A DFT study on the complex formation between desferrithiocin and metal ions (Mg2+, Al3+, Ca2+, Mn2+, Fe3+, Co2+, Ni2+, Cu2+, Zn2+)

Computational Biology and Chemistry 67 (2017) 114–121

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Research Article

A DFT study on the complex formation between desferrithiocin and metal ions (Mg2+, Al3+, Ca2+, Mn2+, Fe3+, Co2+, Ni2+, Cu2+, Zn2+) Sadegh Kaviani, Mohammad Izadyar* , Mohammad Reza Housaindokht Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, Mashhad, Iran

A R T I C L E I N F O

Article history: Received 6 June 2016 Received in revised form 15 November 2016 Accepted 29 December 2016 Available online 3 January 2017 Keywords: Siderphore Desferrithiocin Binding energy Stability constants Complex formation

A B S T R A C T

In recent years, Metal-chelating compounds, namely siderphores have been considered very much because of their crucial role in various fields of the environmental researches. Their importance lies in the fact that they are able to be bonded to a variety of metals in addition to iron. A theoretical study on the structures of desferrithiocin siderphore coordinated to Mg2+, Al3+, Ca2+, Mn2+, Fe3+, Co2+, Ni2+, Cu2+ and Zn2+ metal ions was carried out, using the CAM-B3LYP/6-31G(d) level of the theory in the water. In order to understand the factors which control the stability, reactivity and the strength of toxic metals excretion as well as microbial uptake of the metal-siderphore complexes, we examined the stability and binding energies of the desferrithiocin and various metal ions with different spin states. The binding affinity of desferrithiocin to Fe3+ (log b2 = 23.88) showed that the desferrithiocin can scavenge the excess iron(III) from the labile sources. Also, the binding energy values were well described by addition of the dispersioncorrected D3 functional. Because of the importance of the charge transfer in the complex formation, donor-acceptor interaction energies were evaluated. Based on this analysis, an increase in the effective nuclear charge increases E(2) values. Vibrational analysis showed that the critical bonds (C¼O stretching H bending) are in the range of 1300–1800 cm1. Finally, some probable correlations between the and C complexation behavior and quantum chemistry descriptors have been analyzed. © 2016 Elsevier Ltd. All rights reserved.

1. Introduction Metal ions play a vital role in the pathology of many diseases such as Alzheimer’s disease (Budimir, 2011; Gaeta and Hider, 2005), iron overload (Kalinowski and Richardson, 2005), Wilson’s disease (Delangle and Mintz, 2012) and cancer (Corce et al., 2016). In all of these conditions, an increase in the level of metal ions in particular tissues of the body is very dangerous. Therefore, the investigation of the metal chelator properties such as binding energy and affinity for therapeutic applications is very crucial. Heavy metal ions such as Ni2+, Co2+ and Mn2+ can detoxificated with some chelators and consequently decrease in the toxicity and deposition in the brain (Flora and Pachauri, 2010; Andersen, 1999). In spite of the fact, metal ions are essential for the proper functioning of the living systems, their overload in the body leads to metal pollution. Hence, in the introduction of metal ion complexes, ligand to the biological systems, it is essential to investigate the reactivity and the distribution of the metal ion, ligand and final complex.

* Corresponding author. E-mail address: [email protected] (M. Izadyar). http://dx.doi.org/10.1016/j.compbiolchem.2016.12.012 1476-9271/© 2016 Elsevier Ltd. All rights reserved.

Because the permeability in the biological membranes depends on the hydrophobicity and ionic charge, charged metal ions must able to cross through the membranes by transmembrane ion channels (Florence and Attwood, 2015). In the search of therapeutic metal ion chelator and the incorporation of suitable donor atoms for the target metal, it is essential to consider the hard/soft-acid/base (HSAB) theory. HSAB theory describes the tendency of metal ions as electron acceptors and coordinating molecules as electron donors to interact with those of similar hardness or softness (Pearson, 1997). This interaction not only affects the stability of the final complex, but also alters ligand selectivity for the corresponding metal ion in the presence of other ions in solution such as Fe3+ and Al3+ (Crisponi et al., 2013). In the study of the therapeutic chelating agents to bind specific metal ions, the affinities of metal ion to the proposed chelator must be compared with endogenous metal ions in the body (Aaseth et al., 2015). Since metal ions which involve in to the redox cycle under the physiological conditions and likely bind to other ligands or biomolecules such as nucleic acid residues, the corresponding metal-binding molecules must participate in a series of ligand exchange reactions to form intended complex (Vidossich and Magistrato, 2014).

S. Kaviani et al. / Computational Biology and Chemistry 67 (2017) 114–121

Thus, the effect and affinity of chelating agents not only are probed by biological experiments, but also are investigated by theoretical methods (Duckworth et al., 2008; Chen et al., 2012a, 2012b; Zborowski et al., 2012; Domagal-Goldman et al., 2009). Therefore, although metal ions are essential to the proper functioning of living systems, but their overload in the body may cause toxic effects such as oxidative stress (Jomova and Valko, 2011). The metal overload disease treatment necessitates the administration of appropriate chelating agents to remove the metals from the body (Zhou et al., 2012; Hider, 2014; Ma et al., 2012). Siderphores are biogenic chelating agents with 200–2000 Da molecular masses that facilitate the solubilization and uptake of metal ions from their stable complexes and thus can affect on the assimilation, and transport of contaminant and nutrient metals (Ahmed and Holmstrom, 2014; Neilands, 1995). Siderphores containing multi-dentate combinations of hydroxamate, carboxylate, and chatecholate moieties secreted by microorganisms to scavenge various insoluble metals (Winkelmann, 2002). Therefore, siderphores can form stable complexes with a wide range of metal ions (Amini et al., 2016; Anderegg and Raber, 1990; Hahn et al., 1990; Rao et al., 2000), which may affect their adsorption on the mineral surfaces (Hepinstall et al., 2005; Kraemer et al., 1999), redox chemistry Dhungana and Crumbliss, 2005). Consequently, they may have strong affinity or selectivity for a particular metal due to the high stability constants of the corresponding metalsiderphore complex. The stability constants of the most siderphore-metal complexes are very high when the corresponding metal ion is Fe(III) and consequently, siderphores play an important role in the Fe(III) solubilization and uptake (Maumita et al., 2016). In addition to ferric ion, some metal ions may complex siderphores with relatively high affinities (Springer and Butler, 2016). The selectivity of siderphores for different metal cations, as well as the stability of the resulting complexes, is related to the chemical structure of the metal-siderphore complexes and this affinity may be used to expand the process of metal damages improvement or remediation of waste sites. Furthermore, knowledge of non-ferric metal siderphore affinity may also help to comprehend the anticipated mobility in natural systems such as dangerous metals in the water (Ahmed and Holmstrom, 2014). Thereby, siderphores are highly effective metal chelators and are significant tools in chemical separations, decontamination, and environmental migration of metal ions. Furthermore, siderphores play an important role in bioremediation, which is an affordable and Eco-friendly technique (Kumar and Gopal, 2015). Coordination chemistry and stability of aqueous metal-siderphore complexes with various metal ions is essential to describe the factors that control their biological uptake by microbs (Haas and Franz, 2009; Johnstone and Nolan, 2015; Hershko et al., 2005; Carrano et al., 1996; Vraspir and Butler, 2009). In addition, microbial shortcoming of some metals may cause metal uptake via siderphore-mediated pathways (Liermann et al., 2005; Bellenger et al., 2008). One of the first siderphores that was shown to be

Fig. 1. Chemical Structure of desferrithiocin.

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orally active is desferrithiocin (Bergeron et al., 2011, 2014) (Fig. 1). It belongs to a unique class of metal-complexing natural compounds and was originally observed as a metabolite in the micro-organism of Streptomyces antibuticus (Naegeli and Zahner, 1980). Desferrithiocin is known as a tridentate siderphore that forms metal stable complexes with a 2:1 stoichiometry, which the thiazoline nitrogen, the phenolic oxygen, and the carboxylate comprise the donor groups (Winkelmann, 2002; Amini et al., 2016). Unlike the hexadentate ligands, tridentates such as desferrithiocin have oral activities and thus widely used in chelation therapy (Kalinowski and Richardson, 2005) Ultraviolet-visible (UV–vis), Fourier transform infrared (FTIR) and Raman spectroscopies of the complexes used in chelation therapy have been investigated previously, like the UV–vis and Raman study of 3-Hydroxy-4-pyridinones by Sebestic and coworkers (Sebestik et al., 2012) or IR study of desferrioxamine B by Kruft and coworkers (Kruft et al., 2013). In addition to the medical aspects, the analysis of the binding geometry of siderphores and their electronic properties is a current area of research. In the present study using the density functional theory, we comparatively studied the structures and stabilities of the various metal ions forming coordination complexes with desferrithiocin. CAM-B3LYP calculations were performed to quantify the binding affinities of divalent and trivalent metals for desferrithiocin. 2. Computational details Density functional theory (DFT) calculations were performed using the Gaussian 09 program (Frisch et al., 2009). We have 2 2+ optimized the metal complexes of andML 2 and ML2 (M = Mg , 3+ 2+ 2+ 3+ 2+ 2+ 2+ 2+ Al , Ca , Mn , Fe , Co , Ni , Cu , Zn ; L = desferrithiocin) in the water by using the hybrid CAM-B3LYP exchange-correlation functional, a modified functional which is suitable for long orbital distance calculations (Yanai et al., 2004), in combination with 6– 31G(d) basis set (Rassolov et al., 1998). Low-spin (LS), intermediate-spin (IS) and high-spin (HS) states for metal desferrithiocin complexes have been considered. We also used the dispersion corrected density functional theory (DFT-D3), as suggested by Grimme (Grimme et al., 2010). The vibrational frequencies of the complexes were calculated at the same level of the theory, which showed only real frequencies. Solvent effects were taken into account by the conductor like polarizable continuum model (CPCM) (Barone and Cossi, 2001; Cossi et al., 2003; Tomasi et al., 2005). Wiberg bond indexes (WBIs), as well as the population analysis of the low-energy complexes of

ML+, ML2 , ML and ML2 2 were calculated by the natural bond orbital (NBO) method (Reed et al., 1988), as implemented in the Gaussian 09 software. 3. Results and discussion 3.1. Structural parameters Fig. 2 shows the optimized structures of the metal-desferrithiocin complexes with atom numbering. Main optimized geometries of the metal-desferrithiocin complexes (ML2 ; ML2 2 ) have been reported in Table 1, including the average length of the N bonds (dMN) within the OM O (u OMO Þ and MO (dMO), M NM O bending angles (uNMO Þ. Based on Table 1, there is not a significant change in uOMO due to a change in the metal ion, while, some important changes inuNMO , dMO and dMN have been observed. This means that an increase in the effective nuclear charge, changes the structural parameters. For example, dMO decreases with an effective nuclear charge increment further from Co2+ (Fig. 3). This trend is according to the

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Fig. 2. Optimized structures of the desferrithiocin complexes with divalent metals: a) ML without explicit water molecules b) ML with three explicit water molecules around the central metal ion c) ML2 .

Table 1 Main geometrical parameters of the desferrithiocin complexes with various metal ions. Metal ion

dMO (Å)

dMN (Å)

Mg2+ Al3+ Ca2+ Mn2+ Fe3+ Co2+ Ni2+ Cu2+ Zn2+

2.40 1.90 2.30 2.30 1.98 2.71 2.44 2.20 2.05

2.21 2.00 2.55 2.85 2.84 2.06 1.90 2.80 2.79

uOMO ðdegÞ 90.00 90.52 90.63 90.24 90.16 90.70 90.80 90.55 90.75

MLþ þ L2 Ð ML2

K2

ð2Þ

M2þ þ L2 Ð ML

K1

ð3Þ

ML þ L2 Ð ML2 2

K2

ð4Þ

uNMO ðdegÞ 75.58 83.46 68.72 67.21 69.98 86.36 78.28 69.77 69.66

After optimization of all the structures in the water, Gibbs free energies were calculated at 298.15 K and reported in Table S1. Based on the obtained DG values, the equilibrium constants and the overall stability, log b2=log K1+log K2 were computed and reported in Table 2. According to Table 2, the binding energies of the complexes are increased according to the trend of: HS > IS > LS. Therefore, an increase in the spin multiplicity improves the stability constants. Furthermore, the stability constants of the studied complexes as is follows: Fe+3 > Al+3 > Cu+2 > Zn+2 > Ni+2 > Co+2 > Mn+2 > Ca+2 > Mg+2. High stability constants of the Fe+3 and Al+3 complexes indicate the proper application of the ligand for the iron and aluminum overload diseases. The most stability constant values are in accordance with previously experimental data (Anderegg and Raber, 1990; Langemann et al., 1996). Also, Fig. 4 shows that the

Table 2 Calculated stability constants of the metal-desferrithiocin complexes with various metal ions in the water at the at the different spin states. Fig. 3. Calculated M-O bond lengths of the complexes of the various metal ions.

experimental data on the hexaaqua complexes (Yang et al., 2014; Aakesson et al., 1994). Furthermore, the bond length of divalent metal ions is greater than for trivalent metal ions.

Metal ion

Spin state

log K1

log K2

log b2

Mg2+ Al3+ Ca2+ Mn2+

– – – HS IS LS HS IS LS HS LS HS LS – –

2.21 10.11 5.60 6.98 6.06 1.24 6.78 1.68 3.78 9.82 5.70 10.22 8.66 15.25 10.66

6.94 11.96 5.75 8.30 2.41 1.30 17.1 3.76 4.38 7.20 0.70 8.47 3.86 6.80 9.53

9.15 22.07 11.35 15.28 8.47 2.54 23.88 5.44 8.16 17.02 6.4 18.69 12.52 22.05 20.19

Fe3+

3.2. Stability constants The equilibrium equations between the trivalent, and divalent metal ions with desferrithiocin have been shown by the Eqs. (1)(2) and (3)-(4), respectively.

Co2+

M3þ þ L2 Ð MLþ

Cu2+ Zn2+

K1

ð1Þ

Ni2+

S. Kaviani et al. / Computational Biology and Chemistry 67 (2017) 114–121

30 25 R² = 0.9623

logβ2

20 15 10

117

In the divalent metal ions, lower frequency of the C¼O stretching band relative to trivalent metal ions is due to the Jahn-Teller distortion (Deeth and Hitchman, 1986). For example, in Mn2+ and Cu2+ complexes, the corresponding bands are in 1759.4 cm1 and 1749.1 cm1, respectively. The relationship between the M O bond length and C¼O vibrational frequency have been presented in Fig. 6. Based on this Figure, a decrease in the M-O bond length, increases the C¼O vibrational frequency.

5 3.4. NBO analysis

0 Fe3+

Al3+ Cu2+

Zn2+ Ni2+ Co2+

Mn2+ Ca2+ Mg2+

Fig. 4. Stability constant of the studied complexes of various metal ions at the different spin states.

stability constant of trivalent metal ions is greater than for divalent metal ions. It is interesting to be mentioned that the stability constants of the desferrithiocin with metal ions, especially, Fe3+ (logb2 = 23.88) are higher than other metal-siderphores that experimentally studied through the pH-potentiometric technique by Fazary and coworkers (Fazary et al., 2016). They reported logb2 = 23.48, 19.42, 9.85 and 7.02 for the most stable complexes of the Fe-, Cu-, Ni- and Co-CIDs complexes, which are lower than the studied metal-siderphore complexes, here. The obtained results of this comparison between the proposed and applied chelators can be served as an important tool in the reasonable designing of the iron chelators for clinical uses.

Mulliken population analysis is used for understanding the electronic structure and reactivity through the charge distribution on a molecule (Murrel et al., 1985). Table 3 indicates the atomic charges on the metal cations after complexation. According to Table 3, an increase in the effective nuclear charge decreases the atomic charge, due to an increment in the covalent nature of the MO bond and consequently increase in the charge transfer from the ligand to the metal ion. However, in the case of the hexaaqua complexes, there is not a uniform decrease in atomic charge with nuclear charge increasing. In the natural bond orbital analysis, electronic wave function is elucidated in terms of occupied Lewis and unoccupied Lewis localized orbitals. The strength of donor-acceptor interactions, E (2), are evaluated by the second–order perturbation theory (Anderson et al., 1991), which is due to the delocalization of electrons from donor to acceptor. For each donor (i) and acceptor

3.3. UV–vis and IR frequencies

3 M-O bond length(Å)

Fig. S1 indicates the UV–vis spectrum of the Fe-desferrithiocin complex. Absorption maximum is at 383.6 nm which is related to HUMO to LUMO transition. Frontier molecular orbital of HOMO and LUMO have been shown in Fig. S2. In the HOMO, electron density has been distributed around the desferrithiocin ligand while in the LUMO, the electron density is shifted from desferrithiocin to Fe. Fig. 5 indicates the IR spectrum of desferrithiocin-Fe complex. There are four intense peaks at 361.58, 1398.35, 1685.25 and 1778.14 cm1 .The vibrational mode of 361.58 cm1 is related to FeO stretching, 1685.25 cm1 to C23 = N2, C3 = N1 and C14 = N19 stretching, 1778.14 cm1 to C7¼O8 and C28¼O21 stretching and 1398.35 cm1 to the C H bond bending.

Co2+ Ni2+

2.5

Mg2+ Mn2+ Ca2+ Cu2+

R² = 0.9052 3+ Zn2+ Fe

2

Al3+

1.5 1 0.5 0 1600

1650

1700

1750

1800

1850

C=O vibrational frequency (cm-1) Fig. 6. Linear correlation of the M-O bond length and the C=O vibrational frequency.

Fig. 5. IR spectrum of desferrithiocin-Fe complex, calculated at the CAM-B3LYP level.

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Table 3 Natural atomic charges on the metal atoms after complexation.

binding energies have been computed according to equation 5 (Matin et al., 2015).

Metal ion

Atomic charges

Mg2+ Al3+ Ca2+ Mn2+ Fe3+ Co2+ Ni2+ Cu2+ Zn2+

1.37 1.94 1.51 1.51 1.60 1.19 0.97 1.17 1.27

Ebind ¼

(j), the stabilization energy associated with i!j is determined by the Eq. (4). Eð2Þ ¼ DEði; jÞ ¼ qi

F ði; jÞ2 Ej  E i

ð4Þ

Where qi is the donor orbital occupancy, Ei and Ej are the diagonal elements and F(i,j) is the off-diagonal elements associated with the NBO Fock matrix (Bader, 1991). Donor-acceptor interactions in terms of E(2) values have been reported in Table 4. The most important interaction energies of these complexes are due to interactions between the lone pair electrons of O atom of the ligand (LPO) with nonbonding orbital of the metal ion (LP*M) as well as lone pair electron of N atom (LPN) with nonbonding orbital of the metal ion (LP*M). According to Table 4, there is a relatively good linear relationship between the effective nuclear charge and E(2), because E(2) values increases with an increase in the effective nuclear charge. This means that charge transfer from ligand to metal increase with the effective nuclear charge enhancement. 3.5. Metal- ligand binding energies In this section, we investigated the metal-ligand binding energies of the corresponding divalent and trivalent metal ions. After optimizing the complex and ligand, separately, metal-ligand

ðEComplex  EMetal  2ELigand Þ 2

ð5Þ

Where Ecomplex, Emetal and Eligand are the energies of the complex, corresponding metal ion and ligand components, respectively. In order to verify the results and predict the dispersion interactions, properly, the binding energies were calculated at the CAM-B3LYPD3/6-31G(d) level of theory. Theoretical metal-ligand binding energies have been reported in Table 5, were depicted in Fig. 7. According to Table 5 and Fig. 7, the D3 functional showed the higher binding energy values than CAM-B3LYP, about 5–30 kcal mol1, confirming the importance of the dispersion interactions in metal-ligand binding. The binding energies increase, generally, with an increase in the effective nuclear charge due to increase in the electrostatic interactions. Decreasing of the binding energy from Ca2+ to Mn2+ is due to Jahn-Teller distortion of the metal complex (Aakesson et al., 1994). The minimum binding energy is observed for Mn2+, because single occupation of electrons in dx2–y2 orbital does not provide an effective ligand to metal charge transfer. Furthermore, the binding energy values in the HS state is higher than IS and LS states in all cases. 3.6. Electronic chemical hardness According to the frontier molecular orbital (FMO) theory (Fukui, 1982), electronic chemical hardness can be defined on the basis of the energy gap between the HOMO and LUMO, according to equation 6 (Pearson, 1997).

h¼

ELUMO  EHOMO 2

ð6Þ

HOMO-LUMO energies and electronic chemical hardness of the desferrithiocin complexes with various metal ions in the aqueous solution have been calculated and reported in Table 6. Based on the data, Fe3+ has the maximum chemical hardness among the studied metal ions.

Table 4 Significant interactions of the desferrithiocin complexes with various metal ions. Metal ion

Donor-acceptor

E(2) (kcal. mol1)

Metal ion

Donor-acceptor

E(2) (kcal. mol1)

Mg2+

LPN1 ! LP*Mg LPN2 ! LP*Mg LPO36 ! s *Mg LPO38 ! s *Mg LPN1 ! LP*Al LPN2 ! LP*Al LPO9 ! LP*Al LPO36 ! LP*Al LPO37 ! LP*Al LPO38 ! LP*Al LPN1 ! LP*Ca LPN2 ! LP*Ca LPO9 ! LP*Ca LPO36 ! LP*Ca LPO37 ! LP*Ca LPO38 ! LP*Ca LPN1 ! LP*Mn LPO9 ! LP*Mn LPO36 ! LP*Mn LPO37 ! LP*Mn LPO38 ! LP*Mn LPN1 ! LP*Fe LPO9 ! LP*Fe LPO36 ! LP*Fe LPO37 ! LP*Fe LPO38 ! LP*Fe

11.23 9.44 10.44 11.86 29.87 36.25 28.72 21.74 28.30 23.87 11.77 11.64 12.79 17.49 13.74 10.76 12.44 15.38 29.31 27.35 16.76 19.6 22.3 20.33 20.50 24.28

Co2+

LPN1 ! LP*Co LPO9 ! LP*Co LPO36 ! LP*Co LPO37 ! LP*Co LPN1 ! LP*Ni LPN2 ! LP Ni LPO9 ! LP Ni LPO37 ! LP*Ni

19.65 17.69 27.26 18.41 84.65 61.59 2.46 23.61

Cu2+

LPN1 ! LP* Cu LPO9 ! LP*Cu LPO36 ! LP*Cu LPO37 ! LP*Cu LPO37 ! LP*Cu

11.02 19.51 16.52 18.28 20.57

Zn2+

LPN1 ! LP*Zn LPO9 ! LP* Zn LPO36 ! LP*Zn LPO37 ! LP*Zn LPO38 ! LP*Zn

20.79 36.38 32.90 34.03 40.46

Al3+

Ca2+

Mn2+

Fe3+

Ni2+

S. Kaviani et al. / Computational Biology and Chemistry 67 (2017) 114–121 Table 5 Calculated binding energy of the metal-desferrithiocin complexes with various metal ions in the water at the different spin states.

Mg Al

2+

Spin state

Method

Ebind (kcal mol1)

Metal ion

HOMO (a.u)

LUMO (a.u)

Eg (a.u)

h (a.u)

–

CAM-B3LYP CAM B3LYP-D3 CAM-B3LYP CAM B3LYP-D3 CAM-B3LYP CAM B3LYP-D3 CAM-B3LYP CAMB3LYP-D3 CAM-B3LYP CAM B3LYP-D3 CAM-B3LYP CAM B3LYP-D3 CAM-B3LYP CAM B3LYP-D3 CAM-B3LYP CAM B3LYP-D3 CAM-B3LYP CAM B3LYP-D3 CAM-B3LYP CAM B3LYP-D3 CAM-B3LYP CAM B3LYP-D3 CAM-B3LYP CAM B3LYP-D3 CAM-B3LYP CAM B3LYP-D3 CAM-B3LYP CAM B3LYP-D3 CAM-B3LYP CAM B3LYP-D3

181.97 196.41 210.21 222.76 213.35 225.90 128.63 138.05 135.05 150.60 147.46 160.01 178.84 188.25 181.09 191.39 189.88 200.8 150.60 160.01 160.05 172.56 138.05 144.32 160.01 166.35 164.72 194.52 190.16 202.37

Mg2+ Al3+ Ca2+ Mn2+ Fe3+ Co2+ Ni2+ Cu2+ Zn2+

0.13537 0.24030 0.13616 0.22372 0.24573 0.17431 0.19690 0.21693 0.18317

0.03773 0.05428 0.03243 0.09566 0.05545 0.03601 0.03362 0.03243 0.00576

0.0976 0.1860 0.1037 0.1280 0.1903 0.1383 0.1632 0.1845 0.1774

0.04881 0.09300 0.05186 0.06403 0.09514 0.06915 0.08164 0.09225 0.08870

3+

–

2+

–

Ca

Mn2+

LS IS HS

Fe3+

LS IS HS

Co2+

LS HS

Ni2+

Table 6 HOMO-LUMO energies, energy gap (Eg), and chemical hardness of the desferrithiocin complex with various metal ions (a.u).

LS HS

Cu2+

–

Zn2+

–

Predicted linear correlation of the stability constants as a function of chemical hardness has been presented in Fig. 8. Considering the regression coefficient value of 0.97 shows that there is a linear relationship between the stability constant and electronic chemical hardness. This means that an increase in the chemical hardness of the desferrithiocin complex, elevates the thermodynamic stability the complex. 4. Conclusion In this work, we have performed a systematic DFT study on the electronic structure, binding and IR spectra of the complexes between the desferrithiocin as the ligand and different metal ions (Mg2+, Al3+, Ca2+, Mn2+, Fe3+, Co2+, Ni2+, Cu2+, Zn2+) in the aqueous solution. The quantum chemistry approach has been applied to calculate logb2 values for these complexes at the CAM-B3LYP/6-31G

30 25

Mg2+ Ca2+ Mn2+

R² = 0.9719

20 log β2

Metal ion

119

Zn2+

15

Ni2+

Co2+

Cu2+ Al3+

10 Fe3+

5 0 0.04

0.05

0.06

0.07 0.08 Chemical hardness (a.u)

0.09

0.1

Fig. 8. The stability constant as a function of the chemical hardness for the desferrithiocin complexes.

(d) level of theory. Calculated stability constants agree well with the experimental data. Also, the effect of spin states on the stability constants and binding energies showed that the stability constant and binding energy values in the HS state is higher than IS and LS states. Vibrational analysis indicated that IR intensity is correlated with the metal charge and the C¼O stretching mode is sensitive to the metal ion charge. Furthermore, through the NBO analysis, the metal-ligand interactions have been studied. This analysis showed that there is a linear correlation between the stabilization energy, E (2), and the effective nuclear charge. NBO analysis showed an increase in the nuclear charge decreases the atomic charge on the metal. Furthermore, the binding energy of the various metal ionsdesferrithiocin were calculated and Mn2+ complexes showed the lowest energy of binding. Finally, According to calculations of HOMO-LUMO energy gap, a linear correlation between the electronic chemical hardness and stability constant was obtained.

Fig. 7. Metal-ligand binding energies of the desferrithiocin complexes with various metal ions at a) CAM-B3LYP and b) CAM-B3LYP-D3 level.

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