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          Institute: MPI für biophysikalische Chemie     Collection: NMR-basierte Strukturbiologie (Prof. Christian Griesinger)     Display Documents

ID: 433676.0, MPI für biophysikalische Chemie / NMR-basierte Strukturbiologie (Prof. Christian Griesinger)
A combined solid-state NMR and MD characterization of the stability and dynamics of the HET-s(218-289) prion in its amyloid conformation.
Authors:Lange, A.; Gattin, Z.; Van Melckebeke, H.; Wasmer, C.; Soragni, A.; van Gunsteren, W. F.; Meier, B. H.
Date of Publication (YYYY-MM-DD):2009-07-06
Title of Journal:ChemBioChem
Issue / Number:10
Start Page:1657
End Page:1665
Review Status:not specified
Audience:Not Specified
Abstract / Description:The three-dimensional structure of amyloid fibrils of the prion-forming part of the HET-s protein [HET-s(218-289)], as determined by solid-state NMR, contains rigid and remarkably well-ordered parts, as witnessed by the narrow solid-state NMR line widths for this system. On the other hand, high-resolution magic-angle-spinning (HRMAS) NMR results have shown that HET-s(218-289) amyloid fibrils contain highly flexible parts as well. Here, we further explore this unexpected behaviour using solid-state NMR and molecular dynamics (MD). The NMR data provide new information on order and dynamics in the rigid and flexible parts of HET-s(218-289), respectively. The MD study addresses whether or not small multimers, in an amyloid conformation, are stable on the 10 ns timescale of the MD run and provides insight into the dynamic parameters on the nanosecond timescale. The atom-positional, root-mean-squared fluctuations (RMSFs) and order parameters S-2 obtained are in agreement with the NMR data. A flexible loop and the N terminus exhibit dynamics on the ps-ns timescale, whereas the hydrophobic core of HET-s(218-289) is rigid. The high degree of order in the core region of HET-s(218-289) amyloids, as observed in the MID simulations, is in agreement with the narrow, solid-state, NMR lines. Finally, we employed MD to predict the behaviour of the salt-bridge network in HET-s(218289), which cannot be obtained easily by experiment. Simulations at different temperatures indicated that the network is highly dynamic and that it contributes to the thermostability of the HET-s(218-289) amyloids.
Free Keywords:amyloid fibrils; molecular dynamics; prions; solid-state structures
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für biophysikalische Chemie/AG Adam Lange
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