Constant-pH molecular dynamics simulations reveal a β-rich form of the human prion protein.
The misfolding of the prion protein (PrP) into a pathogenic β-rich form (PrP(Sc)) has been suggested to occur in the endocytic pathway, triggered by low pH. In this work we performed several constant-pH molecular dynamics simulations of human PrP 90-231 in the pH range 2-7, totaling more than 2 μs. We observed a strong conformational pH dependence where on average the helix content decreased and the β content increased toward acidic pH. Unlike some proposed models, the flexible N-terminus region did not gain stable structure at low pH. Rather, the main structural changes occurred on the helix-rich C-terminus core, as proposed in other models, namely, in the regions around 135-155 and 185-200. The protonation of His187 is found to be associated with a loss of interaction between two PrP subdomains, potentially playing a major role in the misfolding process. In one of the simulations at pH 2, a stable β-rich structure was formed that may be an intermediate of PrP(Sc) formation, indicating that misfolding may precede dimerization.
Campos
Sara R R
SR
Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Av. da República, EAN, 2780-157 Oeiras, Portugal.
Machuqueiro
Miguel
M
Baptista
António M
AM
D006801:Humans; D006863:Hydrogen-Ion Concentration; D056004:Molecular Dynamics Simulation; D011328:Prions / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013997:Time Factors
D011328:Prions