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Metadynamics simulation of prion protein: beta-structure stability and the early stages of misfolding

Alessandro Barducci1, Riccardo Chelli, Piero Procacci

  • 1Dipartimento di Chimica, Università di Firenze, Sesto Fiorentino, Italy.

Journal of the American Chemical Society
|February 24, 2006
PubMed

Insights

The prion protein

Area of Science:

  • Biophysics
  • Structural Biology
  • Computational Biology

Background:

  • Cellular prion protein (PrP(C)) misfolding is implicated in neurodegenerative diseases.
  • The structural stability of PrP(C) is crucial for its function and dysfunction.

Purpose of the Study:

  • To investigate the stability of the antiparallel beta-sheet in wild-type PrP(C) and the pathogenic D178N mutant.
  • To elucidate the molecular mechanisms underlying beta-sheet destabilization in the D178N mutant.

Main Methods:

  • Molecular dynamics simulations were employed to study protein stability.
  • Non-Markovian metadynamics was utilized to calculate free energy landscapes related to beta-sheet dynamics.

Main Results:

  • The antiparallel beta-sheet is significantly less stable in the D178N mutant compared to wild-type PrP(C).
  • Destabilization correlates with a weakened hydrogen bonding network involving Arg164 and Tyr128.
  • This network appears to act as a safety mechanism against beta-sheet unzipping in PrP(C).

Conclusions:

  • The D178N mutation destabilizes the antiparallel beta-sheet in PrP(C).
  • Under pathogenic conditions, the antiparallel beta-sheet is prone to disruption rather than growth.
  • Findings align with models suggesting a parallel beta-helix in misfolded prion monomers.

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