Résumé
In transmissible spongiform encephalopathies (TSEs), which are lethal neurodegenerative diseases that affect humans and a wide range of other mammalian species, the normal "cellular" prion protein (PrPc) is transformed into amyloid aggregates representing the "scrapie form" of the protein (PrPsc). Continued research on this system is of keen interest, since new information on the physiological function of PrPc in healthy organisms is emerging, as well as new data on the mechanism of the transformation of PrPc to PrPsc. In this paper we used two different approaches: a combination of the well-tempered ensemble (WTE) and parallel tempering (PT) schemes and metadynamics (MetaD) to characterize the conformational free-energy surface of PrPc. The focus of the data analysis was on an 11-residue polypeptide segment in mouse PrPc(121-231) that includes the beta 2-alpha 2 loop of residues 167-170, for which a correlation between structure and susceptibility to prion disease has previously been described. This study includes wild-type mouse PrPc and a variant with the single residue replacement Y169A. The resulting detailed conformational landscapes complement in an integrative manner the available experimental data on PrPc, providing quantitative insights into the nature of the structural transition-related function of the beta 2-alpha 2 loop.