Specific structure–stability relations in metallopeptides
Introduction
Peptides are very effective and often specific ligands for a variety of metal ions. They contain a range of potential donor atoms and the complexes formed exist in a variety of conformations [1], [2]. Among metal ions, Cu(II) and Ni(II) have been widely studied and seem to have the most interesting chemistry. In particular, these two metal ions share the peptidic binding site at the N-terminus of human serum albumin, which is their transport form in the human body [3], [4], [5], [6].
Peptides with non-coordinating side-chains possess amino and amide nitrogens and carbonyl and carboxyl oxygens as donor sites. Oligoalanine (Fig. 1) is a good example of such a ligand. Although the basic binding mode provided by a peptide with non-coordinating side-chains is simple, a number of variations can occur, when particular residues are inserted into the peptide sequence. The residues containing aromatic rings, like Tyr or Phe, may contribute to stability of the complex or its structure through hydrophobic interactions or ring stacking. The interactions between peptide residues may favour a particular peptide conformation, which in turn may have an essential impact on metal–peptide coordination equilibria, both in a thermodynamic and a structural sense. As the number of biologically important amino acid residues exceeds twenty, the side chains thus available may be involved in a variety of intramolecular interactions, making metallopeptide systems structurally very specific. This may result in metal-assisted modulation of biological activity, e.g. when a neuropeptide interacts with its receptor.
Conformational consequences of metal ion binding to peptide ligands may also have a critical impact on the peptide folding processes. Protein folding, and in particular hydrophobic effects, although receiving much attention, are only partly understood [7]. The existence of a relation between the binding of metal ions to proteins and the local hydrophobicity at the binding site has been recognised only recently [8]. Thus, detailed studies on the relations between the peptide sequence, complex structure and thermodynamical stability are instrumental for the understanding of biological functions of peptides as well as the impact of metal ions on protein folding and conformation.
The main aim of this review is the presentation of specific interactions in Cu(II) and Ni(II)–peptide systems, like unusual binding modes or very high complex stabilities that involve interactions additional to the direct coordination of a metal ion to a peptide donor system. The first part is devoted to oligopeptides of four or more amino acid residues, because they are principally capable of providing the saturated (four nitrogen, or 4N)1 equatorial binding site. The shorter peptides have been extensively reviewed [9], [10]. We made an exception for α-hydroxymethyl-l-serine (HmS)-containing tripeptides for the striking complex stability-enhancing capabilities of this amino acid. The second part of this review describes coordination properties of peptides containing histidine residues, for their unique binding efficacy and biological relevance of their Cu(II) and Ni(II) complexes.
Section snippets
Metal ion binding to simple peptides with non-coordinating side-chains
Oligopeptides composed of glycine or alanine are good examples of simple peptides.
Coordination of Cu(II) or Ni(II) ions to oligoglycine or oligoalanine starts at the N-terminal amino nitrogen, which acts as an anchoring binding site, preventing metal ion hydrolysis. The adjacent carbonyl oxygen is the second donor, completing the chelate ring [1], [2], [9], [10]. As the pH is raised, both metal ions are able to deprotonate successive peptide nitrogens, forming M–N− bonds, until eventually a [MH
Superstability through indirect interactions
In the Cu(II)–Asn–Ser–Phe–Arg–Tyr–NH2 (NSFRY–NH2) system [17] the coordination modes are analogous to those shown in Fig. 1. The Cu(II) binding begins at the N-terminus and, with pH increase, the 1N, 2N, 3N and 4N species are formed. However, the comparison of the species distribution of Cu(II)–NSFRY–NH2 with that of Cu(II)–pentaalanine amide (Fig. 4) indicates clearly that the coordination equilibria in both systems are very different. The formation of a 4N complex is observed at much lower pH
Impact of the proline break-point on coordination abilities of oligopeptides
Proline (Pro) is the only protein-building amino acid having a secondary amino nitrogen. While Pro residue inserted as the N-terminal residue into the peptide sequence is an effective anchoring site for metal ions, its introduction into the peptide chain in position two, three or further, results in a peptide bond that does not have an amide proton that may be displaced by metal ions. As a consequence, the simple stepwise coordination of consecutive amide nitrogens, discussed above, is no
Coordination of Cu(II) and Ni(II) to histidine peptides
The histidine residue possesses a very efficient nitrogen donor in its side chain imidazole ring. The cooperativity of all three donor groups of this amino acid in metal binding is made possible by the formation of two fused chelate rings: the five-membered {NH2, COO−} (amino acid-like) and the six-membered {NH2, Nim} (histamine-like). The high thermodynamic stability of five- and six-membered rings versus larger ones results in the selection of the N-1 rather the N-3 imidazole nitrogen (Fig. 8
Specific peptide hydrolysis in His peptides
There is emerging evidence that the coordination of Cu(II) to histidine peptides may result in a specific peptide hydrolysis reaction which does not involve oxidative reactions. An extensive study revealed a particular susceptibility of Xaa–Ser–His and Xaa–Thr–His sequences to Cu(II)-assisted hydrolysis at alkaline pH, with specific hydrolysis of the Xaa–Ser(Thr) bond [112]. The proposed driving force of this reaction is a high stability of the Cu(II) complex of the leaving Ser(Thr)–His
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