DFT investigation of copper–peptide complexes related to the octarepeat domain of the prion protein

Recently, it has been demonstrated that the prion protein binds Cu(II) ions by the N-terminal domain [Chem. Eur. J. 6 (2000) 4195; Biochemistry 38 (1999) 11560], which is composed of four or more repeats of the eight-residue sequence PHGGGWGQ (octarepeat). X-ray diffraction experiments [Biochemistry 41 (2002) 3991] have shown that the peptide HGGGW embraces the fundamental Cu2+ binding unit and EPR and circular dichroism (CD) experiments, carried out on the Cu(HGGG) complex, show subtle differences in the local coordination geometry with respect to the Cu(HGGGW) species. In this contribution we have investigated Ac–HGGG–NH2/Cu2+ model complexes by means of DFT calculations, showing that the relative stabilities of four- and five-coordinated species are affected by the extent of the H-bond network and by peptide strain. However, when these contributions are not significant, square-planar coordination of Cu is definitely preferred. These observations fit well with the data from EPR experiments [Biochem. J. 344 (1999) 1; Trends Neurosci. 24 (2001) 85; Curr. Opin. Chem. Biol. 4 (2000) 184] that pointed out how a modification in the coordination environment of Cu can take place by going from Cu(HGGGW) to Cu(HGGG).