title: Ab initio simulations of Cu binding sites on the N-terminal region of prion protein.
abstract: The human prion protein binds Cu2+ ions in the octarepeat domain of the N-terminal tail up to full occupancy at pH 7.4. Recent experiments have shown that the HGGG octarepeat subdomain is responsible for holding the metal bound in a square-planar configuration. By using first principle ab initio molecular dynamics simulations of the Car-Parrinello type, the coordination of copper to the binding sites of the prion protein octarepeat region is investigated. Simulations are carried out for a number of structured binding sites. Results for the complexes Cu(HGGGW)(wat), Cu(HGGG), and [Cu(HGGG)]2 are presented. While the presence of a Trp residue and a water molecule does not seem to affect the nature of the copper coordination, high stability of the bond between copper and the amide nitrogen of deprotonated Gly residues is confirmed in all cases. For the more interesting [Cu(HGGG)]2 complex, a dynamically entangled arrangement of the two domains with exchange of amide nitrogen bonds between the two copper centers emerges, which is consistent with the short Cu-Cu distance observed in experiments at full copper occupancy.
authors.affiliation: National Research Council, Institute for Chemistry of Organo-metallic Compounds, Via Madonna Del Piano, 50019, Sesto Fiorentino (Florence), Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Furlan
authors.forename: Giovanni
authors.initials: G
authors.lastname: La Penna
authors.forename: Francesco
authors.initials: F
authors.lastname: Guerrieri
authors.forename: Silvia
authors.initials: S
authors.lastname: Morante
authors.forename: Gian Carlo
authors.initials: GC
authors.lastname: Rossi
mesh_terms: D001665:Binding Sites; D019295:Computational Biology; D003198:Computer Simulation; D003300:Copper / Q000737:chemistry* / Q000378:metabolism*; D019281:Dimerization; D008958:Models, Molecular; D011328:Prions / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D013696:Temperature
chemical_list: D011328:Prions; D003300:Copper