The misfolding of the prion protein (PrP) into a pathogenic beta-rich form (PrPsc) 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 us. We observed a strong conformational dependence where on average the helix content decreased and the beta 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 His 187 is found to be associated with a loss of interaction between two PH' subdomains, potentially playing a major role in the misfolding process. In one of the simulations at pH 2, a stable beta-rich structure was formed that may be an intermediate of PrPs' formation, indicating that misfolding may precede dimerization.