Structural and hydration properties of the partially unfolded states of the prion protein

Misfolding and aggregation of the prion protein ( PrP) is responsible for the development of transmissible spongiform encephalopathies ( TSE). To gain insights into possible aggregation- prone intermediate states, we construct the free energy surface of the C- terminal globular domain of the PrP from enhanced sampling of replica exchange molecular dynamics. This cellular domain is characterized by three helices H1 - H3 and a small beta- sheet. In agreement with experimental studies, the partially unfolded states display a stable core built from the central portions of helices H2 and H3 and a high mobility of helix H1 from the core. Among all identified conformational basins, a marginally populated state appears to be a very good candidate for aggregation. This intermediate is stabilized by four TSE- sensitive key interactions, displays a longer helix H1 with both a dry and solvated surface, and is featured by a significant detachment of helix H1 from the PrP- core.