Theoretical insights on Organotin (IV)-protein interaction: Density Functional Theory (DFT) studies on di-n-butyltin(IV) derivative of Glycylvaline

 

Sandeep Pokharia

Chemistry Section, Mahila Mahavidyalaya, Banaras Hindu University, Varanasi-221005, U.P., India.

*Corresponding Author E-mail: sspokharia@gmail.com

 

The density functional theory (DFT) based quantum-mechanical calculations have been performed on di-n-butyltin(IV) derivative of glycyl-valine using the Gaussian09 software package. The ground state optimization of the possible trigonal bipyramidal structure was carried out using B3LYP functional with the standard 3-21G basis set for all the atoms, except the tin(IV) atom which was described by LANL2DZ basis set along with the effective core potential, without any symmetry constraint. The harmonic vibrational frequencies were computed at the same level of theory to find the true potential energy surface (PES) minima. The charge distribution within the dipeptide and its di-n-butyltin(IV) derivative was calculated using Mulliken population analysis, Hirshfeld population analysis and natural bond orbital analysis. The frontier molecular orbital analysis was carried out to calculate the energies of highest occupied molecular orbital (E_HOMO) and lowest unoccupied molecular orbital (E_LUMO). The conceptual-DFT based global reactivity descriptors such as, electronic chemical potential, electronegativity, chemical hardness, global softness and electrophilicity index have been obtained for the dipeptide and its di-n-butyltin(IV) derivative using the frontier molecular orbital analysis. The nature of O-Sn, N-Sn, N®Sn and C-Sn bonds is discussed in terms of the Mulliken population analysis and natural bond orbital analysis. The structural analysis of the dipeptide and its di-n-butyltin(IV) derivative has been carried out in terms of the selected bond lengths and bond angles. In order to explain the formation of the studied derivative, the vibrational analysis of its characteristic infrared vibrational frequencies has also been carried out.

 

 

 

INTRODUCTION

The importance of metal ions lies in the fact that they are essential components for various physico-chemical processes occurring in living systems as well as they have potential use as metallopharmaceuticals especially anti-tumour drug. The initial success of platinum chemotherapeutic metallopharmaceuticals has prompted the researchers to non-platinum chemotherapeutics starting from the basic cis-platin framework with the aim to optimize the efficiency of such drugs.¹

 

Among the non-platinum chemotherapeutics, organotin(IV) derivatives of ligands containing hetero donor sites have emerged as potential biologically active metallopharmaceuticals owing to their unique structural features and also due to their wide range of potential biological applications most prominently potential anti-tumour activity.^1-6 In the last two decades, several of the di- and triorganotin(IV) derivatives of dipeptides have been modelled for metal-protein interactions and also been shown to exhibit wide range of biological activities.^7-12

 

These studies have motivation to understand the electronic properties of such derivatives, so as to design the new organotin(IV) derivatives with much broader biological profile. In the contemporary research, the density functional theory (DFT) based quantum-chemical methods holds special significance in order to understand the detailed electronic structure of the molecules and to calculate the properties, so as to form the theoretical basis for the experimental observations. The DFT has been successfully utilized to account for the experimental observations for several organotin(IV) derivatives with hetero donor atoms.^13-16 To the best knowledge of the author, electronic structure calculations using DFT on organotin(IV)-peptide system has not been carried out so far. In order to expand the scope of such studies to organotin(IV)-peptide system, the present study reports the DFT based quantum-mechanical calculations on the previously synthesized di-n-butyltin(IV) derivative of glycylvaline (Figure 1).¹⁷

               

Figure 1: Structure of glycylvaline (gly-val).

 

METHODOLOGY:

All quantum mechanical calculations have been performed using the Gaussian09 software package.¹⁸ The molecular structure of gly-val, and its di-n-butyltin(IV) (n-Bu₂Sn(IV)) derivative was optimized at the density functional theory (DFT) level using the B3LYP functional (combination of Becke’s three parameter (B3) gradient corrected hybrid exchange functional,¹⁹ with the dynamical correlation functional of Lee, Yang and Parr (LYP)²⁰). All the calculations were carried out without any symmetry constraint. The tin(IV) atom was described with LANL2DZ pseudo-potential basis set,²¹ whereas other atoms were described with the standard 3-21G basis set. The absence of imaginary frequencies in a harmonic frequency calculation carried out at the same level of theory indicates that the calculated geometry is a true minimum on the potential energy surface. The optimized geometrical parameters, frontier molecular orbitals, fundamental vibrational frequencies and the atomic charges were calculated theoretically using Gaussian09 package. The conceptual-DFT based global reactivity descriptors viz. electronic chemical potential (m), electronegativity (c), chemical hardness (h), global softness (S) and electrophilicity index (w) have been calculated for the dipeptide and its n-Bu₂Sn(IV) derivative using Koopman’s approximation.^22,23 In order to gain an insight into the nature of possible coordination in the studied derivative Natural Bond Orbital (NBO) analysis was carried out using the Gaussian NBO version 3.1.²⁴

 

RESULTS AND DISCUSSION:

Geometry optimization and electronic properties

The ground state geometry optimization and harmonic frequency calculations (in the gas phase) of gly-val, and its n-Bu₂Sn(IV) derivative was achieved using DFT at B3LYP/3-21G/LANL2DZ(Sn) basis set. The optimized structure and atom notation of the studied derivative is presented in Figure 2. The calculated electronic properties are summarized in Table 1. The band gap (DE = E_LUMO – E_HOMO) and various conceptual-DFT based global reactivity descriptors (on the basis of frontier molecular orbital analysis) for the dipeptide and its n-Bu₂Sn(IV) derivative are also calculated and summarized in Table 1. The Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) plots of the studied n-Bu₂Sn(IV) derivative of the dipeptide are presented in Figure 3.

 

Figure 2: The ground state optimized geometry of the n-Bu₂Sn(IV) derivative of gly-val calculated at B3LYP/3-21G/LANL2DZ(Sn) level of theory.

 

The band gap measures the stability and reactivity of the system.²³ The observed band gap (DE) value indicates that the complex is stable. Further, as evident from the Figure 3, the LUMO of the complex is concentrated around the tin(IV) center. Furthermore, the chemical hardness (h) of a system implies resistance to charge transfer, whereas global softness (S) is proportional to the polarizability of the system.²³ The observed values of  h and S (Table 1) for the studied derivative suggests that the complex resist the charge transfer and hence possess low polarizability.

 

 

Table 1: Calculated thermodynamic properties and conceptual-DFT based global reactivity descriptors of gly-val and its n-Bu₂Sn(IV) derivative calculated at B3LYP/3-21G/LANL2DZ(Sn) level of theory.

Property	Gly-Val	n-Bu2Sn(Gly-Val)
SCF energy (a.u.)a	-607.01373446	-923.29730764
Enthalpy(thermal) (a.u.)b	-606.778587	-922.821937
Free energy(thermal) (a.u.)c	-606.834199	-922.909134
Zero-point vibrational energy (kcal/Mol)	138.28782	280.97391
Dipole moment (Debye)	2.4156	9.9472
EHOMO (eV)	-6.31	-5.92
ELUMO (eV)	-0.76	0.28
DE (ELUMO - E HOMO) (eV)	5.55	6.20
Electronic chemical potential [m = (ELUMO + EHOMO)/2 ]	-3.535	-2.82
Electronegativity [c = -m]	3.535	2.82
Chemical hardness [h = ELUMO - EHOMO]	5.55	6.20
Global softness [S =  1/h ]	0.1802	0.1613
Electrophilicity index [w =  μ2/2h]	1.126	0.641

^aTotal electronic energy without zero-point correction. ^bSum of electronic and thermal enthalpy at 1 atm and 298.15 K. ^cSum of electronic and thermal free energy at 1 atm and 298.15 K.

 

 

Atomic charges and NBO analysis

The atomic charge distribution of gly-val and its n-Bu₂Sn(IV) derivative was determined by Mulliken population analysis (MPA), Hirshfeld population analysis (HPA) and Natural population analysis (NPA) at B3LYP/3-21G/LANL2DZ(Sn) level of theory. The results for the selected atoms are presented in Table 2. Population analysis allows the attribution of net atomic charges in the molecular system. Further, the distribution of positive and negative charges is significant from the perspective of increase or decrease in the bond length between atoms. The results (Table 2) indicate that the most negative atomic charges are attributed to oxygen and nitrogen atoms in the ligand, and to oxygen, nitrogen and organotin(IV) carbon atoms in its n-Bu₂Sn(IV) derivative. In the NBO analysis of the n-Bu₂Sn(IV) derivative, the most negative charges are at the organic carbon atoms. Further, in the trigonal bipyramidal arrangement of ligand around n-Bu₂Sn(IV) moiety, the charge density increases on all the coordinating atoms viz. carboxylic oxygen atom (upon deprotonation), amino nitrogen atom and peptide nitrogen atom upon coordination to the tin(IV) atom. Furthermore, the charge on the selected atoms in the ligand is smaller than the neutral complex, probably due to the high positive charge of tin(IV) atom and also due to the shift of electron density towards coordinating atoms, as reported for other organotin(IV)-oxygen system.^13,14

 

(a)	(b)

                                                                                           

Figure 3: (a) HOMO and (b) LUMO plots of the n-Bu₂Sn(IV) derivative of gly-val calculated at B3LYP/3-21G/LANL2DZ(Sn) level of theory.

 

Table 2: Atomic charges (a.u.) in terms of MPA, HPA and NPA on the selected atoms of gly-val and its n-Bu₂Sn(IV) derivative calculated at B3LYP/3-21G/LANL2DZ(Sn) level of theory.

Element	MPA		HPA		NPA
	Gly-Val	n-Bu2Sn(Gly-Val)	Gly-Val	n-Bu2Sn(Gly-Val)	Gly-Val	n-Bu2Sn(Gly-Val)
Sn	-	1.459	-	0.701	-	2.142
Caa	-	-0.756	-	-0.111	-	-1.004
Ca¢a	-	-0.743	-	-0.118	-	-1.002
Ocarboxylb	-0.546	-0.629	-0.002	-0.327	-0.629	-0.761
Namino	-0.630	-0.735	-0.018	0.151	-0.849	-0.909
Npeptide	-0.709	-0.796	0.012	-0.219	-0.665	-0.823
Ccarboxylc	0.691	0.680	0.212	0.185	0.733	0.721
C(-Namino)d	-0.318	-0.338	0.077	0.108	-0.363	-0.353
C(-CONH-)e	0.637	0.649	0.159	0.149	0.607	-0.601
C(-Npeptide)f	-0.122	-0.113	0.071	0.064	-0.178	-0.167

^aSn-C_a-C_b-C_g-C_d. ^bDeprotonated oxygen atom of the carboxyl group. ^cCarboxylic carbon atom. ^dMethylene carbon (-CH₂) bonded to the amino nitrogen atom. ^eCarbon atom of the peptide linkage (-CONH-). ^fMethyne carbon (-CH) bonded to the peptide nitrogen atom.

 

 

Structural analysis

The selected calculated geometric parameters viz. bond lengths and bond angles in gly-val and its n-Bu₂Sn(IV) derivative are summarized in Table 3. The standard 3-21G basis set, is a sufficient basis set for an accurate prediction of geometric parameters for organic part of the compounds. Also, the LANL2DZ pseudo-potential is sufficient to account for the relativistic effects on the tin(IV) atom. The calculated C-Sn, O-Sn, N-Sn and N®Sn bond lengths are comparable to the reported bond lengths for various diorganotin(IV) derivatives which possess coordination of organotin(IV) moiety with the hetero donor atoms.^11,13-15,17 Further, the calculated C(26)-Sn-C(39) is close to the reported value for the penta-coordinated n-Bu₂Sn(Gly-Val).¹⁷ The distortion of the molecule is evident from the axial angle N_amino-Sn-O(17) of 154.23°, as reported for other diorganotin(IV)-dipeptide system.¹¹ The calculated geometric parameters suggest that the complex adopts distorted trigonal bipyramidal arrangement around the tin(IV) atom with two n-butyl groups and peptide nitrogen occupying equatorial positions and the amino nitrogen and carboxylic oxygen atoms occupying the axial positions, as reported for other diorganotin(IV) derivatives of dipeptides.^{10-12,17,25­-27}

 

 

 

 

Table 3: Selected bond lengths (Å) and bond angles (°) in gly-val and its n-Bu₂Sn(IV) derivative calculated at B3LYP/3-21G/LANL2DZ(Sn) level of theory.

Bond Lengths
	Sn-C(26)	Sn-C(39)		Sn-O(17)	Sn-Npeptide		Sn-Namino		Namino-C(2)	Npeptide-C(5)		O(17)-C(13)		COpeptide
Ca	2.155	2.152		2.010	2.059		2.347		1.508	1.358		1.356		1.245
Lb	-	-		-	-		-		1.471	1.363		1.377		1.247
Bond angles
	C(26)-Sn-C(39)		C(26)-Sn-Npeptide			C(39)-Sn-Npeptide		Namino-Sn-Npeptide			Namino-Sn-O(17)		O(17)-Sn-Npeptide
Ca	118.71		120.09			119.13		74.41			154.23		79.90

^aDi-n-butyltin(IV) derivative of glycylvaline. ^bNeutral glycylvaline molecule

 

 

 

Vibrational Analysis

The n-Bu₂Sn(IV) derivative of gly-val consists of 51 atoms, hence it has 147 normal modes of vibration. The harmonic vibration frequencies were calculated for the neutral molecule in the gas phase at B3LYP/3-21G/LANL2DZ(Sn) level of theory. The theoretical infrared spectrum is presented in Figure 4. The characteristic absorption bands in gly-val and its studied n-Bu₂Sn(IV) derivative are summarized in Table 4. The calculated values for n(NH)_amino, n(CO)_amide, n_asym(OCO), n_sym(OCO) and amide II [n(CN) + d(NH)] bands are in good agreement to the reported values for other diorganotin(IV) dipeptide derivatives.^11,17,25-27 The results suggest that, the amino group is coordinated to the central tin(IV) atom, the carboxylate group acts as a monodentate ligand, the amide I (n(CO)_amide) group is not coordinated with the tin(IV) atom and the peptide nitrogen is the third coordinating site, as reported previously for the diorganotin(IV)-depeptide system.^{11,12,17,25-27} The appearance of a medium intensity absorption band at 518 cm^-1 in the studied derivative, which was otherwise absent in the free gly-val, may be assigned to the Sn-O stretching vibration, as reported previously for several organotin(IV)-oxygen derivatives.^{1,8-12,15,17,25-27} The coordination to the central tin(IV) atom is further confirmed by the appearance of medium intensity bands at 480 and 380 cm^-1, assigned to n(N-Sn) and n(N®Sn), respectively.^11,17,25-27 The n_asym(Sn-C) and n_sym(Sn-C) bands in the studied derivative were observed at 622 and 602 cm^-1, respectively, which suggests the existence of a bent C-Sn-C moiety.^11,17,25-27

Table 4: Characteristic infrared vibrational frequencies (in cm^-1) for gly-val and its n-Bu₂Sn(IV) derivative calculated at B3LYP/3-21G/LANL2DZ(Sn) level of theory.

Ligand/Complex	n(NH)amino	Amide I [n(CO)amide]	Amide II band [n(CN) + d(NH)]	nasym(OCO)	nsym(OCO)
Liganda	3386	1699	1400	1799	1188
Complexb	3469	1696	1349	1738	1204

^aNeutral glycylvaline molecule. ^bDi-n-butyltin(IV) derivative of glycylvaline.

 

Figure 4: Theoretical infrared spectrum of n-Bu₂Sn(IV) derivative of gly-val calculated at B3LYP/3-21G/LANL2DZ(Sn) level of theory.

 

 

CONCLUSIONS:

The present study has satisfactorily achieved the electronic structure calculation of di-n-butyltin(IV)-glycylvaline system at B3LYP/3-21G/LANL2DZ(Sn) level of theory. The atomic charge calculations and the NBO analysis suggest that upon coordination of gly-val molecule to di-n-butyltin(IV) moiety the electron density is concentrated around coordinating amino nitrogen, peptide nitrogen and carboxylic oxygen atoms. The frontier molecular orbital analysis and its use in the calculation of conceptual-DFT based global reactivity descriptors can rationalize the modelling of diorganotin(IV)-dipeptide derivatives for probable metal-protein interactions. Most significantly, the present work emphasizes the growing importance of DFT based quantum-chemical methods for the electronic structure calculations of organotin(IV)-peptide system, so as to design and synthesize novel metallopharmaceuticals.

 

ACKNOWLEDGEMENTS:

The author is thankful to Banaras Hindu University, Varanasi for providing necessary infrastructural facilities. Thanks are also due to Dr. H. Mishra, Physics Section, M.M.V., B.H.U., Varanasi for providing access to the Gaussian software package.

 

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Received on 11.11.2014         Modified on 24.11.2014

Accepted on 12.12.2014         © AJRC All right reserved