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Computational studies on prion proteins: effect of Ala(117)-->Val mutation
Noriaki Okimoto1, Kazunori Yamanaka, Atsushi Suenaga
1Advanced Computing Center, Computational Science Division, Institute of Physical and Chemical Research (RIKEN), 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. okimoto@atlas.riken.go.jp
Biophysical Journal
|April 20, 2002
Summary
The Ala(117)-->Val mutation in prion protein destabilizes its structure, potentially contributing to Gerstmann-Sträussler-Sheinker disease. Molecular dynamics simulations reveal this mutation alters protein conformation and stability.
Area of Science:
- Biochemistry
- Structural Biology
- Computational Biology
Background:
- Prion diseases, such as Gerstmann-Sträussler-Sheinker disease, are linked to mutations in the prion protein (PrP).
- Understanding the structural impact of specific mutations is crucial for elucidating disease mechanisms.
Purpose of the Study:
- To investigate the conformational changes in prion protein induced by the Ala(117)-->Val mutation using molecular dynamics.
- To compare the structural stability of wild-type and mutant prion protein models.
Main Methods:
- Utilized molecular dynamics calculations to simulate three models of human and mouse prion proteins.
- Models included nuclear magnetic resonance structures with and without specific N-terminal peptides containing Ala(117) or Val(117).
Main Results:
- Models with Ala(117) (wild-type) exhibited stable globular domains, with the extra peptide potentially forming an alpha-helix.
- The Val(117) mutation led to an unstable globular domain and an increased beta-sheet region, particularly in human prion protein.
Conclusions:
- The Ala(117)-->Val mutation significantly impacts prion protein structure, promoting instability and altered secondary structures.
- These findings provide insights into the molecular basis of Gerstmann-Sträussler-Sheinker disease pathogenesis.