A family of neurodegenerative disorders including scrapie, chronic wasting disease, bovine spongiform encephalopathy and Creutzfeldt-Jakob disease are thought to be associated with the conversion of normal cellular prion protein (PrP) to a protease resistant prion isoform, PrPSc (prion protein scrapie). The N-terminal region of PrP is highly flexible region of the protein contains poly(L-proline) type II (PPII) helical content and is involved in metal ion binding. While the biological role of this region in the conversion of PrP to PrPSc remains unclear, a recent report indicates that Pro 44 is post translationally modified to 4 hydroxyproline (4-Hyp) (Gill et al, 2000, EMBO, p. 5324.). Using model peptides of the N-terminal domain PrP 37-53 where Pro44 has been systematically replaced with 4-Hyp and 4-Fluoroproline (4-Flp), circular dichroism spectroscopy has been used to determine PPII helix content and characterize changes in thermal stability of the helices. In addition, these three peptides have been examined for their ability to be resist proteinase K digestion. These studies indicate that hydroxylation at Pro 44 increases helical content and exhibits increased resistance to proteinase K digestion whereas the 4-Flp substitution increases thermal stability of the PPII helix.