Cellular prion protein PrP consists of three α-helices, one β-sheet, and an unstructured N-terminal domain. Misfolding of this protein into the scrapie form (PrP) increases dramatically the β-sheet content. H1 is the most stable helix on PrP and contains an unusual number of hydrophilic amino acids. Its fate in PrP is not clear. We performed replica exchange molecular dynamics simulations on H1 alone, H1 together with an N-terminally flanking H1B1 loop and H1 in complex with other hydrophilic regions of the prion protein. In the presence of the HSQWNKPSKPKTNMK sequence, H1 is almost completely converted to a loop structure stabilized by a network of salt bridges. On the other hand, H1 retains its helical structure alone or together with the other sequences considered in this study. We carried out an additional simulation by restraining the distance between the two ends of H1, mimicking a possible geometric restriction by the rest of the protein. Even though the loop was the major conformation, a significant amount of helical structure was also observed. This suggests that the interaction with HSQWNKPSKPKTNMK is necessary for complete helix-to-loop conversion.