Computational studies of transition metal selectivity of octapeptide repeat region of prion protein (PrP).

We have presented a detailed theoretical (density functional theory and ONIOM) study on the structure and M-PrP (prion protein) interaction on various prion models, M(PrP) systems (where PrP = HGG, HGGGW x 3H(2)O, and PrP(61-84), and M = Zn, Cu, Ni, Co, Fe, Mn). It was shown that the geometry of the complex [Mn(HGGGW)(H(2)O)] x 2H(2)O is quite different for M = Mn(III) and Mn(II), and partial unfolding occurs only for the M = Mn(III). In [Zn{PrP(61-84)}], Zn(II) forms a bond with carbonyl oxygen of the Pro(84) residue in the axial position. The coordination of transition metal ions to PrP(61-84) induces the significant geometrical changes in the PrP(61-68) and Prp(69-76) octapeptide repeat regions. The Trp(65) and Trp(73) residues come closer to each other. The glutamines Gln(67) and Gln(75) also come closer to one another and result in the formation of a hydrogen bond between the carbonyl carbon of Gln(67) and one of the NH(2) hydrogens of Gln(75). A specific aggregatory effect is found for Co(II) and Mn(II). The relative binding ability of the metal ions increases in the order Zn(II) < Mn(II) < Cu(II) < Fe(II) < Co(II) < Ni(II). The PrP is most distorted upon binding to Co(II) and least distorted upon binding to Zn(II).