Metadynamics simulation of prion protein: beta-structure stability and the early stages of misfolding.
In the present study we have used molecular dynamics simulations to study the stability of the antiparallel beta-sheet in cellular mouse prion protein (PrP(C)) and in the D178N mutant. In particular, using the recently developed non-Markovian metadynamics method, we have evaluated the free energy as a function of a reaction coordinate related to the beta-sheet disruption/growth. We found that the antiparallel beta-sheet is significantly weaker in the pathogenic D178N mutant than in the wild-type PrP(C). The destabilization of PrP(C) beta-structure in the D178N mutant is correlated to the weakening of the hydrogen bonding network involving the mutated residue, Arg164 and Tyr128 side chains. This in turn indicates that such a network apparently provides a safety mechanism for the unzipping of the antiparallel beta-sheet in the PrP(C). We conclude that the antiparallel beta-sheet is likely to undergo disruption rather than growth under pathogenic conditions, in agreement with recent models of the misfolded monomer that assume a parallel beta-helix.
Dipartimento di Chimica, Università di Firenze, Sesto Fiorentino, Italy.
Alessandro
A
Barducci
Riccardo
R
Chelli
Piero
P
Procacci
Vincenzo
V
Schettino
Francesco L
FL
Gervasio
Michele
M
Parrinello
D000818:Animals; D003198:Computer Simulation; D051379:Mice; D008958:Models, Molecular; D018621:PrPC Proteins / Q000737:chemistry*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013816:Thermodynamics
D018621:PrPC Proteins