title: Molecular dynamics simulations of two tandem octarepeats from the mammalian prion protein: fully Cu2+-bound and metal-free forms.
abstract: Molecular dynamics simulations have been conducted on a model fragment (Ac-PHGGGWGQPHGGGW-NH(2)) of the prion protein octarepeat domain, both in the Cu(2+)-bound and metal-free forms. The copper-bound models are based on the consensus structure of the core Cu(2+)-binding site of an individual octarepeat, relevant to the fully Cu(2+)-occupied prion protein octarepeat region. The model peptides contain Cu(2+) 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.
authors: Structural Biology Research Group, Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
authors: M Jake
authors: MJ
authors: Pushie
authors: Hans J
authors: HJ
authors: Vogel
mesh_terms: D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D003300:Copper / Q000737:chemistry*; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D011328:Prions / Q000737:chemistry* / Q000648:ultrastructure*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D020449:Repetitive Sequences, Amino Acid
chemical_list: D011328:Prions; D003300:Copper
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