Massive conformation change in the prion protein: Using dual-basin structure-based models to find misfolding pathways
Article first published online: 13 FEB 2012
Copyright © 2012 Wiley Periodicals, Inc.
Proteins: Structure, Function, and Bioinformatics
Volume 80, Issue 5, pages 1299–1307, May 2012
How to Cite
Singh, J. P., Whitford, P. C., Hayre, N. R., Onuchic, J. and Cox, D. L. (2012), Massive conformation change in the prion protein: Using dual-basin structure-based models to find misfolding pathways. Proteins, 80: 1299–1307. doi: 10.1002/prot.24026
- Issue published online: 5 APR 2012
- Article first published online: 13 FEB 2012
- Accepted manuscript online: 9 JAN 2012 06:19AM EST
- Manuscript Accepted: 18 NOV 2011
- Manuscript Revised: 19 OCT 2011
- Manuscript Received: 4 JUL 2011
- NSF. Grant Numbers: PHY0822283, NSFMCB0543906, NSFMCB0744732
- protein folding;
We employ all-atom structure-based models with a force field with multiple energetic basins for the C-terminal (residues 166–226) of the mammalian prion protein. One basin represents the known alpha-helical (αH) structure while the other represents the same residues in a left-handed beta-helical (LHBH) conformation. The LHBH structure has been proposed to help describe one class of in vitro grown fibrils, as well as possibly self-templating the conversion of normal cellular prion protein to the infectious form. Yet, it is unclear how the protein may make this global rearrangement. Our results demonstrate that the conformation changes are not strongly limited by large-scale geometry modification and that there may exist an overall preference for the LHBH conformation. Furthermore, our model presents novel intermediate trapping conformations with twisted LHBH structure. Proteins 2012; © 2012 Wiley Periodicals, Inc.