Prion diseases are fatal neurodegenerative diseases characterized by the formation of β-rich oligomers and the accumulation of amyloid fibrillar deposits in the central nervous system. Understanding the conversion of the cellular prion protein into its β-rich polymeric conformers is fundamental to tackling the early stages of the development of prion diseases. In this paper, we have identified unfolding and refolding steps critical to the conversion into a β-rich conformer for different constructs of the ovine prion protein by molecular dynamics simulations. By combining our results with in vitro experiments, we show that the folded C-terminus of the ovine prion protein is able to recurrently undergo a drastic conformational change by displacement of the H1 helix, uncovering of the H2H3 domain, and formation of persistent β-sheets between H2 and H3 residues. The observed β-sheets refold toward the C-terminus exposing what we call a "bending region" comprising residues 204-214. This is strikingly coincident with the region harboring mutations determining the fate of the prion oligomerization process. The β-rich intermediate is used here for the construction of a putative model for the assembly into an oligomeric aggregate. The results presented here confirm the importance of the H2H3 domain for prion oligomer formation and therefore its potential use as molecular target in the design of novel prion inhibitors.