title: Structural and hydration properties of the partially unfolded states of the prion protein.
abstract: 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.
authors.affiliation: Dipartimento delle Scienze Biologiche, Sezione Biostrutture and CNISM, Università di Napoli Federico II, I-80134 Naples, Italy. desimone@chemistry.unina.it
authors.forename: Alfonso
authors.initials: A
authors.lastname: De Simone
authors.forename: Adriana
authors.initials: A
authors.lastname: Zagari
authors.forename: Philippe
authors.initials: P
authors.lastname: Derreumaux
mesh_terms: D008958:Models, Molecular; D018621:PrPC Proteins / Q000737:chemistry*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D014867:Water / Q000737:chemistry*
chemical_list: D018621:PrPC Proteins; D014867:Water