The propensity to form fibril in disease-related proteins is a widely studied phenomenon, but its correlation, if any, with structural characteristics of the associated proteins is not clearly understood. However, the observation has been made that some proteins that readily form amyloid have a significant number of backbone H bonds that are exposed to solvent molecules, suggesting that these regions have a propensity toward protein interaction and aggregation [Fernandez, A. & Scheraga, H. A. (2003) Proc. Natl. Acad. Sci. USA 100, 113–118]. High-resolution x-ray structures of the sheep and human C-terminal prion protein have provided a useful description of surface and partially buried waters. By molecular dynamics simulations, we investigated the structural role of these water molecules. The solvent dynamical behavior on the protein surface reveals significant features about the stability and the potential interactions of the prion protein. The protein presents regions of tightly bound conserved waters that are necessary to hold in place local elements of the fold, as well as regions where the local water is in fast exchange with bulk water. These results are evidenced by a map of the spatial distribution entropy of the solvent around the protein. The particular behavior of the solvent around these regions may be crucial in the folding stability and in terms of aggregation loci.