Metadynamics Simulation of Prion Protein: β-Structure Stability and the Early Stages of Misfolding
METADATA ONLY
Loading...
Author / Producer
Date
2006-03-01
Publication Type
Journal Article
ETH Bibliography
yes
Citations
Altmetric
METADATA ONLY
Data
Rights / License
Abstract
In the present study we have used molecular dynamics simulations to study the stability of the antiparallel β-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 β-sheet disruption/growth. We found that the antiparallel β-sheet is significantly weaker in the pathogenic D178N mutant than in the wild-type PrPC. The destabilization of PrPC β-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 β-sheet in the PrPC. We conclude that the antiparallel β-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 β-helix.
Permanent link
Publication status
published
External links
Editor
Book title
Journal / series
Volume
128 (8)
Pages / Article No.
2705 - 2710
Publisher
American Chemical Society
Event
Edition / version
Methods
Software
Geographic location
Date collected
Date created
Subject
Organisational unit
03575 - Parrinello, Michele (ehemalig) / Parrinello, Michele (former)