Article

Massive conformation change in the prion protein: Using dual-basin structure-based models to find misfolding pathways

  1. Jesse P. Singh1,*,
  2. Paul C. Whitford2,
  3. N. R. Hayre1,
  4. José Onuchic3,
  5. Daniel L. Cox1

Article first published online: 13 FEB 2012

DOI: 10.1002/prot.24026

Issue

Proteins: Structure, Function, and Bioinformatics

Proteins: Structure, Function, and Bioinformatics

Volume 80, Issue 5, pages 1299–1307, May 2012

Additional Information

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

Author Information

  1. 1

    Department of Physics and the Institute for Complex Adaptive Matter (ICAM-I2CAM), University of California at Davis, Davis, California 95616 USA

  2. 2

    Los Alamos National Laboratory, Theoretical Biology and Biophysics, Theoretical Division, MS K710, Los Alamos, New Mexico 87545

  3. 3

    Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA

*Department of Physics, University of California at Davis, Davis, CA 95616

Publication History

  1. Issue published online: 5 APR 2012
  2. Article first published online: 13 FEB 2012
  3. Accepted manuscript online: 9 JAN 2012 06:19AM EST
  4. Manuscript Accepted: 18 NOV 2011
  5. Manuscript Revised: 19 OCT 2011
  6. Manuscript Received: 4 JUL 2011

Funded by

  • NSF. Grant Numbers: PHY0822283, NSFMCB0543906, NSFMCB0744732

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Keywords:

  • left-handed;
  • beta-helix;
  • protein folding;
  • structure-based;
  • disulfide

Abstract

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.

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