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Misfolding Pathways of the Prion Protein Probed by Molecular Dynamics Simulations

Alessandro Barducci ^* , Riccardo Chelli ^* , Piero Procacci ^*  and Vincenzo Schettino ^* 

^* Dipartimento di Chimica, University of Florence, Sesto Fiorentino, Italy; and European Laboratory for Non-linear Spectroscopy, Sesto Fiorentino, Italy

Correspondence: Address reprint requests to Riccardo Chelli, Tel.: 39-055-457-3082; Fax: 39-055-457-3077; E-mail: chelli{at}chim.unifi.it.

Although the cellular monomeric form of the benign prion protein is now well characterized, a model for the monomer of the misfolded conformation (PrP^Sc) remains elusive. PrP^Sc quickly aggregates into highly insoluble fibrils making experimental structural characterization very difficult. The tendency to aggregation of PrP^Sc in aqueous solution implies that the monomer fold must be hydrophobic. Here, by using molecular dynamics simulations, we have studied the cellular mouse prion protein and its D178N pathogenic mutant immersed in a hydrophobic environment (solution of CCl₄), to reveal conformational changes and/or local structural weaknesses of the prion protein fold in unfavorable structural and thermodynamic conditions. Simulations in water have been also performed. Although observing in general a rather limited conformation activity in the nanosecond timescale, we have detected a significant weakening of the antiparallel ß-sheet of the D178N mutant in CCl₄ and to a less extent in water. No weakening is observed for the native prion protein. The increase of ß-structure in the monomer, recently claimed as evidence for misfolding to PrP^Sc, has been also observed in this study irrespective of the thermodynamic or structural conditions, showing that this behavior is very likely an intrinsic characteristic of the prion protein fold.