It has been demonstrated in Section 2 that oxygen, nitrogen and sulfur donor atoms in the side chains of amino acids can significantly influence the metal-binding affinity of the ligands. Among them imidazolyl nitrogen donor atoms of histidyl and thiol sulfur atoms of cysteinyl residues are the most common and most efficient metal-binding sites and their complex formation reactions are discussed in Sections 3.3 and 3.4. In this section we focus on the complex formation of peptides containing alcoholic, phenolate or carboxylate oxygen, lysyl amino nitrogen and thioether or disulfide sulfur atoms in the side chains of natural amino acids. The results obtained on the nickel(II) complexes of various derivatives of peptides including the conjugates of some chelating agents will be discussed as well.
Oxygen donor atoms of seryl, threonyl or tyrosyl residues generally can contribute to the overall stability of peptide complexes of transition metal ions, including copper(II) and zinc(II) and especially the hard trivalent metal ions. However, in the case of nickel(II) there is no unambiguous proof for the existence of Ni-O (alcoholic) or Ni-O(phenolate) binding in peptide complexes. On the contrary, the interaction of the aromatic side chains of phenylalanine or tyrosine with nickel(II) ion was suggested on the basis of NMR measurements. This type of stacking interaction was especially favored in the square planar nickel (II) complexes of tri- and tetra-peptides containing Phe and/or Tyr residues .
The P- and y-carboxylate groups of aspartyl and glutamyl residues, respectively, are also potential metal-binding sites in peptide complexes. The stability enhancement of the P-carboxylate group of the aspartyl residue is generally more evident  because the terminal amino nitrogen and carboxylate oxygen atoms can form a six-membered chelate in the case of aspartic acid, while it is a seven-membered one for glutamic acid. The stability increase of various species can be observed both in copper(II) and nickel(II) complexes with the former being more pronounced, supporting that nickel(II) has a relatively low affinity to bind oxygen donor ligands [86,87].
Some peptides discussed in the previous sections contained also lysine residues, but the involvement of the e-amino group of lysine in metal binding was not suggested in any of these cases [87-89]. The e-amino group, however, can be involved in amide binding too, and this modification of the peptide backbone generally significantly increases the variety of complex formation processes. The nickel(II) binding affinities of y-Glu-e-Lys and Glu-e-Lys were compared in a combined potentiometric and spectroscopic study . In the former ligand the a-amino acid-like binding sites are well separated from each other and also from the amide function. As a consequence, the peptide amide deprotonation and coordination is hindered and a very stable [NiL] species is formed containing the amino acid binding sites supported by a macrochelate or loop structure. The formation of a similar species with outstanding thermodynamic stability was also suggested for the nickel(II)-Gly-Lys(Gly) system, indicating that nickel(II) has a high affinity to form macrochelate structures . The ligands Glu-e-Lys  and Asp-e-Lys  also contain the e-amino group in the amide bond, but it is in the chelating position with the terminal amino group which results in the exclusive formation of various dinuclear complexes.
The sulfur atom is one of the most common metal-binding sites in proteins and it can be found in different chemical forms including thiols, disulfides, and thioethers. Among these, thiols have the highest affinity towards transition elements, including nickel(II), but this topic is discussed in the next section. The oxidation of thiols to disulfides, however, dramatically reduces the affinity of the sulfur atoms towards nickel(II). Although the existence of Ni-S(disulfide) bonds has been proven in the solid state for nickel(II) complexes of several model compounds , similar interactions were ruled out in the nickel(II) complexes of oxidized glutathione, (CysGly)2 and (GlyCys)2 [93,94]. The presence of the separated (NH2, COO) or (NH2, CO) binding sites, however, results in the formation of [NiL] complexes as the major species and their structure is stabilized by the formation of macrochelates. The studies reported on the nickel(II) complexes of the peptide hormones oxytocin and vasopressin came to similar conclusions supporting that the common oxygen and nitrogen donors of peptides in chelating positions are more efficient binding sites for nickel(II) than the disulfide sulfur atoms [95,96].
The formation of Ni(II)-S(thioether) bonds was suggested in the complexes of some nonproteinogenic derivatives of amino acids , but the systematic studies on the nickel(II) complexes of peptides of methionine revealed the existence of only very weak Ni(II)-S interactions in solution [98,99]. The similarity in the complex formation processes of triglycine and the tripeptides of methio-nine is especially remarkable in the square planar, diamagnetic (NH2, N", N", COO)-coordinated species, while a weak interaction of the thioether residue was suggested in the octahedral [NiL] complexes containing N-terminal methio-nyl residues.
The various derivatives of peptides and their metal complexes have received increasing attention in the last decades. These molecules include the insertion of additional functional groups into the side chains of peptides or the replacement of amide and/or carboxylate functions with thioamides and phosphonic/phosphinic groups, respectively. The most interesting ligands are, however, the so-called peptide conjugates in which the peptide molecules are covalently linked to other efficient ligands including chelating agents and macrocycles.
a-Hydroxymethylserine (HmS) is a nonproteinogenic amino acid containing an extra CH2-OH side chain on the a-carbon atom of serine and it can be found in several antibiotics. It has been reported that the insertion of HmS residues into di- or tripeptides, HmS-His and HmS-Hms-His, significantly increases both the copper(II) and nickel(II) binding capacity of these ligands compared with those of GlyHis or GlyGlyHis [100,101]. (Aminoalkyl)phosphonic and (aminoalkyl)phosphinic acids are the phosphorous analogs of the naturally occurring amino acids and their insertion into the peptide backbone provides an efficient way for the modification of the acid-base and complexing properties of the oxygen donor atoms of peptide ligands. Most of the publications, however, came to the conclusion that the carboxylate/phosphonate(phosphinate) substitution does not significantly influence the speciation and thermodynamic stability of the corresponding nickel(II) complexes [102-105].
In contrast with the low nickel(II) binding affinity of thioether and disulfide functions the insertion of the thiocarbonyl groups in the oligopeptide molecules critically changes the coordination ability of the peptide ligands. The Ni(II)-S(thioamide) bonded species of both di- and tetrapeptides predominate around the physiological pH, but this binding mode cannot prevent the deprotonation and coordination of amide functions in alkaline solutions [106-108].
In the last decade an increasing number of studies have been performed on the metal complexes of functionalized peptide molecules containing chelating agents or other biologically important ligands in the side chains. One group of these ligands includes the peptide derivatives of the chelating agent bis(imidazol-2-yl)methylamine (BIMA) which can be linked to the C-termini of peptides via an amide bond. The results obtained on the amino acid derivatives of BIMA
have already been reviewed [47-50] and discussed in the previous section. The data reported on the dipeptide-BIMA conjugates revealed that the presence of the bis(imidazolyl) chelating agent significantly enhances the nickel(II)-binding affinity of the peptides, especially below and in the physiological pH range, but similarly to the common peptides the amide functions will be the major metal ion binding sites in basic solutions .
Peptide nucleic acids (PNA) are synthetic analogs of DNA in which the natural phosphate-deoxyribose backbone is replaced by a peptide chain. It was found that the insertion of nucleobases, especially of thymine, has a critical impact on both the thermodynamic stability of nickel(II) complexes and the conformation of the ligands [110,111].
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