Journal article
Polymorphism at 129 dictates metastable conformations of the human prion protein N-terminal β-sheet
Chemical science (Cambridge), v 8(2), pp 1225-1232
2017
PMID: 28451263
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
We study the thermodynamic stability of the native state of the human prion protein using a new free-energy method, replica-exchange on-the-fly parameterization. This method is designed to overcome hidden-variable sampling limitations to yield nearly error-free free-energy profiles along a conformational coordinate. We confirm that all four (M129V, D178N) polymorphs have a ground-state conformation with three intact β-sheet hydrogen bonds. Additionally, they are observed to have distinct metastabilities determined by the side-chain at position 129. We rationalize these findings with reference to the prion “strain” hypothesis, which links the variety of transmissible spongiform encephalopathy phenotypes to conformationally distinct infectious prion forms and classifies distinct phenotypes of sporadic Creutzfeldt-Jakob disease based solely on the 129 polymorphism. Because such metastable structures are not easily observed in structural experiments, our approach could potentially provide new insights into the conformational origins of prion diseases and other pathologies arising from protein misfolding and aggregation.
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Details
- Title
- Polymorphism at 129 dictates metastable conformations of the human prion protein N-terminal β-sheet
- Creators
- S. Alexis Paz - Department of Chemical and Biological Engineering, Drexel University, Philadelphia, USAEric Vanden-Eijnden - Courant Institute of Mathematical Sciences, New York University, New York, USACameron F Abrams - Department of Chemical and Biological Engineering, Drexel University, Philadelphia, USA
- Publication Details
- Chemical science (Cambridge), v 8(2), pp 1225-1232
- Publisher
- Royal Society of Chemistry
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemical and Biological Engineering
- Web of Science ID
- WOS:000395428300044
- Scopus ID
- 2-s2.0-85011043588
- Other Identifier
- 991014878117004721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Chemistry, Multidisciplinary