Tandem mass spectrometry

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A quadrupole time-of-flight hybrid tandem mass spectrometer.

Tandem mass spectrometry, also known as MS/MS or MS2, involves multiple steps of mass spectrometry selection, with some form of fragmentation occurring in between the stages.[1]

Instrumentation[edit]

Schematic of tandem mass spectrometry

For tandem mass spectrometry in space, the different elements are often noted in shorthand. Multiple stages of mass analysis separation can be accomplished with individual mass spectrometer elements separated in space or using a single mass spectrometer with the MS steps separated in time.

Tandem in space[edit]

Triple quadrupole diagram; and example of tandem mass spectrometry in space.

In tandem mass spectrometry in space, the separation elements are physically separated and distinct, although there is a physical connection between the elements to maintain high vacuum. These elements can be sectors, transmission quadrupole, or time-of-flight. When using multiple quadrupoles, they can act as both mass analyzers and collision chambers.

QQuadrupole mass analyzer
qRadio frequency collision quadrupole
TOFTime-of-flight mass analyzer
B – Magnetic sector
E – Electric sector

The notation can be combined to indicate various hybrid instrument, for example

QqQTriple quadrupole mass spectrometer
QTOF – Quadrupole time-of-flight mass spectrometer (also QqTOF)
BEBE – Four-sector (reverse geometry) mass spectrometer

Tandem in time[edit]

An ion trap mass spectrometer is an example of a tandem mass spectrometry in time instrument.

By doing tandem mass spectrometry in time, the separation is accomplished with ions trapped in the same place, with multiple separation steps taking place over time. A quadrupole ion trap or FTMS instrument can be used for such an analysis. Trapping instruments can perform multiple steps of analysis, which is sometimes referred to as MSn (MS to the n). Often the number of steps, n, is not indicated, but occasionally the value is specified; for example MS3 indicates three stages of separation. Tandem in time MS instruments do not use the modes described next, but typically collect all of the information from a precursor ion scan and a parent ion scan of the entire spectrum. Each instrumental configuration utilizes a unique mode of mass identification.

Tandem in space MS/MS modes[edit]

When tandem MS is performed with an in space design, the instrument must operate in one of a variety of modes. There are a number of different tandem MS/MS experiments and each mode has its own applications and offer their own information. Tandem MS in space uses the coupling of two instrument components which measure the same mass spectrum range but with a controlled fractionation between them in space, while tandem MS in time involves the use of an ion trap.

There are four main scan experiments possible using MS/MS: precursor ion scan, product ion scan, neutral loss scan, and selected reaction monitoring.

For a precursor ion scan, the product ion is selected in the second mass analyzer, and the precursor masses are scanned in the first mass analyzer. Note that precursor ion[2] is synonymous with parent ion[3] and product ion[4] with daughter ion;[5] however the use of these anthropomorphic terms is discouraged.[6][7]

In a product ion scan, a precursor ion is selected in the first stage, allowed to fragment and then all resultant masses are scanned in the second mass analyzer and detected in the detector that is positioned after the second mass analyzer. This experiment is commonly performed to identify transitions used for quantification by tandem MS.

In a neutral loss scan, the first mass analyzer scans all the masses. The second mass analyzer also scans, but at a set offset from the first mass analyzer.[8] This offset corresponds to a neutral loss that is commonly observed for the class of compounds. In a constant-neutral-loss scan, all precursors that undergo the loss of a specified common neutral are monitored. To obtain this information, both mass analyzers are scanned simultaneously, but with a mass offset that correlates with the mass of the specified neutral. Similar to the precursor-ion scan, this technique is also useful in the selective identification of closely related class of compounds in a mixture.

In selected reaction monitoring, both mass analyzers are set to a selected mass. This mode is analogous to selected ion monitoring for MS experiments. A selective analysis mode, which can increase sensitivity.[9]

Fragmentation[edit]

Fragmentation of gas-phase ions is essential to tandem mass spectrometry and occurs between different stages of mass analysis. There are many methods used to fragment the ions and these can result in different types of fragmentation and thus different information about the structure and composition of the molecule.

In-source fragmentation[edit]

Often, the ionization process is sufficiently violent to leave the resulting ions with sufficient internal energy to fragment within the mass spectrometer. If the product ions persist in their non-equilibrium state for a moderate amount of time before auto-dissociation this process is called metastable fragmentation.[10][11] Nozzle-skimmer fragmentation refers to the purposeful induction of in-source fragmentation by increasing the nozzle-skimmer potential on usually electrospray based instruments. Although in-source fragmentation allows for fragmentation analysis, it is not technically tandem mass spectrometry unless metastable ions are mass analyzed or selected before auto-dissociation and a second stage of analysis is performed on the resulting fragments. In-source fragmentation is often used in addition to tandem mass spectrometry (with post-source fragmentation) to allow for two steps of fragmentation in a pseudo MS3-type of experiment.[12]

Collision-induced dissociation[edit]

Post-source fragmentation is most often what is being used in a tandem mass spectrometry experiment. Energy can also be added to the ions, which are usually already vibrationally excited, through post-source collisions with neutral atoms or molecules, the absorption of radiation, or the transfer or capture of an electron by a multiply charged ion. Collision-induced dissociation (CID), also called collisionally activated dissociation (CAD), involves the collision of an ion with a neutral atom or molecule in the gas phase and subsequent dissociation of the ion.[13][14] For example, consider

AB^+ + M \to A + B^+ + M

where the ion AB+ collides with the neutral species M and subsequently breaks apart. The details of this process are described by collision theory.

Higher-energy collisional dissociation (HCD) is a CID technique specific to orbitrap mass spectrometers in which fragmentation takes place external to the trap.[15]

Electron capture and transfer methods[edit]

The energy released when an electron is transferred to or captured by a multiply charged ion can induce fragmentation.

Electron capture dissociation[edit]

If an electron is added to a multiply charged positive ion, the Coulomb energy is liberated. Adding a free electron is called electron capture dissociation (ECD),[16] and is represented by

[M + nH]^{n+} + e^- \to \bigg[ [M + (n-1)H]^{(n-1)+} \bigg]^* \to fragments

for a multiply protonated molecule M.

Electron transfer dissociation[edit]

Adding an electron through an ion-ion reaction is called electron transfer dissociation (ETD).[17][18] Similar to electron-capture dissociation, ETD induces fragmentation of cations (e.g. peptides or proteins) by transferring electrons to them. It was invented by Donald F. Hunt, Joshua Coon, John E. P. Syka and Jarrod Marto at the University of Virginia.[19]

ETD does not use free electrons but employs radical anions (e.g. anthracene or azobenzene) for this purpose:

[M + nH]^{n+} + A^- \to \bigg[ [M + (n-1)H]^{(n-1)+} \bigg]^* + A \to fragments

where A is the anion.[20]

ETD cleaves randomly along the peptide backbone (c and z ions) while side chains and modifications such as phosphorylation are left intact. The technique only works well for higher charge state ions (z>2), however relative to collision-induced dissociation (CID), ETD is advantageous for the fragmentation of longer peptides or even entire proteins. This makes the technique important for top-down proteomics. Much like ECD, ETD is effective for peptides with modifications such as phosphorylation.[21]

Electron-transfer and higher-energy collision dissociation (EThcD) is a combination ETD and HCD where the peptide precursor is initially subjected to an ion/ion reaction with fluoranthene anions in a linear ion trap, which generates c- and z-ions.[22][23] In the second step HCD all-ion fragmentation is applied to all ETD derived ions to generate b- and y- ions prior to final analysis in the orbitrap analyzer.[24] This method employs dual fragmentation to generate ion- and thus data-rich MS/MS spectra for peptide sequencing and PTM localization.[25]

Negative electron transfer dissociation[edit]

Fragmentation can also occur with a deprotonated species, in which an electron is transferred from the specie to an cationic reagent in a negative electron transfer dissociation (NETD):[26]

[M-nH]^{n-} + A^+ \to \bigg[ [M-nH]^{(n+1)-} \bigg]^* + A \to fragments

Following this transfer event, the electron deficient anion undergoes internal rearrangement and fragments. NETD is the ion/ion analogue of electron-detachment dissociation (EDD).

NETD is compatible with fragmenting peptide and proteins along the backbone at the Cα-C bond. The resulting fragments are usually a- and x-type product ions.

Electron-detachment dissociation[edit]

Electron-detachment dissociation (EDD) is a method for fragmenting anionic species in mass spectrometry.[27] It serves as a negative counter mode to electron capture dissociation. Negatively charged ions are activated by irradiation with electrons of moderate kinetic energy. The result is ejection of electrons from the parent ionic molecule, which causes dissociation via recombination.

Photodissociation[edit]

The energy required for dissociation can be added by photon absorption, resulting in ion photodissociation and represented by

AB^+ + h\nu \to A + B^+

where h\nu represents the photon absorbed by the ion. Ultraviolet lasers can be used, but can lead to excessive fragmentation of biomolecules.[28]

Infrared multiphoton dissociation[edit]

Infrared photons will heat the ions and cause dissociation if enough of them are absorbed. This process is called infrared multiphoton dissociation (IRMPD) and is often accomplished with a carbon dioxide laser and an ion trapping mass spectrometer such as a FTMS.[29]

Blackbody infrared radiative dissociation[edit]

Blackbody radiation can be used for photodissociation in a technique known as blackbody infrared radiative dissociation (BIRD).[30] In the BIRD method, the entire mass spectrometer vacuum chamber is heated to create infrared radiation. BIRD uses the light from black body radiation to thermally (vibrationally) excite the ions until a bond breaks.[30][31] This is similar to infrared multiphoton dissociation with the exception of the source of radiation.[14] This technique is most often used with Fourier transform ion cyclotron resonance mass spectrometers.

Surface induced dissociation[edit]

With surface-induced dissociation (SID), the fragmentation is a result of the collision of an ion with a surface under high vacuum.[32][33]

Quantitative proteomics[edit]

Quantitative proteomics is used to determine the relative or absolution amount of proteins in a sample.[34][35][36] Several quantitative proteomics methods are based on tandem mass spectrometry.

Isobaric tag for relative and absolute quantitation[edit]

Isobaric labeling for tandem mass spectrometry: proteins are extracted from cells, digested, and labeled with tags of the same mass. When fragmented during MS/MS, the reporter ions show the relative amount of the peptides in the samples.

An isobaric tag for relative and absolute quantitation (iTRAQ) is a reagent for tandem mass spectrometry that is used to determine the amount of proteins from different sources in a single experiment.[37][38][39] It uses stable isotope labeled molecules that can be covalent bonded to the N-terminus and side chain amines of proteins. The iTRAQ reagents are used to label peptides from different samples that are pooled and analyzed by liquid chromatography and tandem mass spectrometry. The fragmentation of the attached tag generates a low molecular mass reporter ion that can be used to relatively quantify the peptides and the proteins from which they originated.

Tandem mass tag[edit]

A tandem mass tag (TMT) is an isobaric mass tag chemical label used for protein quantification and identification.[40] The tags contain four regions: mass reporter, cleavable linker, mass normalization, and protein reactive group.

Applications[edit]

Peptides[edit]

Chromatography trace (top) and tandem mass spectrum (bottom) of a peptide.

Tandem mass spectrometry can be used for protein sequencing.[41] When intact proteins are introduced to a mass analyzer, this is called "top-down proteomics" and when proteins are digested into smaller peptides and subsequently introduced into the mass spectrometer, this is called "bottom-up proteomics" proteomics. Shotgun proteomics is a variant of bottom up proteomics in which proteins in a mixture are digested prior to separation and tandem mass spectrometry.

Tandem mass spectrometry can produce a peptide sequence tag that can be used to identify a peptide in a protein database.[42][43][44] A notation has been developed for indicating peptide fragments that arise from a tandem mass spectrum.[45] Peptide fragment ions are indicated by a, b, or c if the charge is retained on the N-terminus and by x, y or z if the charge is maintained on the C-terminus. The subscript indicates the number of amino acid residues in the fragment. Superscripts are sometimes used to indicate neutral losses in addition to the backbone fragmentation, * for loss of ammonia and ° for loss of water. Although peptide backbone cleavage is the most useful for sequencing and peptide identification other fragment ions may be observed under high energy dissociation conditions. These include the side chain loss ions d, v, w and immonium ions[46][47] and additional sequence-specific fragment ions associated with particular amino acid residues.[48][49]

Oligosaccharides[edit]

Oligosaccharides may be sequenced using tandem mass spectrometry in a similar manner to peptide sequencing.[50] Fragmentation generally occurs on either side of the glycosidic bond (b, c, y and z ions) but also under more energetic conditions through the sugar ring structure in a cross-ring cleavage (x ions). Again trailing subscripts are used to indicate position of the cleavage along the chain. For cross ring cleavage ions the nature of the cross ring cleavage is indicated by preceding superscripts.[51][52]

Oligonucleotides[edit]

Tandem mass spectrometry has been applied to DNA and RNA sequencing.[53][54] A notation for gas-phase fragmentation of oligonucleotide ions has been proposed.[55]

Newborn screening[edit]

Main article: Newborn screening

Newborn screening is the process of testing newborn babies for treatable genetic, endocrinologic, metabolic and hematologic diseases.[56][57] The development of tandem mass spectrometry screening in the early 1990s led to a large expansion of potentially detectable congenital metabolic diseases that affect blood levels of organic acids.[58]

See also[edit]

References[edit]

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Bibliography[edit]

  • McLuckey, Scott A.; Busch, Kenneth L.; Glish, Gary L. (1988). Mass spectrometry/mass spectrometry: techniques and applications of tandem mass spectrometry. New York, N.Y: VCH Publishers. ISBN 0-89573-275-0. 
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  • Sherman, Nicholas E.; Kinter, Michael (2000). Protein sequencing and identification using tandem mass spectrometry. New York: John Wiley. ISBN 0-471-32249-0. 

External links[edit]