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How a Mass Spectrometer Works, Types of Instrumentation and Interpreting Mass Spectral Data

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How a Mass Spectrometer Works, Types of Instrumentation and Interpreting Mass Spectral Data

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Mass spectrometry (MS) as we know it today is a result of technological advancements of the pioneering work of three remarkable men – Wilhelm Wien, J.J. Thomson and Francis Aston. If one were to select a defining publication that signaled the birth of MS, the 1907 paper by Thomson “On rays of positive electricity”1 is often considered, yet there are many others that merit attention. The history of MS is an intriguing story in and of itself, and interested readers are pointed to the work of Griffiths2 and Munzenberg3 for further reading.

Since those early days, MS has benefitted from significant technical advances. Today, MS plays a role in many varied aspects of day-to-day life. When we visit a doctor and bodily fluids are drawn for testing, many of these will be analyzed by MS. The doped semiconductors that form the basis of all our electronic devices use MS as part of the quality control process. Our safety in the skies is assisted by the use of MS to help identify potential explosives before they make it on board an airplane and can also assist in finding toxins in our food supply. The applications are almost endless.


What is mass spectrometry and how does mass spectrometry work?
Ion sources for mass spectrometry
    - Gas phase methods
    - Desorption methods
    - Spray methods
Types of mass analyzers
    - Time-of-flight (ToF)
    - Quadrupole
    - Magnetic sector
    - Ion trap
    - Orbitrap
    - Tandem mass spectrometry (tandem MS)
Types of mass spectrometer - pairing ionization techniques with mass analyzers
    - MALDI-TOF
    - ICP-MS
    - DART-MS
    - Secondary ion mass spectrometry (SIMS)
Types of ion detector
    - Electron multiplier (EM)
    -  Faraday cup (FC)
    - Photomultiplier conversion dynode
    - Array detectors
Combining mass spectrometers with other techniques
    - Gas chromatography mass spectrometry (GC-MS)
    - Liquid chromatography mass spectrometry (LC-MS)
    - Crosslinking mass spectrometry (XL-MS)
    - Hydrogen-exchange mass spectrometry (HX-MS)
    - Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI)
How to interpret a mass spectrum, what does m/z show and what is a molecular ion peak?
Mass spectrometry abbreviations


What is mass spectrometry and how does mass spectrometry work?


MS is a form of chemical analysis used to measure the mass-to-charge ratio (m/z) of atoms and/or molecules in a sample. It is also capable of distinguishing between different isotopes of the same element. Depending upon the type of mass spectrometer, these measurements can often be used to determine the exact molecular weight of the sample components and to identify unknown compounds.


Figure 1:
Outline of the main steps of MS and common variants available at each step.


There are many different types of mass spectrometers, but they all have three features in common (Figure 1). The first is some means by which atoms or molecules from the sample can be ionized. Neutral species cannot be steered by electric fields used in mass spectrometers, and thus it is necessary to produce ions. There are many different means by which this can be accomplished, and they are collectively referred to as ion sources.


The second component of all mass spectrometers is the mass analyzer itself. There are several different means by which the m/z ratio of ions can be measured. Time-of-flight (ToF), magnetic sector and quadrupole mass analyzers are the most common, each with its own set of strengths and limitations.


The final component common to all mass spectrometer systems is a means of detecting or counting the number of ions of a specific m/z value. These devices are called detectors and they too come in several different forms with the most common being electron multipliers, Faraday cups, channeltrons and channel plates. Again, each has its own particular strength and weakness.4,5


A final factor that needs consideration is how to couple the ion source to the sample so as to produce the ions for measurement, especially in light of the fact that all mass spectrometers must be operated under vacuum. In some cases, the sample will also be housed under vacuum, in others the sample will be at atmospheric pressure (generally referred to as the ambient MS techniques) and some may incorporate some other form of separation technology prior to introduction to the ionization chamber. The following sections will go over these three common components to mass spectrometers in more detail.


Ion sources for mass spectrometry


Ionization is essential for any MS analysis, for which there are many methods suited to different sample types and applications. Broadly, these can be broken down into gas phase methods, desorption methods, and spray methods. An outline of each is given below.

Gas phase methods

-         
Electron ionization (EI) - analyte molecules must be in the vapor phase to allow effective interaction with the energetic electrons produced in a vacuum by a heated filament. EI can be considered a fairly harsh method of molecule fragmentation and ionization and is most commonly used when samples are relatively volatile and have low molecular weight. 6

-          Chemical ionization (CI) - a gas is introduced into an EI ionization chamber at a concentration higher than the analyte. The interaction of the carrier gas with the electrons will produce several molecular ions, which will subsequently react further with the excess carrier gas and form different molecular ions. These ions will then react with the analyte molecules to form analyte molecular ions through several different mechanisms. CI is a very soft ionization technique and does not lead to extensive fragmentation.7

-          Direct analysis in real time (DART) – plasma is created, producing ions, electrons and excited-state species. Interaction of the excited state species with a liquid, solid or vapor phase sample is then responsible for the ionization of the analyte molecule. DART is able to analyze materials of different shapes and sizes with no prior sample preparation and in ambient conditions. 8

-          Inductively coupled plasma (ICP) – a prepared liquid containing the analyte is aerosolized and converted to gas phase ions using plasma. ICP has the ability to ionize almost all elements.

Desorption methods

-         
Matrix assisted laser desorption ionization (MALDI) – a “matrix”, dictated by the type of molecule to be detected, is added in excess to the sample to be analyzed. The sample is then irradiated by a laser, vaporizing the analyte molecules with little to no fragmentation or decomposition. Both positively and negatively charged ions can be created. MALDI is one of the major “soft” ionization methods, particularly useful for the analysis of large or labile molecules. 9

-          Fast atom bombardment (FAB) - a beam of accelerated ionized atoms is focused onto the sample to be analyzed, ejecting and ionizing target analyte.10,11 This is a soft ionization technique, able to produce positively and negatively charged ions.

-          Thermal ionization sources – heated Cs, producing positive ions, is the most common primary ion source and can be focused with electrostatic ion optics for secondary ion MS.

-          Plasma ionization sources – commonly used to produce beams of gaseous ions, electrons are emitted into a gas, often pure oxygen, ionizing it and creating a plasma. The ions can then be filtered by charge and accelerated into a beam.

-          Liquid metal ion sources (LMIS) – sources are low melting point metals, often Ga, to which the application of heat and an electric field produces ions at a small point source. Ion beams produced by LIMS are characterized by the smallest spot sizes and highest brightness, particularly advantageous in MS imaging where high spatial resolution is required.

Spray methods

-         
Electrospray ionization (ESI) – a mist of charged droplets are reduced in size through solvent evaporation until gas phase ions are ejected. This soft ionization technique suitable for analysis of large molecules and macromolecules.12,13

-          Desorption electrospray ionization (DESI) - very similar to ESI except the charged droplets formed in the ESI source are directed to a sample held at ambient pressure. Reflected droplets then carry the desorbed and ionized sample.14


Click below for a more comprehensive look at ion sources.




Types of mass analyzers


Following sample ionization, the ions must be separated and this occurs in the mass analyzer. Commonly used mass analyzers include:

-          Time-of-flight (ToF) – ions are separated according to their m/z ratio based on the length of time it takes them to travel through a flight tube of known length to reach a detector.

-          Quadrupole - ions entering the quadrupole have their trajectory deflected by electrical potential in a manner that is proportional to their m/z value. Changing the potential allows only ions of specific m/z values to reach the chamber end and be detected.

-          Magnetic sector - magnetic fields disperse ions in trajectories according to their m/z ratios in a manner that is analogous to the way a glass prism disperses light into its various wavelengths or colors.

-          Ion trap – works similarly to a quadrupole but the electrodes are ring shaped and ions are separated and detected by discharging ions with unstable oscillations from the system and into the detector rather than detecting those with stable oscillations.

-          Orbitrap - borrows technology from many of the other types of mass analyzers. Two electrically isolated cup-shaped outer electrodes face each other with a spindle-like central electrode around which ions of a specific mass-to-charge ratio spread into orbiting rings. The conical shape of electrodes pushes ions toward the widest part of the trap and the outer electrodes are then used for current detection. It is the only method described here that uses an image current rather than some detection device to detect the ions.

-          Tandem mass spectrometry (tandem MS) - refers to hybrid methods involving more than one type of mass spectrometer to increase specificity and/or mass resolving capability. They are commonly referred to as MS/MS techniques. 15


Click below for a more comprehensive look at mass analyzers.



Types of mass spectrometer - pairing ionization techniques with mass analyzers


With so many different types of ion sources, ionization mechanisms and different types of mass analyzer, there are many different permutations and combinations of systems that could be built with some engineering effort. However, there are some types of ionization sources and mass analyzers that are excellent fits with one another and these comprise the most commonly available commercial instruments. For example, the pulsed nature of many laser systems are an excellent fit for a ToF mass analyzer, which requires a pulsed ion source as its basis for mass discrimination. This section will look at some of the common pairings of source and mass analyzer in more detail.


MALDI-TOF


As mentioned above, the pulsed nature of many laser systems and this requirement for ToF analysis makes this pair of ionization mechanisms and mass analysis ideally suited to one another. When the laser fires on the matrix/sample spot (which is held in vacuum), the ions are formed and accelerated into the ToF flight tube. The “clock starts” and the mass spectrum is measured.


The method is also capable of generating images by step scanning the stage, continuously scanning the stage under repeated firing of the laser or by scanning the laser beam.16 The resulting images can provide a wealth of information on samples such as large tissue sections.


Since MALDI is a soft ionization technique, molecular information is retained and compounds of interest need not be tagged for detection as in fluorescence microscopy. It therefore provides a means of “label-free” imaging.


ICP-MS


Though initially used with quadrupole mass analyzers, the majority of ICP-MS systems now use ToF mass analyzers. The big advantage here is the fact that the entire mass spectrum is generated much more quickly and with much higher mass resolution compared to those systems using quadrupoles. A few specialized systems use magnetic sector instruments, often paired with multicollector detection systems used for high precision isotope ratio measurements.


Furthermore, by coupling with a laser beam to form laser ablation (LA)-ICP-MS, the technique can also be adapted to form images resulting from the mass analysis of the ablated material. Since this is a destructive technique and the material can only be analyzed once, the ability to retrospectively mine and process the ToF data is a big advantage. In ToF imaging, the entire mass spectrum will be stored in each (x,y) pixel location of the resulting image, thus new ion images can be easily generated post-analysis.


DART-MS


DART-MS also uses a ToF mass analyzer, for all of the reasons previously mentioned. However, because it is an ambient pressure technique, attention to the source (ambient) to mass spectrometer (vacuum) interface is important.


In the original design, analyte ions are directed to the mass analyzer through a pair of orifices with a slight potential difference applied between them. The alignment of the two orifices is staggered to trap neutral contamination and protect the high-vacuum region. The ions are guided to the second orifice through an intermediate cylindrical electrode, but neutral molecules travel in a straight pathway and are thus blocked from entering the mass analyzer and are removed by a vacuum pump.


Secondary ion mass spectrometry (SIMS)


The method of ionization used in secondary ion mass spectrometry (SIMS) techniques is a close cousin to FAB. A beam of positively or negatively charged ions is produced, but no collision cell is used to convert the beam of ions to neutral species. This beam of ions is directly used to bombard the surface of the sample. The most commonly used ions are Cs+ and O2+ for positively charged ion beams and O- for negatively charged beams. Cs+ and O ions are formed by the thermal ionization and plasma sources described earlier.


Note that both Cs and O are reactive species and not inert. In SIMS, this is intentional as both will be implanted into the sample and affect its chemical and physical properties. But they affect these properties in a way that will lead to much more efficient production of negative ions if Cs+ is used, or if positive ions of O2+ or O- are used.


Both Cs and O beams are most frequently observed in direct current sources and the high accelerating voltage used results in serious fragmentation of molecules within the sample such that no molecular information is retained during analysis. Their use would be considered a hard ionization method.


To circumvent this, pulsed sources of small and large cluster ions (Au3+, Bi3+, C60+, Ar2000+) have also been developed that would be considered much softer ionization methods and provide much more molecular detail in the resulting mass spectra. These sources typically operate in pulsed mode which further reduces damage to the sample surface.


ToF, magnetic sector and quadrupole mass spectrometers are all commonly used in SIMS instrumentation.


Types of ion detector


A key element to all MS systems is the type of detector used to convert a current of mass separated ions into measurable signal. Different types of detectors are used depending upon factors including dynamic range, spatial information retention, noise and suitability to the mass analyzer.


Commonly used detectors include the:

-          Electron multiplier (EM) - a serial connection of discrete metal plates that amplify a current of ions by a factor of ~108 into a measurable current of electrons

-          Faraday cup (FC) - ions hitting the collector cause a flow of electrons from ground through the resistor and the resulting potential drop across the resistor is amplified.

-          Photomultiplier conversion dynode - ions initially strike a dynode, resulting in electron emission. The electrons produced then strike a phosphor screen which in turn releases photons. The photons then pass into the multiplier where amplification occurs in a cascade fashion – much like the EM.

-          Array detectors (including detectors for simultaneous measurement of several ions of different m/z and detectors for position-sensitive ion detection) - covers a broad range of detector types and systems that may combine multiple detection technologies1


Click below for a more comprehensive look at ion detectors.





Combining mass spectrometers with other techniques


Gas and liquid separation techniques are often used in conjunction with MS in order to increase sensitivity and ease interpretation. Liquid chromatography (LC), gas chromatography (GC), capillary electrophoresis (CE) and gel electrophoresis (GE) are common examples. The combination of methods is especially common in tandem with ICP-MS and DART-MS.


Gas chromatography mass spectrometry (GC-MS)


GC is an analytical/separation technique in which a complex mixture of compounds is injected into a column and separated based on their relative boiling points and affinity for a chromatographic column.


The high temperatures used in GC make it unsuitable for high molecular weight compounds (e.g., proteins) as heat denatures them. It is well suited for use in the petrochemical, environmental monitoring and remediation and industrial chemical fields. Samples may be solid, liquid, or gaseous in nature.


After separation, the compounds may be analyzed by a mass spectrometric technique, such as ICP-MS, for identification, or ionized using EI or CI and analyzed in a ToF mass analyzer17. Advances in the GC-MS field have been recently reviewed. 17,18


Liquid chromatography mass spectrometry (LC-MS)


LC is similar to gas phase chromatography except the sample is now in the liquid phase. The sample is dissolved in a solvent and injected onto a chromatographic column which consists of the solubilized compounds (the mobile phase) and a solid (stationary) phase.


The relative affinity between the sample constituents and the stationary phase of the column results in separation of the sample components which may then be detected by MS. As the effluents are in the liquid phase, this separation technique lends itself very well to being coupled with ICP-MS and ESI-MS methods, but is also found linked to ion trap and Orbitrap mass spectrometers too. The principles and applications in clinical biochemistry has been reviewed by Pitt19 and more recently Seger20, while applications in drug discovery have been reviewed by Korfmacher.21


Crosslinking mass spectrometry (XL-MS)


Understanding the structure and organization of multiprotein complexes is critical to understanding cellular function. Chemical crosslinking coupled with mass spectrometry (XL-MS) is a method that is complementary to structural biology techniques such as cryogenic electron microscopy (cryo-EM) and X-ray crystallography but provides lower-resolution structural information.


In XL-MS, a protein or protein complex is treated with a crosslinking reagent that introduces covalent linkages between specific functional groups in the protein. The crosslinked protein is then digested with an enzyme that breaks down the protein(s) and the resulting mixture is analyzed by LC-MS methods to identify crosslinked peptides and determine their sequences. The locations of crosslinks provide structural information about the system under study. However, interpretation is complex as samples prepared in this manner contain far more unique chemical species than a digest of the non-crosslinked protein. The number of potential crosslinked peptides increases quadratically with the sequence length. Nonetheless, XL-MS can be a useful tool to aid in the development of structural models for protein-protein interactions.22


Hydrogen-exchange mass spectrometry (HX-MS)


The objective of hydrogen-exchange mass spectrometry (HX-MS) is similar to that of XL-MS – to study multiprotein complexes and in particular, protein structure and dynamics.


Advantages of HX-MS include the fact that it probes the structure of proteins in solution so crystallization is not necessary, it requires only tiny amounts of sample (500 - 1,000 picomoles), it is amenable to studying proteins that are hard to purify and it can reveal changes in structure and dynamics over time.


HX-MS makes use of a chemical reaction whereby certain H atoms in proteins are in continuous exchange with the H atoms in solution. If an aqueous H2O solvent is replaced with heavy water (D2O), then this exchange process can be followed. In particular, the H bonded to the amino acid backbone N atoms (also referred to as the backbone amide H) is useful for probing protein structure. Once the exchange of H with D is complete, the sample can be analyzed by MS to provide information about protein structure changes with small molecule binding, protein folding or information about the structure of proteins that do not crystallize or are not amenable to other structural biology methods.23,24


Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI)


Not only is MALDI-TOF an excellent method for MS analysis, it is also capable of generating images by step scanning the stage, continuously scanning the stage under repeated firing of the laser or by scanning the laser beam.25 This techniques is called matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). The resulting images can provide a wealth of information on, for example, large tissue sections, at a spatial resolution between 50-200
mm. Since MALDI is a soft ionization technique, molecular information is retained and thus compounds of interest need not be tagged for detection, as in fluorescence microscopy. Thus, it provides a means of “label-free” imaging.


How to interpret a mass spectrum, what does m/z show and what is a molecular ion peak?


A typical mass spectrum is represented in Figure 2. In this case, the mass spectrum and structure for pentane (C5H12) is shown, consisting of CH3 and CH2 groups.


Figure 2:
The pentane mass spectrum.


The vertical axis represents the relative intensity or signal of the ions detected in the mass spectrometer, while the horizontal axis represents their m/z ratio (the mass divided by charge number). The strongest peak will therefore have a relative intensity of 100.


Pentane has the chemical formula C5H12. The approximate mass of the molecule is therefore ((12 x 5) + (1 x 12)), or 72 amu. Notice that on the mass spectrum a peak with relative intensity of ~ 10% is observed at m/z = 72 amu. This is the molecular peak. The entire molecule has been ionized in the source as a single entity without any fragmentation. But what of the other, stronger peaks? These are the result of fragmentation during the ionization process of pentane. How can the next heaviest mass observed be interpreted (at m/z = 57 amu with ~ 20% relative intensity)? With a bit of math, we can propose it might be C4H9, which would suggest one of the CH3 groups was fragmented off during the ionization process, leaving the C4H9 fragment molecular ion. Similarly, the strongest signal observed at m/z = 43 amu can be interpreted as C3H7, meaning a C2H5 molecule was fragmented. This is the equivalent of one of the CH3 and CH2 groups. Note that there are also strong lines at m/z = 41 and 42. These are due to extra Hs being stripped from the C3H7 molecular ion during fragmentation. This forms the basis of interpreting mass spectra and requires a knowledge of not only the chemistry but also the structure of the parent molecule. Clearly this could be a daunting task for all of the organic materials in existence. Fortunately, there are databases available that show mass spectra for many of these to assist interpretation.


There is one more complicating factor that is more often observed in mass spectra from elements or small molecules. This is from the different isotopes from each element. In the pentane example we assumed that carbon has a mass of 12 amu. This is not strictly valid as carbon has 2 stable isotopes: one at mass 12 and the other at mass 13 (the atom contains an extra neutron). The natural abundance of these two isotopes is about 99% 12C and 1% 13C. So, if one was using a hard ionization technique and looking at the mass spectrum in this region, one would find a peak at both m/z = 12 and 13, with the peak at 12 being roughly 100 times greater than the peak at m/z = 13. Note that the peak at m/z = 13 could also easily be due to 12C1H, so the importance of mass resolution on a mass spectrometer becomes readily apparent.


However, multiple isotopes of the same element can be useful. It is the basis of HX-MS described earlier, and also the basis for multi-isotope imaging mass spectrometry26,27 where stable isotope are intentionally added to compounds and then isotope ratio images derived from the sample. Those regions where the isotope ratio is greater than the natural abundance indicate the regions of the sample where the compound has been incorporated. Two common stable isotopes used to this effect are 13C and 15N.


Mass spectrometry abbreviations

CCD                        Charge couple device

CE                           Capillary electrophoresis

CI                            Chemical ionization

DART                     Direct analysis in real time

DC                          Direct current

DESI                       Desorption electrospray ionization

EI                            Electron ionization

EM                         Electron multiplier

ESI                          Electrospray ionization

FAB                        Fast atom bombardment

FC                           Faraday cup

GC                          Gas chromatography

GE                          Gel electrophoresis

HX-MS                  Hydrogen exchange mass spectrometry

ICP                         Inductively coupled plasma

LC                           Liquid chromatography

MALDI                  Matrix assisted laser desorption ionization

MCP                      Microchannel plate

MS                         Mass spectrometry

RAE                        Resistive anode encoder

RF                           Radio frequency

SIMS                      Secondary ion mass spectrometry

ToF                         Time of flight

XL-MS                   Cross linking mass spectrometry

References


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