The effect of point mutations on copper(II) complexes with peptide fragments encompassing the 106-114 region of human prion protein.

The tetrapeptides Ac-SKHM-NH2, Ac-TKHM-NH2, Ac-MKHS-NH2, Ac-S(OMe)KHM-NH2, and Ac-MKHS(OMe)-NH2 and the nonapeptides Ac-KTNSKHMAG-NH2 and Ac-KTNMKHSAG-NH2 were synthesized and their copper(II) complexes were studied by potentiometric, UV-Vis, circular dichroism (CD), and electron paramagnetic resonance (EPR) spectroscopic methods. These peptides mimic the 109-112 and 106-114 residues of the sequence of human prion protein. The imidazole-N donor atoms of histidyl residues were found to be the primary metal binding sites of all peptide fragments. This binding mode provides a good possibility for the cooperative deprotonation and metal ion coordination of two amide functions preceding histidine. The (Nim,N-,N-)-bonded species predominate in the pH range 5.5-7.0 and the free coordination sites of these species make possible the metal binding of weakly coordinating side chains. The comparison of the potentiometric and spectroscopic results revealed the stabilizing role of the oxygen donors of seryl, threonyl, or methoxyseryl residues of Ac-SKHM-NH2, Ac-TKHM-NH2, Ac-S(OMe)KHM-NH2, and Ac-KTNSKHMAG-NH2 containing the mutations in position 109. These interactions were, however, not observed in the peptides containing the specific amino acids in other locations of the peptide sequence.