Prion proteins and copper ions. Biochemical and chemical controversies.

The Prion protein (PrPc) involvement in some neurodegenerative diseases is well assessed although its normal biological role is not completely understood. It is known that PrPC can bind Cu(II) ions with high specificity but the order of magnitude of the corresponding affinity constant(s) is still highly debated. This perspective is an attempt to collect the current knowledge on these topics and to build up a bridge between the biological and the chemical points of view

Is the monomeric prion octapeptide repeat PHGGGWGQ a specific ligand for Cu2+ ions?

Ac-PHGGGWGQ-NH2, an octarepeat peptide fragment of prion, is a relatively effective ligand for Cu2+ ions. At a pH of about 7.4 the major binding sites involve the imidazole nitrogen and two amide nitrogens of (3)Gly and (4)Gly giving a CuH-2L species. The stability of the complex formed is similar to other peptides having a similar type of coordination. The NMR spectra indicate that in CuH-2L the complex side chain of the Trp residue is located very close to the metal ion. The geometry around the Cu2+ ion seems to be slightly distorted from the tetragonal one. In strongly basic solution the coordination involves an additional amide nitrogen. In CuH-2L, CuH-3L and CuH-4L complexes the amide nitrogens involved in the metal ion binding are those placed towards the C-terminal from the His residue. The N-terminal of the unprotected octapeptide is very effective in binding the Cu2+ ion although at high pH the imidazole nitrogen may not be involved in metal ion binding

Molecular Dynamics Simulations of Two Tandem Octarepeats from the Mammalian Prion Protein: Fully Cu2+-bound and Metal-Free Forms

Molecular dynamics simulations have been conducted on a model fragment (Ac-PHGGGWGQPHGGGW-NH2) of the prion protein octarepeat domain, both in the Cu2+-bound and metal-free forms. The copper-bound models are based on the consensus structure of the core Cu2+-binding site of an individual octarepeat, relevant to the fully Cu2+-occupied prion protein octarepeat region. The model peptides contain Cu2+ bound through a His imidazole ring and two deprotonated amide N-atoms in the peptide backbone supplied by the following two Gly residues. Both the copper-bound and metal-free models have been simulated with the OPLS all-atom force field with the GROMACS molecular dynamics package. These simulations, with two tandem copper-binding sites, represent the minimum model necessary to observe potential structuring between the copper-binding sites in the octarepeat region. The GWGQ residues constitute a flexible linker region that predominantly adopts a turn, serving to bring adjacent His residues into close proximity. The consequent formation of stable structures demonstrates that the copper-bound octarepeat region allows the copper-coordinating sites to come into van der Waals contact, packing into particular orientations to further stabilize the bend in the GWGQ linker region