Faculty Collaboration Database

Direct observation of protein folding, aggregation, and a prion-like conformational conversion. J Biol Chem 2005 Dec 02;280(48):40235-40

Date

10/06/2005

Pubmed ID

16204250

DOI

10.1074/jbc.M506372200

Scopus ID

2-s2.0-28844506608 (requires institutional sign-in at Scopus site)   81 Citations

Abstract

Protein conformational transition from alpha-helices to beta-sheets precedes aggregation of proteins implicated in many diseases, including Alzheimer and prion diseases. Direct characterization of such transitions is often hindered by the complicated nature of the interaction network among amino acids. A recently engineered small protein-like peptide with a simple amino acid composition features a temperature-driven alpha-helix to beta-sheet conformational change. Here we studied the conformational transition of this peptide by molecular dynamics simulations. We observed a critical temperature, below which the peptide folds into an alpha-helical coiled-coil state and above which the peptide misfolds into beta-rich structures with a high propensity to aggregate. The structures adopted by this peptide during low temperature simulations have a backbone root mean square deviation less than 2 A from the crystal structure. At high temperatures, this peptide adopts an amyloid-like structure, which is mainly composed of coiled anti-parallel beta-sheets with the cross-beta-signature of amyloid fibrils. Most strikingly, we observed conformational conversions in which an alpha-helix is converted into a beta-strand by proximate stable beta-sheets with exposed hydrophobic surfaces and unsaturated hydrogen bonds. Our study suggested a possible generic molecular mechanism of the template-mediated aggregation process, originally proposed by Prusiner (Prusiner, S. B. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 13363-13383) to account for prion infectivity.

Author List

Ding F, LaRocque JJ, Dokholyan NV

Author

Joshua J. Larocque MD Assistant Professor in the Neurology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amyloid
Computer Simulation
Crystallography, X-Ray
Dimerization
Hydrogen Bonding
Models, Molecular
Peptides
Prions
Protein Binding
Protein Conformation
Protein Folding
Protein Structure, Secondary
Protein Structure, Tertiary
Temperature
Thermodynamics