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.