The nature of the factors leading to the conversion of the cellular prion protein (PrP C ) into its amyloidogenic isoform (PrP Sc ) is still matter of debate in the field of structural biology. The NMR structures of non-mammalian PrP C (non-mPrP) from frog, chicken and turtle [Calzolai, L., Lysek, D.A., Perez, D.R., Guntert, P. and Wuthrich, K. (2005) Prion protein NMR structures of chickens, turtles, and frogs. Proc. Natl. Acad. Sci. USA 102, 651–655] have provided some new and valuable information on the scaffolding elements that preserve the PrP C folding, despite their low sequence identity with the mammalian prions (mPrP). The present molecular dynamics study of non-mPrP C focuses on the hydration properties of these proteins in comparison with the mammalian ones. The data reveal new insights in the PrP hydration and focus on the implications for PrP C folding stability and its propensity for interactions. In addition, for the first time, a role in disfavoring the PrP C aggregation is suggested for a conserved β-bulge which is stabilized by the local hydration.