期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：36
页码：9617-9622
DOI：10.1073/pnas.1712155114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 ( PrP C ) is transformed into amyloid aggregates representing the “scrapie form” of the protein ( PrP Sc ). Continued research on this system is of keen interest, since new information on the physiological function of PrP C in healthy organisms is emerging, as well as new data on the mechanism of the transformation of PrP C to PrP Sc . 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 PrP C . The focus of the data analysis was on an 11-residue polypeptide segment in mouse PrP C (121–231) that includes the β 2– α 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 PrP C and a variant with the single-residue replacement Y169A. The resulting detailed conformational landscapes complement in an integrative manner the available experimental data on PrP C , providing quantitative insights into the nature of the structural transition-related function of the β 2– α 2 loop.
