The determinants of stability in the human prion protein: Insights into folding and misfolding from the analysis of the change in the stabilization energy distribution in different conditions

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.