Observation of β-Sheet Aggregation in a Gas-Phase Tau-Peptide Dimer

Vaden, Timothy D.; Gowers, Sally A. N.; Snoek, Lavina C.

doi:10.1021/ja807760d

Cited by 38 publications

(50 citation statements)

References 19 publications

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“…This indicates that diverse β structures may be readily accessible at the physiological condition, consistent with previous experimental observations that Tau aggregates as β sheet structures. 59, 60 …”

Section: Resultsmentioning

confidence: 99%

The IDP-Specific Force Field ff14IDPSFF Improves the Conformer Sampling of Intrinsically Disordered Proteins

Dong

Luo

Chen

2017

J. Chem. Inf. Model.

157

187

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Intrinsically disordered proteins (IDPs) or intrinsically disordered regions have not fixed tertiary structure, but play key roles in signal regulation, molecule recognition, and drug target. However it is difficult to study the structure and function of IDPs by traditional experimental methods because of their diverse conformations. Limitations of current generic protein force fields and solvent models were reported in the previous simulations of IDPs. We have also explored to overcome these limitations by developing ff99IDPs and ff14IDPs force fields to correct the dihedral distribution for eight disordered promoting residues often observed in IDPs and found encouraging improvements. Here, we extend our correction of backbone dihedral terms to all 20 naturally occurring amino acids in the IDP-specific force field (ff14IDPSFF) to further improve the quality in the modeling of IDPs. Extensive tests of seven IDPs and 14 unstructured short peptides show that the simulated Cα chemical shifts with the ff14IDPSFF force field are in quantitative agreement with those from NMR experiment and are more accurate than the base generic force field and also our previous ff14IDPs that only corrects the eight disorder-promoting amino acids. The influences of solvent models were also investigated and found to be less important. Finally our explicit solvent MD simulations further show that ff14IDPSFF can still be used to model structural and dynamical properties of two tested folded proteins, with a slightly better agreement in the loop regions for both structural and dynamical properties. These findings confirm that the newly developed IDP-specific force field ff14IDPSFF can improve the conformer sampling of intrinsically disordered proteins.

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Section: Resultsmentioning

confidence: 99%

The IDP-Specific Force Field ff14IDPSFF Improves the Conformer Sampling of Intrinsically Disordered Proteins

Dong

Luo

Chen

2017

J. Chem. Inf. Model.

157

187

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“…Molecular mechanics and density-functional theory were used to evaluate 10,000 conformers, most of which contained the stable β-sheet motif, which was corroborated by FT-IR studies (Vaden et al 2009). Similarly, replica exchange molecular dynamics (MD) and forward-flux sampling simulations of VQIINK and VQIVYK hexapeptides (Figure 2) have provided insight into the mechanism, rates, and free energy landscapes during aggregation (Ganguly et al 2015; Smit et al 2016).…”

Section: Computational Approachesmentioning

confidence: 91%

Structural evaluations of tau protein conformation: methodologies and approaches

Zabik

Imhof

Martic-Milne

2017

Biochem. Cell Biol.

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Protein-misfolding diseases are based on a common principle of aggregation initiated by intra- and intermolecular contacts. The structural and conformational changes, induced by biochemical transformations, such as post-translational modifications (PTMs), often lead to protein unfolding and misfolding. Thus, these order-to-disorder or disorder-to-order transitions may regulate cellular function. Tau, a neuronal protein, regulates microtubule (MT) structure and overall cellular integrity. However, misfolded tau modified by PTMs results in MT destabilization, toxic tau aggregate formation, and ultimately cell death, leading to neurodegeneration. Currently, the lack of structural information surrounding tau severely limits understanding of neurodegeneration. This mini-review focuses on the current methodologies and approaches aimed at probing tau conformation and its role in various aspects of tau biochemistry. The recent applications of nuclear magnetic resonance, mass spectrometry, Förster resonance electron transfer, and molecular dynamics simulation toward structural analysis of conformational landscapes of tau will be described. The strategies developed for structural evaluation of tau may significantly improve our understanding of misfolding diseases.

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“…The indigestiblity of some of these may be due to their adopting the resistant β-pleating configuration. This is true of both β-amyloid within plaques and the hyperphosphorylated tau protein forming neurofibrillary tangles found in Alzheimer’s disease [21,22], aberrant prion protein found in bovine spongy encephalomyelitis [23], and β-synuclein inclusions found in Parkinson’s disease [24] as well as the mutant huntingtin protein found in Huntington’s Disease [25]. Table 1 is an incomplete listing of the aggregates and their constituent proteins, associated with various neurodegenerative conditions.…”

Section: The Aggregation Of Intrinsic Protein Species Within Nervous mentioning

confidence: 99%

Nanoparticles and Colloids as Contributing Factors in Neurodegenerative Disease

Bondy

2011

IJERPH

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This review explores the processes underlying the deleterious effects of the presence of insoluble or colloidal depositions within the central nervous system. These materials are chemically unreactive and can have a prolonged residence in the brain. They can be composed of mineral or proteinaceous materials of intrinsic or exogenous origin. Such nanoparticulates and colloids are associated with a range of slow-progressing neurodegenerative states. The potential common basis of toxicity of these materials is discussed. A shared feature of these disorders involves the appearance of deleterious inflammatory changes in the CNS. This may be due to extended and ineffective immune responses. Another aspect is the presence of excess levels of reactive oxygen species within the brain. In addition with their induction by inflammatory events, these may be further heightened by the presence of redox active transition metals to the large surface area afforded by nanoparticles and amphipathic micelles.

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Observation of β-Sheet Aggregation in a Gas-Phase Tau-Peptide Dimer

Cited by 38 publications

References 19 publications

The IDP-Specific Force Field ff14IDPSFF Improves the Conformer Sampling of Intrinsically Disordered Proteins

The IDP-Specific Force Field ff14IDPSFF Improves the Conformer Sampling of Intrinsically Disordered Proteins

Structural evaluations of tau protein conformation: methodologies and approaches

Nanoparticles and Colloids as Contributing Factors in Neurodegenerative Disease

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