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

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