Issue 2, 2017

Polymorphism at 129 dictates metastable conformations of the human prion protein N-terminal β-sheet

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.

Graphical abstract: Polymorphism at 129 dictates metastable conformations of the human prion protein N-terminal β-sheet

Supplementary files

Article information

Article type
Edge Article
Submitted
23 Jul 2016
Accepted
30 Sep 2016
First published
30 Sep 2016
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2017,8, 1225-1232

Polymorphism at 129 dictates metastable conformations of the human prion protein N-terminal β-sheet

S. A. Paz, E. Vanden-Eijnden and C. F. Abrams, Chem. Sci., 2017, 8, 1225 DOI: 10.1039/C6SC03275C

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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