Prion proteins cause neurodegenerative illnesses in humans and animals. The diseases are associated with a topological change from a predominantly alpha (PrP(C)) to beta-sheet (PrP(Sc)) structure. Many studies have focused on the minimum sequence requirements and key events for developing or transmitting disease. Here, we report on the application of molecular modeling studies to predict the lowest-energy conformations for five fragments in solution at pH 7. We show that PrP(143-158) adopts a helix, the model PrP(106-126), PrP(142-167), and PrP(143-178) peptides have a clear preference for a variety of beta-sheet structures, whereas PrP(127-164) has two iso-energetic conformations with all beta or alphabeta native-like structures. Such a finding for PrP(127-164), which explains a large body of experimental data, including the location of all mutations causing prion diseases, may have important implications for triggering or propagating the topological change.