Modeling by Assembly and Molecular Dynamics Simulations of the Low Cu2+ Occupancy Form of the Mammalian Prion Protein Octarepeat Region: Gaining Insight into Cu2+-Mediated β-Cleavage

The prion protein has garnered considerable interest because of its involvement in prion disease as well as its unresolved cellular function. The octarepeat region in the flexible N-domain is capable of binding copper through multiple coordination modes. Under conditions of low pH and low Cu2+ concentration, the four octarepeats (ORs) cooperatively coordinate a single copper ion. Based on the average structure of the PHGG and GWGQ portions of a copper-free OR2 model from molecular dynamics simulations, the starting structures of the OR4 complex could be constructed by assembling the repeating structure of PHGG and GWGQ fragments. The resulting model contains a preformed site suitable for Cu2+ coordination. Molecular dynamics simulations of Cu2+ bound to the assembled OR4 model (Cu:OR4) reveal a close association of specific Trp and Gly residues with the Cu2+ center. This low Cu2+-occupancy form of prion protein is redox-active and can readily initiate cleavage of the OR region, mediated by reactive oxygen species generated by Cu+. The OR region is known to be required for β-cleavage, as are the Trp residues within the OR region. The β-cleaved form of the prion protein accumulates in amyloid fibrils. Hence, the close approach of Trp and Gly residues to the Cu2+ coordination site in the low Cu2+-occupancy form of the OR region may signal an important interaction for the initiation of prion disease.