34

0.348

0.282

0.507

0.366

9.154

7.318

H34-O11

0.026

0.063

-0.020

-0.035

1.000

1.204

O11-Se1

0.133

0.068

-0.061

-0.038

1.534

1.24

*For atom numbering see Figure 2.

According to Table 2, negative values of the Laplacian dominate a shared sell interaction indicating the covalently bond atoms such as Se1-N5, H31-O33, H34-O11 and O11-Se1 (For atom numbering see Figure 2). On the other hand, low value of electron density ρ(r) and positive character of the Laplacian are the evidences for the covalently rupture of O30-H31 and O33-H34. Moreover, a change in the sign of the Laplacian from the positive values in the reactant to a negative character in the TS, indicates the depletion of the charge density confirming the N5-H10 and O11-Se1 bond cleavage. An electron density increment for the Se1-N5, H10-O30, H31-O33 and H34-O11 bonds is accompanied by bond formation. The obtained ratios of ǀV(r)ǀ / G(r) >2 at the BCPs, are related to the covalent bond and pure shared shell nature.


Page 15 of 24

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 4. Electron location function and localized orbital locater of the Se….N and Se….O bonds. Furthermore, a pictorial view of the electron location function (ELF) and localized orbital locator (LOL) of the Se1-N5 and Se1-O11 bonds were shown in Figure 4. The greatly localized electrons, lone pairs or inner shells of an atom are described by a large value of ELF. According to Figure 4, the lowest values of ELF and LOL in the reactant between the Se…N and Se…O atoms express their electrostatic nature of interaction, while a high value of the ELF and LOL at the TS displays the bond formation between these atoms.

3-7. NBO ANALYSIS The effects of the electronic charge changes and intermolecular orbital interactions on the reaction proceeding have been analyzed by NBO procedure.63 Natural atomic charges of the atoms at the center of the reaction were calculated and reported in Table 3. According to Table 3, a positive charge was developed on O30, H10, H31 and H34 atoms, while Se1, N5, O33 and O11 atoms support a negative character. In the presence of the large negative atomic charge value of O11 at the TS and the positive character of H34 atom induces a strong attraction followed by a chemical bond formation. Moreover, positive charge 15 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 24

loss by Se1 atom at the TS within a negative charge development on O11 makes the bond depletion, more possible. Table 3. The individual atomic charges calculated by the NBO method for the reactant and TS at the RDS (step 4→1). R

TS

Δq≠

Se1

0.57

0.47

-0.10

N5

-0.63

-0.76

-0.13

H10

0.45

0.55

0.10

O30

-1.06

-0.94

0.12

H31

0.53

0.56

0.03

O33

-1.05

-1.05

0.0

H34

0.52

0.55

0.03

O11

-0.96

-1.12

-0.16

The global electron density transfer (GEDT) which is an important parameter in the kinetics of the organic reaction was calculated. A value of -0.11e for the theoretical GEDT indicates the electronic charge depletion at the TS, showing the importance of the electron donor-acceptor groups on the designed mimics. Using the NBO analysis, donor-acceptor interaction energies were calculated and reported in Table 4. Based on this Table, the largest stabilization energies belong to the lpO11 and lpO33

σ*H31-O30, lpO11

σ*Se1-N5 and lpN5

σ*H23-O24 in the reactant

σ*H10-O30 at the TS. Moreover, the lack of the

main orbital interactions of the reactant in the TS structure shows that the electronic charge transfer between the frontier molecular orbitals are different. In addition to this fact, an increment or depletion in the donoracceptor interaction energies can be considered as a scale of the charge transfer direction between the cleaving and forming bonds during the reaction proceeding. Finally, a greater value of the sum of the stabilization energies for the TS, 232.76 kcal.mol-1, relative to the reactant, 10.18 kcal.mol-1, shows that one of the effective stabilizing parameters of the TS structure is the energy of the donor-acceptor interactions.


Page 17 of 24

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 4. Significant donor-acceptor interactions at the RDS and stabilization energies E(2).

R

TS

Donor

Acceptor

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

lpO11

σ*Se1

4.15

lpO11

σ*H32-O24

8.81

lpO11

σ*H32-O24

1.22

σSe1-N5

σ*H10-O30

11.47

lpN5

σ*H10-O30

36.99

σ*H10-O30

σ*O30-H31

31.38

lpO11

σ*Se1-N5

64.94

lpO11

σ*H23-O24

20.86

lpO33

σ*H31-O30

67.12

4. CONCLUSION Kinetic and mechanism aspects of the proposed glutathione peroxidase mimic 1 was investigated by DFT-SAPE computational modeling. Four-step pathway was considered for the mechanism of action of the mimic 1. Thermodynamic studies showed that all proposed steps are favorable. After evaluation of the activation Gibbs energies, it was confirmed that the fourth step (4→1) with an activation barrier of 30.10 kcal.mol-1 is the rate determining step of the reaction. Single point energy calculations at a higher accuracy level, mPW1PW91 functional, showed the importance of the dispersion interactions. Based on the NBO analysis, it was confirmed that charge changes of the H34 and O11 atoms at the TS within the stabilization energies of lpO33

σ*H31-O30 are the driving forces of the reaction at the RDS.

Finally, the nature of the bond formation and cleavage at the TS was confirmed through the topological parameters of electron density and the ratio of potential to the kinetic energy densities, using the QTAIM procedure. 17 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 24

ACKNOWLEDGEMENT Research Council of Ferdowsi University of Mashhad, international Campus is acknowledged for financial supports (Grant No. 3/38560). We hereby acknowledge that part of this computation was performed on the HPC center of Ferdowsi University of Mashhad. SUPPORT INFORMATION The comparison of the main interatomic distances (Å) of the optimized reactant (R), transition states (TS) and products (P) at the B3LYP/6 31+G(d,p) level of the theory (Table S1), Cartesian coordinates for all of the studied compounds in the catalytic cycle of the GPX mimic 1 in the water solvent (Table S2-S5). REFERENCES 1.

Reich, H.J.; Hondal, R.J. Why Nature Chose Selenium. ACS Chem. Biol. 2016, 11, 821-841.

2. Prasad, P.R.; Singh, H.B.; Butcher, R.J. Synthesis, Structure and Antioxidant Activity of Cyclohexene-Fused Selenuranes and Related Derivatives. Molecules. 2015, 20, 12670-12685. 3. Santi, C.; Tidei, C.; Scalera, C.; Piroddi, M.; Galli. F. Selenium Containing Compounds from Poison to Drug Candidates: A Review on the GPx-Like Activity. Curr. Chem. Biol. 2013, 7, 25-36. 4. Mugesh, G. Glutathione Peroxidase Activity of Ebselen and Its Analogues: Some Insights into the Complex Chemical Mechanisms Underlying the Antioxidant Activity. Curr. Chem. Biol. 2013, 7, 47-56. 5. Alberto, E.E.; Nascimento, V.d.; Braga, A.L. Catalytic Application of Selenium and Tellurium Compounds as Glutathione Peroxidase Enzyme Mimetics. J. Braz. Chem. Soc. 2010, 21, 2032-2041. 6. Huang, X.; Liu, X.; Luo, Q.; Liu, J.; Shena, J. Artificial Selenoenzymes: Designed and Redesigned. Chem. Soc. Rev. 2011, 40, 1171-1184. 7. Seiler, A.; Schneider, M.; Forster, H.; Roth, S.; Wirth, E.K.; Culmsee, C.; Plesnila, N.; Kremmer, E.; Radmark, O.; Wurst, W., et al. Glutathione Peroxidase 4 Senses and Translates Oxidative Stress into 12/15Lipoxygenase Dependent-and Aif-Mediated Cell Death. Cell Metab. 2008, 8, 237-248. 8. Niki, E. Lipid Peroxidation: Physiological Levels and Dual Biological Effects. Free Radic Biol Med. 2009, 47, 469-484. 9. Zaccaria, F.; Wolters, P.; Guerra, C. F.; Orian, L. Insights on Selenium and Tellurium Diaryldichalcogenides: A Benchmark DFT Study. J. Comput. Chem. 2016, 37, 1672-1680. 10. Orian, L.; Mauri, P.; Roveri, A.; Toppo, S.; Benazzi, L.; Bosello-Travain, V.; De Palma, A.; Maiorino, M.; Miotto, G.; Zaccarin, M., et.al. Selenocysteine Oxidation in Glutathione Peroxidase Catalysis: An Ms-Supported Quantum Mechanics Study. Free Radic Biol Med. 2015, 87, 1-14. 18 ACS Paragon Plus Environment

Page 19 of 24

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


11. Mukherjee, A.J.; Zade, S.S.; Singh, H.B.; Sunoj, R.B. Intramolecular Interactions. Chem. Rev. 2010, 110, 4357-4416.

Organoselenium Chemistry: Role of

12. Bhabak, K.P.; Mugesh, G. Functional Mimics of Glutathione Peroxidase: Bioinspired Synthetic Antioxidants. Acc. Chem. Res. 2010, 43, 1408-1419. 13. Bayse, C.A.; Antony, S. Molecular Modeling of Bioactive Selenium Compounds. Main Group Chem. 2007, 6, 185-200. 14. Bhabak, K.P.; Bhowmick, D.; Mugesh, G. Synthetic Glutathione Peroxidase Mimics: Effect of Nucleophilicity of the Aryl Thiol Cofactor on the Antioxidant Activity. Indian J. Chem. 2013, 52, 10191025. 15. Kuzma, D.; Parvez, M.; Back, T.G. Formation of A Spirodiazaselenurane and Its Corresponding Azaselenonium Derivatives from the Oxidation of 2, 2′-Selenobis (Benzamide). Structure, Properties and Glutathione Peroxidase Activity. Org. Biomol. Chem. 2007, 5, 3213-3217. 16. Sarma, B.K.; Manna, D.; Minoura, M.; Mugesh, G. Synthesis, Structure, Spirocyclization Mechanism, and Glutathione Peroxidase-Like Antioxidant Activity of Stable Spirodiazaselenurane and Spirodiazatellurane. J. Am. Chem. Soc. 2010, 132, 5364-5374. 17. Donovan, J.; Copeland, P.R. Threading the Needle: Getting Selenocysteine into Proteins. Antioxid. Redox Signal. 2010, 12, 881-892. 18. Wolters, L. P.; Orian, L. Peroxidase Activity of Organic Selenides: Mechanistic Insights from Quantum Chemistry. Curr. Org. Chem. 2016, 20, 189-197 19. Orian, L.; Toppo, S. Organochalcogen Peroxidase Mimetics as Potential Drugs: A Long Story of a Promise Still Unfulfilled. Free Radic Biol Med. 2014, 66, 65-74. 20 Manjare, S.T.; Kim, Y.; Churchill, D.G. Selenium-and Tellurium-Containing Fluorescent Molecular Probes for the Detection of Biologically Important Analytes. Acc. Chem. Res. 2014, 47, 2985-2998. 21. Bayse, C.A.; Pavlou, A. Tuning the Activity of Glutathione Peroxidase Mimics through Intramolecular Se⋯N,O Interactions: A DFT Study Incorporating Solvent-Assisted Proton Exchange (Sape). Org. Biomol. Chem. 2011, 9, 8006-8015. 22. Wang, R.; Chen, L.; Liu, P.; Zhang, Q.; Wang, Y. Sensitive Near‐Infrared Fluorescent Probes for Thiols Based on Se-N Bond Cleavage: Imaging In Living Cells and Tissues. Chem. Eur. J. 2012, 18, 1134311349. 23. Sarma, B.K.; Mugesh, G. Antioxidant Activity of the Anti‐inflammatory Compound Ebselen: A Reversible Cyclization Pathway via Selenenic and Seleninic Acid Intermediates. Chem. Eur. J. 2008, 14, 10603-10614. 24. Heverly-Coulson, G.S.; Boyd, R.J. Systematic Study of the Performance of Density Functional Theory Methods for Prediction of Energies and Geometries of Organoselenium Compounds. J. Phys. Chem. A. 2011, 115, 4827-4831. 25. Bayse, C.A. Transition States for Cysteine Redox Processes Modeled by DFT and Solvent-Assisted Proton Exchange. Org. Biomol. Chem. 2011, 9, 4748-4751. 19 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 24

26. Bayse, C.A.; Shoaf, A.L. Effect of Methoxy Substituents on the Activation Barriers of the Glutathione Peroxidase-Like Mechanism of an Aromatic Cyclic Seleninate. Molecules. 2015, 20, 1024410252. 27. Bayse, C.A.; Antony, S. Modeling the Oxidation of Ebselen and other Organoselenium Compounds Using Explicit Solvent Networks. J. Phys. Chem. A. 2009, 113, 5780-5785. 28. Pearson, J.K.; Boyd, R.J. Effect of Substituents on the Gpx-Like Activity of Ebselen: Steric Versus Electronic. J. Phys. Chem. A. 2008, 112, 1013-1017. 29. Bortoli, M.; Wolters, L.P.; Orian, L.; Bickelhaupt, F.M. Addition–Elimination or Nucleophilic Substitution? Understanding the Energy Profiles for the Reaction of Chalcogenolates with Dichalcogenides. J. Chem. Theory Comput. 2016, 12, 2752-2761. 30. Kona, J.; Fabian, W.M. Hybrid QM/MM Calculations on the First Redox Step of the Catalytic Cycle of Bovine Glutathione Peroxidase GPx1. J. Chem. Theory Comput. 2011, 7, 2610-2616. 31. Arai, K.; Kumakura, F.; Takahira, M.; Sekiyama, N.; Kuroda, N.; Suzuki, T.; Iwaoka, M. Effects of Ring Size and Polar Functional Groups on the Glutathione Peroxidase-Like Antioxidant Activity of WaterSoluble Cyclic Selenides. J. Org. Chem. 2015, 80, 5633-5642. 32. Behera, R.N.; Panda, A. Effect of Chelate Ring and Rigidity on Se⋯N Interactions: A Computational Study. RSC Advances. 2012, 2, 6948-6956. 33. Heverly-Coulson, G.S.; Boyd, R.J. Theoretical Investigations on the Reaction of Monosubstituted Tertiary-Benzylamine. J. Phys. Chem. A. 2010, 114, 10706-10711. 34. Kheirabadi, R.; Izadyar, M.; Housiandokht, M.R. Computational Kinetic Modeling of the Selenol Catalytic Activity as the Glutathione Peroxidase Nanomimic. J. Theor. Biol. 2016, 409, 108-114. 35. Wilson, S. R.; Zucker, P. A.; Huang, R. R. C.; Spector, A. Development of Synthetic Compound with Glutathione Peroxidase Activity. J. Am. Chem. Soc. 1989, 111, 5936−5939. 36. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; V. Barone, B. M.; Petersson, G. A.; Nakatsuji, H., et al. Gaussian 09, Revision A. 02, Gaussian. Inc., Wallingford, CT, 2009, 200. 37. Pearson, J.K.; Ban, F.; Boyd, R.J. An Evaluation of Various Computational Methods for the Treatment of Organoselenium Compounds. J. Phys. Chem. A. 2005, 109, 10373-10379. 38. Lee, C.; Yang, W.; Parr, R.G. Development of the Colle-Salvetti Correlation-Energy Formula into a Functional of the Electron Density. J. Phys. Chem. B. 1988, 37, 785-798. 39. Becke, A.D. Density‐Functional Thermochemistry. III. The Role of Exact Exchange. J. Phys. Chem. B. 1993, 98, 5648-5652. 40. Peng, C.; Schlegel, H.B.; Frisch, M.J. Using Redundant Internal Coordinates to Optimize Equilibrium Geometries and Transition States. J. Comput. Chem. 1996, 17, 49-56. 41. Niu, S.; Hall, M.B. Theoretical Studies on Reactions of Transition-Metal Complexes. Chem. Rev. 2000, 100, 353-406.


Page 21 of 24

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


42. Antony, S.; Bayse, C.A. Modeling the Mechanism of the Glutathione Peroxidase Mimic Ebselen. Inorg. Chem. 2011, 50, 12075-12084. 43. Heverly-Coulson, G.S.; Boyd, R.J. Reduction of Hydrogen Peroxide by Glutathione Peroxidase Mimics: Reaction Mechanism and Energetics. J. Phys. Chem. A. 2009, 114, 1996-2000. 44. Scalmani, G.; Frisch, M.J. Continuous Surface Charge Polarizable Continuum Models of Solvation. I. General Formalism. J. Chem. Phys. 2010, 132, 114110-114118. 45. Adamo, C.; Barone, V. Exchange Functionals with Improved Long-Range Behavior and Adiabatic Connection Methods without Adjustable Parameters: The MPW and MPW1PW Models. J. Phys. Chem. B. 1998, 108, 664-670. 46 Perdew, J.P.; Wang, Y. Accurate and Simple Analytic Representation of the Electron-Gas Correlation Energy. Phys. Rev. B. 1992, 45, 13244-13252. 47.

Matta, C.F.; Boyd, R.J. The Quantum Theory of Atoms in Molecules. Wiley-VCH, 2007.

48. Spackman, M.A.; Byrom, P.G. A Novel Definition of a Molecule in a Crystal. Chem. Phys. Lett. 1997, 267, 215-220. 49. Scherer, W.; Sirsch, P.; Shorokhov, D.; Tafipolsky, M.; McGrady, G.S.; Gullo, E. Valence Charge Concentrations, Electron Delocalization and Β‐Agostic Bonding in d0 Metal Alkyl Complexes. Chem. Eur. J. 2003, 9, 6057-6070. 50. Shurki, A.; Hiberty, P.C.; Shaik, S. Charge-shift Bonding in Group IVB Halides: A Valence Bond Study of MH3-Cl (M= C, Si, Ge, Sn, Pb) Molecules. J. Am. Chem. Soc. 1999, 121, 822-834. 51. Becke, A.D.; Edgecombe, K.E. A Simple Measure of Electron Localization in Atomic and Molecular Systems. J. Chem. Phys. 1990, 92, 5397-5403. 52. Savin, A.; Nesper, R.; Wengert, S.; Fassler, T.F. ELF: The Electron Localization Function. Angew. Chem. Int. Ed. Engl. 1997, 36, 1808-1832. 53. Burdett, J.K.; McCormick, T.A. Electron Localization in Molecules and Solids: The Meaning of ELF. J. Phys. Chem. A. 1998, 102, 6366-6372. 54. Savin, A., Nesper, R.; Wengert, S.; Fassler, T.F. Electron Localization in Solid‐State Structures of the Elements: The Diamond Structure. Angew. Chem. Int. Ed. Engl. 1992, 31, 187-188. 55. Tsirelson, V.; Stash, A. Determination of the Electron Localization Function from Electron Density. Chem. Phys. Lett, 2002, 351, 142-148. 56. Jacobsen, H. Localized-Orbital Locator (LOL) Profiles of Chemical Bonding. Can. J. Chem. 2008, 86, 695-702. 57. Lu, T.; Chen, F. Multiwfn: A Multifunctional Wavefunction Analyzer. J. Comput. Chem. 2012, 33, 580-592. 58. Pyykko, P.; Atsumi, M. Molecular Single-Bond Covalent Radii for Elements 1–118. Chem. Eur. J. 2008, 15, 186-197. 59. Bhabak, K.P.; Mugesh, G. A Simple and Efficient Strategy to Enhance the Antioxidant Activities of Amino‐Substituted Glutathione Peroxidase Mimics. Chem. Eur. J. 2008, 14, 8640-8651. 21 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 24

60. Fischer H.; Dereu N. Mechanism of the Catalytic Reduction of Hydroperoxides by Ebselen: A Selenium-77 NMR Study. Bull Soc Chim Belg. 1987, 96, 757–68. 61. Parnham, M.J.; Sies, H. The Early Research and Development of Ebselen. Biochem. Pharmacol. 2013, 86, 1248-1253. 62. Farrugia, L.J.; Evans, C.; Lentz, D.; Roemer, M. The QTAIM Approach to Chemical Bonding between Transition Metals and Carbocyclic Rings: A Combined Experimental and Theoretical Study of (ɳ5C5h5) Mn (Co)3, (ɳ6-C6h6) Cr (Co)3, and (E)-{(ɳ5-C5h4) Cf- Cf (ɳ5-C5h4)}(ɳ5-C5h5) 2Fe2. J. Am. Chem. Soc. 2008, 131, 1251-1268. 63. Gangadharan, R.P.; Krishnan, S.S. Natural Bond Orbital (NBO) Population Analysis of 1Azanapthalene-8-Ol. Acta. Phys. Pol. A. 2014, 125, 18-22.


Page 23 of 24

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table of Contents Graphic

Catalytic Activity of Glutathione Peroxidase Nanomimic



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

262x193mm (96 x 96 DPI)

ACS Paragon Plus Environment

Page 24 of 24

Computational Modeling of the Catalytic Cycle of Glutathione

Recommend Documents