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

Structural Biology Research Group, Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada

Correspondence: Address reprint requests to Hans J. Vogel, Dept. of Biological Sciences, University of Calgary, 2500 University Dr. NW, Calgary, Alberta, T2N 1N4, Canada. Tel.: 403-220-6006; Fax: 403-289-9311; E-mail: vogel{at}ucalgary.ca.

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.