Energy landscape of the prion protein helix 1 probed by metadynamics and NMR.
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.
Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
Carlo
C
Camilloni
Daniel
D
Schaal
Kristian
K
Schweimer
Stephan
S
Schwarzinger
Alfonso
A
De Simone
D000595:Amino Acid Sequence; D003198:Computer Simulation; D004735:Energy Transfer; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011328:Prions / Q000737:chemistry*; D011487:Protein Conformation
D011328:Prions