The normal form of the prion protein(PrPC) has mostly alpha-helical (AH) secondary structure in the C-terminal region (residues 166-230), while the infectious form (PrPSc) has been proposed to have a left-handed beta helical (LHBH) structure(1). The mechanism of conformational change from PrPC to PrPSc is unknown, but recent electron microscope data(2) and computer modeling(3) of in vitro grown prion fibrils suggest a possible LHBH structure in the C-terminal region. We use high temperature (500K) AMBER molecular dynamics over 10 ns runtimes to study the unfolding transitions commencing from both LHBH and AH C-terminal starting structures. Using stability, contact map, and energetic analyses we find that both structures unfold to very similar AH-like conformations and discuss the potential implications of this result for normal prion cellular function and for prion disease.References1) Govaerts, C., et al. (2004) PNAS101, 8342-8347.2) Tattum, M. H., et al. (2006) J. Mol. Biol.357, 975-985.3) Kunes, K. C., et al. (2008) Prion2, 81-90.The image below compares computational models of the initial LHBH structure(left), the initial AH structure(right), and the unfolded AH-like structure(middle).View Large Image | View Hi-Res Image | Download PowerPoint Slide