Journal
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
Volume 62, Issue 3, Pages 698-707Publisher
WILEY
DOI: 10.1002/prot.20804
Keywords
human prion protein; misfolding; molecular dynamics; conformational changes
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The dynamic evolution of the PrPC from its NAIR-derived conformation to a beta-sheet-rich, aggregation-prone conformation is studied through all-atom, explicit solvent molecular dynamics in different temperature and pH conditions. The trajectories are analyzed by means of a recently introduced energy decomposition approach aimed at identifying the key residues for the stabilization and folding of the protein. It is shown that under native conditions the stabilization energy is concentrated in regions of the helices H1 and H3, whereas under misfolding conditions (low pH, high temperature, or mutations in selected sites) it is spread out over helix H2. Misfolding appears to be a rearrangement of the chain that disrupts most of the native secondary structure of the protein, producing some beta-rich conformations with an energy distribution similar to that of the native state.
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