ArticleChemical science2017
Polymorphism at 129 dictates metastable conformations of the human prion protein N-terminal β-sheet.
Article in Chemical science, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Replica Exchange of Expanded Ensembles: A Generalized Ensemble Approach with Enhanced Flexibility and Parallelizability.Journal of chemical theory and computation · 2024Article
- Single-molecule visualization determines conformational substate ensembles in β-sheet-rich peptide fibrils.Science advances · 2023Article
- Molecular Dynamics Simulations of Ion Permeation in Human Voltage-Gated Sodium Channels.Journal of chemical theory and computation · 2023Article
- Optimizing String Method's Reproducibility Using Generalized Solute Tempering Replica Exchange.The journal of physical chemistry. B · 2021Article
- A Case of Autosomal Dominant Ataxia with Vocal Cord Palsy Attributed to a Mutation in theMovement disorders clinical practice · 2020Article
- The metastable states of proteins.Protein science : a publication of the Protein Society · 2020Review
- Structural basis for the complete resistance of the human prion protein mutant G127V to prion disease.Scientific reports · 2018Article
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Authors and funding
3 authors.
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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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