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Structural and Hydration Properties of the Partially Unfolded States of the Prion Protein

Alfonso De Simone ^* , Adriana Zagari ^*  and Philippe Derreumaux 

^* Dipartimento delle Scienze Biologiche, Sezione Biostrutture and CNISM, Università di Napoli Federico II, I-80134 Naples, Italy; CEINGE-biotechnology avanzate S.C.A.R.L., Naples, Italy; and Laboratoire de Biochimie Théorique, UPR 9080 CNRS, Institut de Biologie Physico-Chimique, et Université Paris 7 Denis-Diderot, 75005 Paris, France

Correspondence: Address reprint requests to Philippe Derreumaux, Tel.: 33-1-58-41-51-72; E-mail: philippe.derreumaux{at}ibpc.fr; or Alfonso De Simone, Tel.: 39-081-25-36-603; E-mail: desimone{at}chemistry.unina.it.

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 ß-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.

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