NR AUGO
AU Barducci,A.; Chelli,R.; Procacci,P.; Schettino,V.; Gervasio,F.L.; Parrinello,M.
TI Metadynamics simulation of prion protein: beta-structure stability and the early stages of misfolding.
QU Journal of the American Chemical Society 2006 Mar 1; 128(8): 2705-10
PT journal article
AB In the present study we have used molecular dynamics simulations to study the stability of the antiparallel beta-sheet in cellular mouse prion protein (PrPc) 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 PrPc. The destabilization of PrPc 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 PrPc. 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.
MH Animals; Computer Simulation; Mice; Models, Molecular; PrPc Proteins/*chemistry; Protein Folding; Protein Structure, Secondary; Research Support, Non-U.S. Gov't; Thermodynamics
AD Dipartimento di Chimica, Universita di Firenze, Sesto Fiorentino, Italy.
SP englisch
PO USA