Theory Investigation On The Interaction Of Metal Ions With Glutathione And The Derivation

Reduced glutathione （GSH）, a thiol-containing tripeptide, γ-Glu-Cys-Gly, is the most important low molecularweight antioxidant. Glutathione also plays an important role in the complexation and elimination of some toxicmetals from organisms. Due to its important bioactivity and pharmaceutical applications, glutathione has beentargeted by researcher in many fields. Moreover, glutathione molecule possesses all kinds of biological donoratoms: two carboxyls, one thiol, one amino, and two pairs of carbonyl and amide donors within two peptide bonds.Thus, the coordination chemistry of glutathione is of vital importance as it serves as a model system for bindingmetal ions of larger peptide and protein molecules.In order to better understand the physiological function of the metal ions and the defence mech anism of GSHagainst metal ion toxicity, in this article, a thorough and comparative study of the interactions of metal ions withGSH are conducted using quantum chemistry. Moreover, In order to better understand spectra property of theGSH-OPA and the effect of metal ion on it, the electronic vertical singlet transition energies of the GSH-OPA andthe coordination complex of GSH-OPA with Zn （labeled GSH-OPA-Zn） are also presented in this work. The mainresults are as follows:（1） Density functional theory methods, AIM and NBO analysis were applied to explore the interaction ofglutathione with metal cations (Li⁺, Na⁺, K⁺, Be²⁺, Mg²⁺, Ca²⁺, Al³⁺). The different affinity of the studied metalions for different position of GSH, the structure of the complexes, the influence of the metal ions on the structureof GSH have been quantitatively characterized, which are helpful to understand the specific coordination propertyof metal ion in organism. The results show that the intramolecular hydrogen bonds of GSH are broken, newhydrogen bonds are formed, and the hydrogen transfer happened during the coordination process of metal ionswith GSH. Further, the alkali （Li⁺, Na⁺, K⁺） and alkaline earth metal (Be²⁺, Mg²⁺, Ca²⁺) are inclined tocoordination with oxygen atom of GSH. The trivalent cation Al³⁺behaves differently with alkali （Li⁺, Na⁺, K⁺）and alkaline metal ions (Be²⁺, Mg²⁺, Ca²⁺). The change of the GSH structure is significant in presence of Al³⁺ion.Firstly, the Al³⁺ion may activate the carboxyl dissociating from GSH. Secondly, it was found that the S atom andO （26） atom of carbonyl was inclined to form covalent bond in Aluminum complexes.（2） The coordination of GSH with transition metal ions (Cr²⁺, Mn²⁺, Fe²⁺, Co²⁺, Ni²⁺, Cu²⁺, Zn²⁺, Cd²⁺, Hg²⁺)and Pb²⁺are explored using density functional theory method. Through analyze the interaction energies betweenions and GSH, the deformation energies of GSH, the Wiberg Bond Index between acceptor and the donor, hybridbond orbital of complexes and the charge transfer between metal ion and GSH, We discuss the influence of metalions on the structure of GSH and the origin of metal ions selectivity. It is found that the trend of binding energies,deformed energies and the amount of charge transfer are not different in various binding mode. Generally, thebinding energies of Ni²⁺and Cu²⁺with GSH are relatively large, Cd²⁺、Hg²⁺and Pb²⁺are relatively small.Moreover, Zn²⁺、Cd²⁺、Hg²⁺and Pb²⁺are inclined to coordinate with the S atom of GSH, but Cr²⁺and Mn²⁺tend tobind with the N and O atom. Furthermore, the Cu²⁺and Ni²⁺exhibit strong oxidation to GSH.（3） In order to understanding the toxicity of metal ion of different valence state, we investigated thecoordination behavior of metal ions (Cr²⁺、Cr3+、Cr6+、Cu²⁺、Cu+、Hg²⁺、Hg+) with GSH using density functionalmethod in gas and water. Two different forms of GSH, corresponding to the prevalent ones in gas-phase （neutralGSH） and in aqueous solution （zwitterionic GSH） are also taken into account. The binding energies of metal ionswith GSH would depend on the size, the charge and the coordination number of the cation, as well as the bindingsite in GSH. Larger the charge of metal ion is, bigger the deformation of GSH is. In presence of Cr6+, themolecular skeleton of GSH is broken and the carboxyl dissociated from GSH no matter in gas phase or in aqueous solution. In the complexes of Cr3+and Cr²⁺, the covalent bonding degree of metal ion with O atom is higher thanthat with S or N atom. However, the Cu²⁺, Cu+, Hg²⁺and Hg+have higher covalent degree with S and N than thatwith O atom in the complexes. The binding energies of metal ion with zwitterionic GSH in aqueous are muchsmaller than that of the metal ions with the neutral GSH （“basket-like” conformation） in gas phase. Furthermore,the influence of aqueous on the binding energies are various for different metal ion complexes.（4） In order to better understand spectra property of the GSH-OPA and the effect of metal ion on it, theelectronic vertical singlet transition energies of the GSH-OPA and the coordination complex of GSH-OPA withZn （labeled GSH-OPA-Zn） are presented in this work. The computed absorption maximum of GSH-OPA in gasphase, water and methanol are334.6,331.7and331.6nm, respectively, which compare well with the experimentalvalue （340nm）. Coordination of Zn²⁺to GSH-OPA makes the absorption spectra red shift and gives rise to a newligand-to-metal charge transfer transition at729nm. The red shift of absorption spectra calculated in water andmethanol is smaller than in vacuum. However, the emission band of GSH-OPA at380nm is not observedred-shifted in presence of Zn （Ⅱ） ion. The maximum emission band of GSH-OPA-Zn can be assigned to theGSH-OPA intraligand π*�'π transition. The difference of maximum emission band of GSH-OPA andGSH-OPA-Zn are not significant in water and methanol. The computed maximum absorption of GSH-OPA atabout328nm and emission band at380nm compare well with the experimental value. The analysis of thestructure of GSH-OPA and GSH-OPA-Zn indicated that the enhancement of fluorescence of GSH-OPA by Zn²⁺could be due to the decrease of flexibility of GSH-OPA in present of Zn²⁺.