Unveiling the binding interaction of zinc (II) complexes of homologous Schiff‐base ligands on the surface of BSA protein: A combined experimental and theoretical approach (original) (raw)
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Two zinc(II) complexes, DBZ and DBZH4, that have (ZnN3S2) cores and differ in the bridging mode of the ligating backbone, effectively bind to BSA. The binding affinity varies as DBZ > DBZH4 and depends on the ligand structure. At low concentrations, both complexes exhibit dynamic quenching, whereas at higher concentrations they exhibit mixed (static and dynamic) quenching. The energy transfer mechanism from the BSA singlet excited state to DBZ and DBZH4, is highly likely according to steady-state fluorescence and time-correlated singlet photon counting. Molecular docking was used to support the mode of interaction of the complexes with BSA and showed that DBZ had more energy for binding. Furthermore, antibacterial testing revealed that both complexes were active but to a lesser extent than chloramphenicol. In comparison to DBZH4, DBZ has higher antibacterial activity, which is consistent with the binding constants, molecular docking, and particle size of adducts. These findings m...
A DSC study of zinc binding to bovine serum albumin (BSA)
Journal of the Serbian Chemical Society, 2007
The thermal denaturation of bovine serum albumin (BSA) is a kinetically and thermodynamically controlled process. The effects of zinc binding to bovine serum albumin (BSA), followed by differential scanning calorimetry (DSC), were investigated in this work, with the purpose of obtaining a better understanding of the albumin/zinc interaction. From the DSC curves, the thermodynamic parameters of protein denaturation were obtained, i.e., the temperature of thermal transition maximum (T m ), calorimetric enthalpy (DH cal ), van't Hoff enthalpy (DH vH ), the number of binding sites (I, II), the binding constants for each binding site (K bI, K bII ) and the average number of ligands bound per mole of native protein X N . The thermodynamic data of protein unfolding showed that zinc binding to bovine serum albumin increases the stability of the protein (higher values of DH cal ) and the different ratio DH cal /DH vH indicates the perturbation of the protein during thermal denaturation.
Using UV-Vis, FT-IR, fluorescence spectroscopy and protein-ligand docking, the interactions between the zinc complexes with drug analogues and bovine serum albumin were investigated. In addition, considering the ubiquitous presence of zinc ions in the human system, we studied the interactions between this ion with hymecromone, dihydropyridine analogue, and acetamide, as well as the pH influence on these systems. The complexes were synthesized by interaction between the ligands and the Zn (II) ion in a 2:1 M ratio. Elemental analysis , FT-IR, and UV-Vis spectroscopy studies investigated the structure of the synthesized complexes. Fluorescence spectroscopy, UV-Vis, molecular docking and molecular dynamics were used to study the interactions of the Zn complexes with the BSA. The drug-Zn (II) system's pH effect was investigated using UV-Vis spec-troscopy. After the complexation with the zinc, the drug molecules exhibited higher apparent binding affinity to BSA. BSA's fluorescence efficiency by the drug analogues was enhanced. In addition, molecular modelling was used to classify the residue of amino acids in the BSA playing key roles in this binding interaction. An increase in pH appears to contribute to alkaline hydrolysis of the Zn (II) molecules.
Analysis of zinc binding sites in protein crystal structures
Protein Science, 1998
The geometrical properties of zinc binding sites in a dataset of high quality protein crystal structures deposited in the Protein Data Bank have been examined to identify important differences between zinc sites that are directly involved in catalysis and those that play a structural role. Coordination angles in the zinc primary coordination sphere are compared with ideal values for each coordination geometry, and zinc coordination distances are compared with those in small zinc complexes from the Cambridge Structural Database as a guide of expected trends. We find that distances and angles in the primary coordination sphere are in general close to the expected (or ideal) values. Deviations occur primarily for oxygen coordinating atoms and are found to be mainly due to H-bonding of the oxygen coordinating ligand to protein residues, bidentate binding arrangements, and multi-zinc sites. We find that H-bonding of oxygen containing residues (or water) to zinc bound histidines is almost universal in our dataset and defines the elec-His-Zn motif. Analysis of the stereochemistry shows that carboxyl elec-His-Zn motifs are geometrically rigid, while water elec-His-Zn motifs show the most geometrical variation. As catalytic motifs have a higher proportion of carboxyl elec atoms than structural motifs, they provide a more rigid framework for zinc binding. This is understood biologically, as a small distortion in the zinc position in an enzyme can have serious consequences on the enzymatic reaction. We also analyze the sequence pattern of the zinc ligands and residues that provide elecs, and identify conserved hydrophobic residues in the endopeptidases that also appear to contribute to stabilizing the catalytic zinc site. A zinc binding template in protein crystal structures is derived from these observations.
Proteins: Structure, Function, and Bioinformatics, 2007
Zinc is one of the most important metal ions found in proteins performing specific functions associated with life processes. Coordination geometry of the zinc ion in the active site of the metalloprotein-ligand complexes poses a challenge in determining ligand binding affinities accurately in structure-based drug design. We report here an all atom force field based computational protocol for estimating rapidly the binding affinities of zinc containing metalloprotein-ligand complexes, considering electrostatics, van der Waals, hydrophobicity, and loss in conformational entropy of protein side chains upon ligand binding along with a nonbonded approach to model the interactions of the zinc ion with all the other atoms of the complex. We examined the sensitivity of the binding affinity predictions to the choice of Lennard-Jones parameters, partial atomic charges, and dielectric treatments adopted for system preparation and scoring. The highest correlation obtained was R 2 = 0.77 (r = 0.88) for the predicted binding affinity against the experiment on a heterogenous dataset of 90 zinc containing metalloprotein-ligand complexes consisting of five unique protein targets. Model validation and parameter analysis studies underscore the robustness and predictive ability of the scoring function. The high correlation obtained suggests the potential applicability of the methodology in designing novel ligands for zinc-metalloproteins. The scoring function has been web enabled for free access at www.scfbio-iitd.res.in/software/ drugdesign/bapplz.jsp as BAPPL-Z server (Binding Affinity Prediction of Protein-Ligand complexes containing Zinc metal ions).
Egyptian Journal of Chemistry, 2018
T HE synthesis of Schiff base HL has been done by taking an equimolar ratio of 2-hydroxy-4-methoxybenzaldehyde and 2-amino-6-methylbenzothiazole. Ligand HL has been characterized by elemental analysis, IR, 1 H NMR, 13 C NMR and ESI-mass spectrometry. The metal complexes 1-6 have been synthesized by the reaction of ligand HL with hydrated Co(II), Ni(II) and Cu(II) chlorides in ethanol, in the ligand to metal molar ratio 1:1 and 2:1. The synthesized metal complexes 1-6 were characterized by elemental analysis, molar conductance, electronic spectra, IR, UV-visible and EPR spectra. TGA has been done to check the thermal stablity of ligand as well as metal complexes. Spectral data reveals that the ligand HL acts as uninegative bidentate for all metal complexes. The geometries of metal complexes 1-6 have been given on the basis of spectroscopic studies and optimized by density functional theory. The fluorescence techniques have been used to study the interactions of metal complexes towards bovine serum albumin (BSA). The results revealed that the fluorescence static quenching of BSA by metal complexes 1-6 and entropy driven hydrophobic interactions has been seen which could be useful for further drug design.
Characterization of interactions and metal ion binding sites in proteins
Current Opinion in Structural Biology, 1994
Recent investigations show that as a class of interactions for designing proteins, hydrophobic interactions are not specific enough, hydrophilic interactions are typically too weak, and water interactions are always on the exterior. In terms of overall protein stability, there is a substantial advantage to a nucleus with strong, directional interactions. Metal ion sites in proteins exhibit strong directional preferences for their coordinate ligands, and the specificities manifested by ions have been demonstrated to be useful in reducing molecular fluctuations. The engineered introduction of zinc binding sites has been shown to improve the stabilities of designed proteins. Metal binding sites can therefore provide important structural building blocks for protein design.
Structural Studies of an Engineered Zinc Biosensor Reveal an Unanticipated Mode of Zinc Binding
Journal of Molecular Biology, 2005
Protein engineering was used previously to convert maltose-binding protein (MBP) into a zinc biosensor. Zn 2C binding by the engineered MBP was thought to require a large conformational change from "open" to "closed", similar to that observed when maltose is bound by the wild-type protein. We show that although this re-designed MBP molecule binds Zn 2C with high affinity as previously reported, it does not adopt a closed conformation in solution as assessed by small-angle X-ray scattering. Highresolution crystallographic studies of the engineered Zn 2C -binding MBP molecule demonstrate that Zn 2C is coordinated by residues on the N-terminal lobe only, and therefore Zn 2C binding does not require the protein to adopt a fully closed conformation. Additional crystallographic studies indicate that this unexpected Zn 2C binding site can also coordinate Cu 2C and Ni 2C with only subtle changes in the overall conformation of the protein. This work illustrates that the energetic barrier to domain closure, which normally functions to maintain MBP in an open concentration in the absence of ligand, is not easily overcome by protein design. A comparison to the mechanism of maltose-induced domain rearrangement is discussed.
Analysis of zinc-ligand bond lengths in metalloproteins: Trends and patterns
Proteins-structure Function and Bioinformatics, 2007
Zinc is one of the biologically most abundant and important metal elements, present in a plethora of enzymes from a broad array of species of all phyla. In this study we report a thorough analysis of the geometrical properties of Zinc coordination spheres performed on a dataset of 994 high quality protein crystal structures from the Protein Data Bank, and complemented with Quantum mechanical calculations at the DFT level of theory (B3LYP/SDD) on mononuclear model systems. The results allowed us to draw interesting conclusions on the structural characteristics of Zn centres and to evaluate the importance of such effects as the resolution of X-ray crystallographic structures, the enzyme class in which the Zn centre is included, and the identity of the ligands at the Zn coordination sphere. Altogether, the set of results obtained provides useful data for the enhancement of the atomic models normally applied to the theoretical and computational study of zinc enzymes at the quantum mechanical level (in particular enzymatic mechanisms), and for the development of molecular mechanical parameters for the treatment of zinc coordination spheres with molecular mechanics or molecular dynamics in studies with the full enzyme. Proteins 2007. © 2007 Wiley-Liss, Inc.