Misfolding pathways of the prion protein probed by molecular dynamics simulations
Alessandro Barducci 1, Riccardo Chelli 1*, Piero Procacci 1 and Vincenzo Schettino 1
1 Universita' di Firenze
* To whom correspondence should be addressed. E-mail: chelli{at}chim.unifi.it.
Submitted on July 19, 2004
Revised on September 14, 2004
Accepted on 10 November 2004
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Abstract |
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While the cellular monomeric form of the benign prion protein is now well characterized, a model for the monomer of the misfolded conformation (PrPSc) remains elusive. PrPSc quickly aggregates into highly insoluble fibrils making very difficult experimental structural characterization. The tendency to aggregation of PrPSc 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), in order 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. While observing in general a rather limited conformation activity in the nanosecond time scale, we have detected a significant weakening of the antiparallel beta-sheet of the D178N mutant in CCl4 and to a less extent in water. No weakening is observed for the native prion protein monomer. The increase of beta-structure in the monomer, recently claimed as evidence for misfolding to PrPSc, 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.
Key Words:
D178N point mutation, computer simulations, mouse PrP, trasmissible spongiform encephalopathies
