Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

Kamp, Marc W. van der; Daggett, Valerie

doi:10.1007/128_2011_158

Cited by 25 publications

(20 citation statements)

References 173 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Met 166 and Tyr 218 ) to solvent ( Figure 4). Similar findings have also been reported in the NMR structure of the E200K mutant [33], X-ray structures of F198S and D178N mutants [34] and in independent MD (molecular dynamics) studies [35][36][37]. These findings indicate that the structural disorder of the β 2 -α 2 loop region together with the increased distance between the loop and the α 3 helix represent key pathological structural features.…”

Section: Discussionsupporting

confidence: 82%

Structural basis for the protective effect of the human prion protein carrying the dominant-negative E219K polymorphism

Biljan

Giachin

Ilc

et al. 2012

Biochemical Journal

View full text Add to dashboard Cite

The most common form of prion disease in humans is sCJD (sporadic Creutzfeldt-Jakob disease). The naturally occurring E219K polymorphism in the HuPrP (human prion protein) is considered to protect against sCJD. To gain insight into the structural basis of its protective influence we have determined the NMR structure of recombinant HuPrP (residues 90-231) carrying the E219K polymorphism. The structure of the HuPrP(E219K) protein consists of a disordered N-terminal tail (residues 90-124) and a well-structured C-terminal segment (residues 125-231) containing three α-helices and two short antiparallel β-strands. Comparison of NMR structures of the wild-type and HuPrPs with pathological mutations under identical experimental conditions revealed that, although the global architecture of the protein remains intact, replacement of Glu²¹⁹ with a lysine residue introduces significant local structural changes. The structural findings of the present study suggest that the protective influence of the E219K polymorphism is due to the alteration of surface charge distribution, in addition to subtle structural rearrangements localized within the epitopes critical for prion conversion.

show abstract

Section: Discussionsupporting

confidence: 82%

Structural basis for the protective effect of the human prion protein carrying the dominant-negative E219K polymorphism

Biljan

Giachin

Ilc

et al. 2012

Biochemical Journal

View full text Add to dashboard Cite

show abstract

“…Molecular dynamics simulations of PrP fragment similar to PrP106–126 and full-length PrP provided some structural insights of PrP106–126 [72]–[78]. The study by Derreumaux suggested that PrP106–126 had a clear preference for β-sheet structure [72].…”

Section: Resultsmentioning

confidence: 98%

“…As for PrP109–213, residues 111–114, 120–123 of PrP109–213 participated in three-stranded β-sheet which was found in equilibrium with β-hairpin and random states [75]. Additionally, some mutations [75], [76] and low pH [77], [78] can incline the fragments including PrP106–126 to acquired β-stranded structure. In summary, the residues involved in PrP106–126 displayed high propensity to acquire β-sheets or β-hairpins.…”

Section: Resultsmentioning

confidence: 99%

Structural Diversity and Initial Oligomerization of PrP106–126 Studied by Replica-Exchange and Conventional Molecular Dynamics Simulations

et al. 2014

View full text Add to dashboard Cite

Prion diseases are marked by cerebral accumulation of the abnormal isoform of the prion protein. A fragment of prion protein composed of residues 106–126 (PrP106–126) exhibits similar properties to full length prion and plays a key role in the conformational conversion from cellular prion to its pathogenic pattern. Soluble oligomers of PrP106–126 have been proposed to be responsible for neurotoxicity. However, the monomeric conformational space and initial oligomerization of PrP106–126 are still obscure, which are very important for understanding the conformational conversion of PrP106–126. In this study, replica exchange molecular dynamics simulations were performed to investigate monomeric and dimeric states of PrP106–126 in implicit solvent. The structural diversity of PrP106–126 was observed and this peptide did not acquire stable structure. The dimeric PrP106–126 also displayed structural diversity and hydrophobic interaction drove the dimerization. To further study initial oligomerization of PrP106–126, 1 µs conventional molecular dynamics simulations of trimer and tetramer formation were carried out in implicit solvent. We have observed the spontaneous formation of several basic oligomers and stable oligomers with high β-sheet contents were sampled in the simulations of trimer and tetramer formation. The β-hairpin formed in hydrophobic tail of PrP106–126 with residues 118–120 in turn may stabilize these oligomers and seed the formation oligomers. This study can provide insight into the detailed information about the structure of PrP106–126 and the dynamics of aggregation of monomeric PrP106–126 into oligomers in atomic level.

show abstract

“…The picture is further complicated because not only on-pathway intermediate states can exist, but also off-pathway ones. Characterization of the latter are of particular interest for reproducing in MD the conditions leading to misfolded protein conformations [36]. As in the case of unfolded states, results on intermediates can be checked against NMR [37] and several other experimental techniques [2], including time-resolved single-molecule fluorescence based on Förster resonance energy transfer (FRET) [38].…”

Section: Exploring the Free Energy Landscape Of Protein Foldingmentioning

confidence: 99%

Using simulations to provide the framework for experimental protein folding studies

Rizzuti¹,

Daggett²

2013

Archives of Biochemistry and Biophysics

Self Cite

View full text Add to dashboard Cite

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

Cited by 25 publications

References 173 publications

Structural basis for the protective effect of the human prion protein carrying the dominant-negative E219K polymorphism

Structural basis for the protective effect of the human prion protein carrying the dominant-negative E219K polymorphism

Structural Diversity and Initial Oligomerization of PrP106–126 Studied by Replica-Exchange and Conventional Molecular Dynamics Simulations

Using simulations to provide the framework for experimental protein folding studies

Contact Info

Product

Resources

About