Modelling of the Metal Binding Sites in Proteins Involved in Neurodegeneration

Abstract

Many proteins involved in the neurodegeneration processes are potential metalloproteins. In some of them the metal binding domain is flexible or unstructured (e.g., prion proteins, β-amyloid peptide, α-synuclein) resembling oligo-peptide chains. The regular protein structure usually has a critical impact on the binding ability of metal ion to protein scaffold, while in peptides with random structures the individual binding ability of the particular amino acid residue may decide about the peptide binding to metal ion (Kozlowski et al., 1999; Kozlowski et al., 2005; Kozlowski et al., 2008). Thus, it seems to be reasonable to use short peptide fragments of the unstructured protein to establish the detailed characteristics of the metal-protein interactions. In the peptide or protein systems with no distinct structural arrangements the major anchoring binding sites for metal ions like Cu2+ are the N-terminal aminonitrogen and nitrogen donor of imidazole side chain of histydyl residue. When N-terminal function is protected like it happens for peptide fragments in the protein sequence, the major anchoring sites are imidazoles of His residues. Cu2+ ions anchored on the His side chain can then coordinate to the successive deprotonated nitrogen donors of adjacent amide bonds (Kozlowski et al., 1999; Kozlowski et al., 2005). The side chains of the other amino acid residues can affect distinctly the peptide/protein binding ability towards metal ions but it happens usually via indirect interactions e.g., with involvement of hydrogen bond network or stacking between the aromatic side chains. The metal ion interaction with whole protein within its unstructured domain may differ from that observed in metal-peptide system e.g. in thermodynamic stability or kinetics, but the binding sites and the structure around the binding sites should be very similar to each other. In any case the precise information obtained from the studies on the metal-peptide models are very useful in understanding of the interactions with whole proteins showing e.g., the binding preferences and most characteristic features resulting from the metal ion binding to protein. Thus, proteins containing His-rich domains within their unstructured sequences represent strong potential to bind metal ions with possible biological consequences. In this chapter the selected examples for prion proteins, α-synuclein, and β-amyloid peptide will be discussed both from thermodynamic and structural point of view. Some oxidant and anti-oxidant properties of these metallopeptide systems will also be discussed.