Differential Mobility Spectrometry-Hydrogen Deuterium Exchange (DMS-HDX) as a Probe of Protein Conformation in Solution

Zhu, Shaolong; Campbell, J. Larry; Chernushevich, Igor V.; Blanc, J. C. Yves Le; Wilson, Derek J.

doi:10.1007/s13361-016-1364-6

Cited by 19 publications

(21 citation statements)

References 36 publications

(57 reference statements)

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“…In an ideal case, the DMS coupled to HDX would allow for determining the liquid-phase structure of a particular protein and evaluating global structure of protein in solution. DMS-HDX was used to determine charge distribution (800–2400 m/z) and compensation voltages of nTau and pTau (Zhu et al 2016). While it was found that nTau existed in an unfolded state, pTau existed in a mix of states.…”

Section: Mass Spectrometrymentioning

confidence: 99%

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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Section: Mass Spectrometrymentioning

confidence: 99%

Structural evaluations of tau protein conformation: methodologies and approaches

Zabik

Imhof

Martic-Milne

2017

Biochem. Cell Biol.

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“…The level of incorporation of deuterons from the surrounding gas by a protein depends on the surface accessibility of its protons and thus on its conformation. Even though low levels of exchange have been correlated with compact structures and higher levels of exchange with more elongated conformations, the actual mechanisms of exchange in the gas-phase are still not completely understood and more studies are needed to support the validity of such direct correlations [47,48]. Differences in the deuterated gas used, sampling time after ESI of the protein ions and the time allowed for deuterium exchange complicate the interpretation of the available data.…”

Section: Preserving Native or Near-native Protein Conformations Inmentioning

confidence: 99%

“…Differences in the deuterated gas used, sampling time after ESI of the protein ions and the time allowed for deuterium exchange complicate the interpretation of the available data. Nevertheless, recently developed instrumental setups have delivered results that suggest that solution-phase structural features can be preserved in the gas-phase [48,49,50,51]. Gas-phase fragmentation methods that are specific to surface-exposed regions, such as electron capture dissociation (ECD) and electron transfer dissociation (ETD) have also been extensively used to decipher gas-phase conformations [52,53,54,55,56,57,58,59].…”

Section: Preserving Native or Near-native Protein Conformations Inmentioning

confidence: 99%

Native Mass Spectrometry in Fragment-Based Drug Discovery

Pedro

Quinn

2016

Molecules

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Abstract:The advent of native mass spectrometry (MS) in 1990 led to the development of new mass spectrometry instrumentation and methodologies for the analysis of noncovalent protein-ligand complexes. Native MS has matured to become a fast, simple, highly sensitive and automatable technique with well-established utility for fragment-based drug discovery (FBDD). Native MS has the capability to directly detect weak ligand binding to proteins, to determine stoichiometry, relative or absolute binding affinities and specificities. Native MS can be used to delineate ligand-binding sites, to elucidate mechanisms of cooperativity and to study the thermodynamics of binding. This review highlights key attributes of native MS for FBDD campaigns.

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“…The separation of many types of isomeric biomolecules has been demonstrated using DMS, including structural isomers, 23−39 stereoisomers, 20 isotopomers, 40 and protein conformers. 41 Besides separation by DMS, our instrument's configuration also enables the use of gas-phase hydrogen−deuterium exchange (HDX) experiments. 41−45 The HDX reactions occur post-DMS such that we can separate the ions first and investigate their gas-phase structures with HDX thereafter.…”

mentioning

confidence: 99%

Separating Isomers, Conformers, and Analogues of Cyclosporin using Differential Mobility Spectroscopy, Mass Spectrometry, and Hydrogen–Deuterium Exchange

Lam

Blanc²,

Campbell

2020

Anal. Chem.

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Cyclosporins are an invaluable class of drug used to prevent the rejection of transplanted tissue. While the most popular drug in this group is cyclosporin A, several other analogues are available, including some enantiomeric and structurally isomeric forms. Unfortunately, the presence of such isomers can make the detection and identification of these drugs by mass spectrometry (MS) alone quite challenging. Here, we demonstrate the separation and analysis of six cyclosporin analogues using liquid chromatography (LC) and differential mobility spectroscopy (DMS) coupled to MS. Using DMS, we demonstrate the separation of three isomers: CycA and CycH (cyclosporin H), which are enantiomers, and isocyclosporin A (a structural isomer of CycA and CycH). For several of the cyclosporins, we can separate different conformers for each isomeric form. After DMS separation, tandem mass spectrometry (MS/MS) analyses of the separated isomers also distinguish these isomeric forms of cyclosporin. In addition, we have probed differences between each isomer by using gas-phase hydrogen–deuterium exchange (HDX) immediately after DMS separation, which reveals differences in the levels of intramolecular hydrogen bonding between each of the cyclosporins.

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Differential Mobility Spectrometry-Hydrogen Deuterium Exchange (DMS-HDX) as a Probe of Protein Conformation in Solution

Cited by 19 publications

References 36 publications

Structural evaluations of tau protein conformation: methodologies and approaches

Structural evaluations of tau protein conformation: methodologies and approaches

Native Mass Spectrometry in Fragment-Based Drug Discovery

Separating Isomers, Conformers, and Analogues of Cyclosporin using Differential Mobility Spectroscopy, Mass Spectrometry, and Hydrogen–Deuterium Exchange

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