期刊
BIOPHYSICAL JOURNAL
卷 102, 期 1, 页码 158-167出版社
CELL PRESS
DOI: 10.1016/j.bpj.2011.12.003
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资金
- Federation of European Biochemical Societies
- Engineering and Physical Sciences Research Council
- Deutsche Forschungsgemeinschaft [SCHW 901/3-1]
- Engineering and Physical Sciences Research Council [EP/G049998/2] Funding Source: researchfish
- EPSRC [EP/G049998/2] Funding Source: UKRI
The characterization of the structural dynamics of proteins, including those that present a substantial degree of disorder, is currently a major scientific challenge. These dynamics are biologically relevant and govern the majority of functional and pathological processes. We exploited a combination of enhanced molecular simulations of metadynamics and NMR measurements to study heterogeneous states of proteins and peptides. In this way, we determined the structural ensemble and free-energy landscape of the highly dynamic helix 1 of the prion protein (PrP-H1), whose misfolding and aggregation are intimately connected to a group of neurodegenerative disorders known as transmissible spongiform encephalopathies. Our combined approach allowed us to dissect the factors that govern the conformational states of PrP-H1 in solution, and the implications of these factors for prion protein misfolding and aggregation. The results underline the importance of adopting novel integrated approaches that take advantage of experiments and theory to achieve a comprehensive characterization of the structure and dynamics of biological macromolecules.
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