Premium
Massive conformation change in the prion protein: Using dual‐basin structure‐based models to find misfolding pathways
Author(s) -
Singh Jesse P.,
Whitford Paul C.,
Hayre N. R.,
Onuchic José,
Cox Daniel L.
Publication year - 2012
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.24026
Subject(s) - protein structure , prion protein , chemistry , protein folding , biophysics , computational biology , crystallography , biology , biochemistry , medicine , disease , pathology
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.