Model Studies on the Coordination of Copper in Biological Systems. The Deprotonated Peptide Nitrogen as a Potential Binding Site for Copper(II)

Abstract

1. A large number of potentially bidentate and tridentate amides, X-Y-CONH-Z, were used as model ligands to investigate the complex formation of Cu(1I) with the deprotonated peptide nitrogen in biological molecules. A combination of potentiometric titration, spectrophotometry and electron paramagnetic resonance was applied to analyse the structure of the Cu(I1) chelates formed at neutral and basic pH.2. By systematic variation of the primary binding function X, the ring size of the chelate, and the spatial properties of the C-terminal and N-terminal substituents, three classes of amide ligands could be established with reference to their capacity for Cu(I1)-induced deprotonation of NHCO and metal binding.3. Under physiological conditions of pH, peptide (class A) chelates are only formed by those bidentate amide ligands with X being either an imidazole (sp2) nitrogen or a terminal (sp3) amino nitrogen. Mercaptide sulfur must also be considered to belong in this group of strong copper(I1)-binding sites, but in our low-molecular-weight model ligands the redox equilibrium 2 Cu(I1) + 2 RSH Z 2 Cu(1) + RSSR + 2 H f interferes, yielding insoluble Cu(1)-S polymers above pH 4. In addition to the unidentate binding strength of X, entropy effects play an important role. Depending on whether X is an imidazole or amino nitrogen, only five-membered or sixmembered monocyclic chelate structures respectively cause coordination of the deprotonated peptide function.4. Biuret (class B) Cu(I1) chelates are only formed under non-physiological conditions at pH > 11.5 producing the well known violet chromophores Cu"N4. In general these complexes, which also include the Cu(I1) biguanides, show a clearly resolved electron paramagnetic resonance spectrum with nitrogen superhyperfine structure.5. A third class of peptide model ligands (class C) consists of those amides where the Cu"-X bond does not provide enough thermodynamic stability. The binding site of these class C amides includes functional groups such as carboxylate (COO-), methionine sulfur (RSR'), aliphatic or aromatic hydroxyl (OH) and amide nitrogen (NHCO) itself. When X is a pyridine (sp2) nitrogen or an amino (sp3) nitrogen, NHCO deprotonation is only promoted in five-membered but not six-membered ring chelates. On the other hand, a combination of COO-and NH2, as in asparagine, will allow deprotonation of NHCO in the presence of Cu(I1). And third, despite a pronounced unidentate affinity of the imidazole nitrogen for Cu(II), N-acetylhistamine acts as a class C amide, in contrast to imidazolylacetamide, which forms a stable Cu(I1) peptide chelate. This difference in Cu binding is explained on the basis of space-filling models. These clearly demonstrate that in the case of the 2 : l complex of Cu(I1) with N-acetylhistamine, the planarity of the ionised peptide function can not be retained in a square planar arrangement of the two amide ligands around the copper center.Over the past two decades copper-containing bioazurin have been successfully analysed by X-ray crystallography ...

Copper Coordination in the Full-Length, Recombinant Prion Protein

“…In the nonoctarepeat site, Cu 2+ interacts with backbone amides on the N-terminal side of His96, whereas in the octarepeat sites, the metal ion is directed toward the C-terminal side of each respective His (Figure 10). Typically, N-terminal coordination is preferred as observed in both model peptides and proteins (35). Recent theoretical studies by Pushie and Rauk identified the 3N 1O Cu 2+ coordination in HGGGW, observed in our crystallographic and EPR work, as the lowest energy configuration (36).…”

“…In known copper-dependent SODs, this involves Cu + and Cu 2+ (42). Although Cu 2+ readily coordinates to deprotonated amide bonds, as shown here and in our previous work, this is not the case for Cu + (35). Consequently, the binding sites identified in our studies will likely not coordinate Cu + as required for SOD function.…”

Manganese Complexes of Pyrrole‐ and ­Indolecarboxamide Ligands: Synthesis, Structure, Electrochemistry, and Applications in Oxidative and Lewis‐Acid‐­Assisted Catalysis

“…This interest is further intensified owing to the identification of such functional groups in several metalloenzymes. [76][77][78][79][80][81][82][83][84][85][86] As a consequence, several such functional groups have been incorporated with an amide group(s) to afford assorted hybrid ligands. Intriguingly, pyrrole and indole moieties, despite having importance in anion recognition, [87][88][89][90][91] have been scarcely used as far as their coordination chemistry is concerned.…”

Bonding properties and electronic structures of glycylglycinato copper(II) complexes. Molecular structure of acetylhistaminegly-cylglycinatocopper(II) dihydrate

“…It is particularly important to recognize that the acidity of the peptide hydrogen can be enhanced by orders of magnitude upon ligation of the peptide to metal ions <~'s). Hcmmerich et al have investigated a number of copper(II) complexes with bidentate and tridentate amides and concluded that deprotonation of the peptidc hydrogen can process at physiological pH ranges provided that the amide with a strong neighbouring binding site, such as amino or imidazole donors, forms a five-or six-membered chelate with the central copper ion (6). The structures of some oligopeptide-eopper(II) complexes have been confirmed by XRD, showing that deprotonated peptide nitrogen binds to the copper(II) ion.…”