One gene, two diseases and three conformations: Molecular dynamics simulations of mutants of human prion protein at room temperature and elevated temperatures
Article first published online: 28 FEB 2005
Copyright © 2005 Wiley-Liss, Inc.
Proteins: Structure, Function, and Bioinformatics
Volume 59, Issue 2, pages 275–290, 1 May 2005
How to Cite
Shamsir, M. S. and Dalby, A. R. (2005), One gene, two diseases and three conformations: Molecular dynamics simulations of mutants of human prion protein at room temperature and elevated temperatures. Proteins, 59: 275–290. doi: 10.1002/prot.20401
- Issue published online: 21 MAR 2005
- Article first published online: 28 FEB 2005
- Manuscript Accepted: 4 OCT 2004
- Manuscript Revised: 27 SEP 2004
- Manuscript Received: 20 JUL 2004
Fatal familial insomnia (FFI) and Creutzfeldt-Jakob disease (CJD) are associated to the same mutation at codon 178 but differentiate into clinicopathologically distinct diseases determined by this mutation and a naturally occurring methionine–valine polymorphism at codon 129 of the prion protein gene. It has been suggested that the clinical and pathological difference between FFI and CJD is caused by different conformations of the prion protein. Using molecular dynamics (MD), we investigated the effect of the mutation at codon 178 and the polymorphism at codon 129 on prion protein dynamics and conformation at normal and elevated temperatures. Four model structures were examined with a focus on their dynamics and conformational changes. The results showed differences in stability and dynamics between polymorphic variants. Methionine variants demonstrated a higher stability than valine variants. Elongation of existing β-sheets and formation of new β-sheets was found to occur more readily in valine polymorphic variants. We also discovered the inhibitory effect of proline residue on existing β-sheet elongation. Proteins 2005. © 2005 Wiley-Liss, Inc.