Abstract
Cage metal complexes iron(ii) clathrochelates, which are inherently CD silent, were discovered to demonstrate intensive output in induced circular dichroism (ICD) spectra upon their assembly to albumins. With the aim to design clathrochelates as protein-sensitive CD reporters, the approach for the functionalization of one chelate α-dioximate fragment of the clathrochelate framework with two non-equivalent substituents was developed, and constitutional isomers of clathrochelate with two non-equivalent carboxyphenylsulfide groups were synthesized. The interaction of designed iron(ii) clathrochelates and their symmetric homologues with globular proteins (serum albumins, lysozyme, β-lactoglobulin (BLG), trypsin, insulin) was studied by protein fluorescence quenching and CD techniques. A highly-intensive ICD output of the clathrochelates was observed upon their association with albumins and BLG. It was shown that in the presence of BLG, different clathrochelate isomers gave spectra of inverted signs, indicating the stabilization of opposite configurations (Λ or Δ) of the clathrochelate framework in the assembly with this protein. So, we suggest that the isomerism of the terminal carboxy group determined preferable configurations of the clathrochelate framework for the fixation in the protein binding site. MALDI TOF results show the formation of BLG–clathrochelate complex with ratio 1 : 1. Based on the docking simulations, the binding of the clathrochelate molecule (all isomers) to the main BLG binding site (calyx) in its open conformation is suggested. The above results point that the variation of the ribbed substituents at the clathrochelate framework is an effective tool to achieve the specificity of clathrochelate ICD reporting properties to the target protein.
Highlights
IntroductionBecause protein macromolecules commonly possess the large surface motifs without well-formed binding pockets and the low-molecular probes are poorly matched to them
The design and synthesis of macrocyclic compounds which are able to recognize speci c surface elements of proteins seem to be undoubtedly important for various biochemical and biomedical applications.1 These surface elements are generally hardly recognizable by regular small organic molecules, because protein macromolecules commonly possess the large surface motifs without well-formed binding pockets and the low-molecular probes are poorly matched to them
With the aim to design the functionalized iron(II) clathrochelates as induced circular dichroism (ICD) protein-sensing reporters, we developed the synthetic approach for the modi cation of one chelate a-dioximate fragment of the macrobicyclic tris-dioximate framework with two non-equivalent ribbed substituents
Summary
Because protein macromolecules commonly possess the large surface motifs without well-formed binding pockets and the low-molecular probes are poorly matched to them. Macrobicyclic metal complexes, i.e. iron(II) clathrochelates are three-dimensional, easy-to-modify molecular scaffolds prospective for the design of biologically active compounds Their interactions with biomolecules have been extensively studied to date, revealing iron(II) monoand bis-clathrochelates to be efficient (submicromolar) inhibitors in the transcription system of T7 RNA polymerase, and (low micromolar) Taq DNA polymerase.. Intensive ICD signals observed for iron(II) clathrochelates with ribbed carboxyl-terminated phenylsul de substituents were shown affected by a constitutional isomerism of the substituents (i.e., ortho-, meta- or para-positions of the terminal carboxyl groups).16 This behaviour underlines the importance of the precise electrostatic (polar) interactions between the terminal carboxyl groups and the positively charged amino acid residues of a protein for the xation of a given conformation of the clathrochelate framework. The molecular docking calculations were used to deduce the geometry of this complex
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