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Matrix-assisted laser desorption/ionization
Matrix-assisted laser desorption/ionization (MALDI) is a soft ionization technique used in mass spectrometry, allowing the analysis of biomolecules (biopolymers such as DNA, proteins, peptides and sugars) and large organic molecules (such as polymers, dendrimers and other macromolecules), which tend to be fragile and fragment when ionized by more conventional ionization methods. It is similar in character to electrospray ionization (ESI) in that both techniques are relatively soft ways of obtaining ions of large molecules in the gas phase, though MALDI produces far fewer multiply charged ions.
MALDI is thought to be a three-step process. First, the sample is mixed with a suitable matrix material and applied to a metal plate. Second, a pulsed laser irradiates the sample, triggering ablation and desorption of the sample and matrix material. Finally, the analyte molecules are ionized by being protonated or deprotonated in the hot plume of ablated gases, and can then be accelerated into whichever mass spectrometer is used to analyse them. However, considerable evidence suggests analyte ions are produced from charged particles produced in the ablation process.
- 1 History
- 2 Matrix and sample preparation
- 3 Technology and instrumentation
- 4 Applications
- 5 Reproducibility and improving performance
- 6 See also
- 7 References
- 8 Bibliography
- 9 External links
The term matrix-assisted laser desorption ionization (MALDI) was coined in 1985 by Franz Hillenkamp, Michael Karas and their colleagues. These researchers found that the amino acid alanine could be ionized more easily if it was mixed with the amino acid tryptophan and irradiated with a pulsed 266 nm laser. The tryptophan was absorbing the laser energy and helping to ionize the non-absorbing alanine. Peptides up to the 2843 Da peptide melittin could be ionized when mixed with this kind of “matrix”. The breakthrough for large molecule laser desorption ionization came in 1987 when Koichi Tanaka of Shimadzu Corporation and his co-workers used what they called the “ultra fine metal plus liquid matrix method” that combined 30 nm cobalt particles in glycerol with a 337 nm nitrogen laser for ionization. Using this laser and matrix combination, Tanaka was able to ionize biomolecules as large as the 34,472 Da protein carboxypeptidase-A. Tanaka received one-quarter of the 2002 Nobel Prize in Chemistry for demonstrating that, with the proper combination of laser wavelength and matrix, a protein can be ionized. Karas and Hillenkamp were subsequently able to ionize the 67 kDa protein albumin using a nicotinic acid matrix and a 266 nm laser. Further improvements were realized through the use of a 355 nm laser and the cinnamic acid derivatives ferulic acid, caffeic acid and sinapinic acid as the matrix. The availability of small and relatively inexpensive nitrogen lasers operating at 337 nm wavelength and the first commercial instruments introduced in the early 1990s brought MALDI to an increasing number of researchers. Today, mostly organic matrices are used for MALDI mass spectrometry.
Matrix and sample preparation
|Compound||Other Names||Solvent||Wavelength (nm)||Applications|
|2,5-dihydroxy benzoic acid||DHB, Gentisic acid||acetonitrile, water, methanol, acetone, chloroform||337, 355, 266||peptides, nucleotides, oligonucleotides, oligosaccharides|
|3,5-dimethoxy-4-hydroxycinnamic acid||sinapic acid; sinapinic acid; SA||acetonitrile, water, acetone, chloroform||337, 355, 266||peptides, proteins, lipids|
|4-hydroxy-3-methoxycinnamic acid||ferulic acid||acetonitrile, water, propanol||337, 355, 266||proteins|
|α-Cyano-4-hydroxycinnamic acid||CHCA||acetonitrile, water, ethanol, acetone||337, 355||peptides, lipids, nucleotides|
|3-hydroxy picolinic acid||HPA||Ethanol||337, 355||oligonucleotides|
The matrix consists of crystallized molecules, of which the three most commonly used are 3,5-dimethoxy-4-hydroxycinnamic acid (sinapinic acid), α-cyano-4-hydroxycinnamic acid (CHCA, alpha-cyano or alpha-matrix) and 2,5-dihydroxybenzoic acid (DHB). A solution of one of these molecules is made, often in a mixture of highly purified water and an organic solvent (normally acetonitrile (ACN) or ethanol). A counter ion source such as Trifluoroacetic acid (TFA) is usually added to generate the [M+H] ions. A good example of a matrix-solution would be 20 mg/mL sinapinic acid in ACN:water:TFA (50:50:0.1).
The identification of suitable matrix compounds is determined to some extent by trial and error, but they are based on some specific molecular design considerations:
- They are of a fairly low molecular weight (to allow easy vaporization), but are large enough (with a low enough vapor pressure) not to evaporate during sample preparation or while standing in the spectrometer.
- They are often acidic, therefore act as a proton source to encourage ionization of the analyte. Basic matrices have also been reported.
- They have a strong optical absorption in either the UV or IR range, so that they rapidly and efficiently absorb the laser irradiation. This efficiency is commonly associated with chemical structures incorporating several conjugated double bonds, as seen in the structure of cinnamic acid.
- They are functionalized with polar groups, allowing their use in aqueous solutions.
- They typically contain a chromophore.
The matrix solution is mixed with the analyte (e.g. protein-sample). A mixture of water and organic solvent allows both hydrophobic and water-soluble (hydrophilic) molecules to dissolve into the solution. This solution is spotted onto a MALDI plate (usually a metal plate designed for this purpose). The solvents vaporize, leaving only the recrystallized matrix, but now with analyte molecules embedded into MALDI crystals. The matrix and the analyte are said to be co-crystallized. Co-crystallization is a key issue in selecting a proper matrix to obtain a good quality mass spectrum of the analyte of interest.
The matrix can be used to tune the instrument to ionize the sample in different ways. As mentioned above, acid-base like reactions are often utilized to ionize the sample, however, molecules with conjugated pi systems, such as naphthalene like compounds, can also serve as an electron acceptor and thus a matrix for MALDI/TOF. This is particularly useful in studying molecules that also possess conjugated pi systems. The most widely used application for these matrices is studying porphyrin like compounds such as chlorophyll. These matrices have been shown to have better ionization patterns that do not result in odd fragmentation patterns or complete loss of side chains. It has also been suggested that conjugated porphryin like molecules can serve as a matrix and cleave themselves eliminating the need for a separate matrix compound.
Technology and instrumentation
There are several variations of the MALDI technology and comparable instruments are today produced for very different purposes. From more academic and analytical, to more industrial and high throughput. The MS field has expanded into requiring ultrahigh resolution mass spectrometry such as the FT-ICR instruments as well as more high-throughput instruments. As many MALDI MS instruments can be bought with an interchangeable ionization source (Electrospray ionization, MALDI, Atmospheric pressure ionization, etc) the technologies often overlap and many times any soft ionization method could potentially be used. For more variations of soft ionization methods go to Soft laser desorption or Ion source.
MALDI techniques typically employ the use of UV lasers such as nitrogen lasers (337 nm) and frequency-tripled and quadrupled Nd:YAG lasers (355 nm and 266 nm respectively). Although not as common, infrared lasers are used due to their softer mode of ionization. IR-MALDI also has the advantage of greater material removal (useful for biological samples), less low-mass interferences, and compatibility with other matrix-free laser desorption mass spectrometry methods.
The laser is fired at the matrix crystals in the dried-droplet spot. The matrix absorbs the laser energy and it is thought that primarily the matrix is desorbed and ionized (by addition of a proton) by this event. The hot plume produced during ablation contains many species: neutral and ionized matrix molecules, protonated and deprotonated matrix molecules, matrix clusters and nanodroplets. Ablated species may participate in the ionization of analyte, though the mechanism of MALDI is still debated. The matrix is then thought to transfer protons to the analyte molecules (e.g., protein molecules), thus charging the analyte. An ion observed after this process will consist of the initial neutral molecule [M] with ions added or removed. This is called a quasimolecular ion, for example [M+H]+ in the case of an added proton, [M+Na]+ in the case of an added sodium ion, or [M-H]− in the case of a removed proton. MALDI is capable of creating singly charged ions or multiply charged ions ([M+nH]n+) depending on the nature of the matrix, the laser intensity, and/or the voltage used. Note that these are all even-electron species. Ion signals of radical cations (photoionized molecules) can be observed, e.g., in the case of matrix molecules and other organic molecules.
A recent method termed matrix-assisted ionization [MAI] uses matrix preparation identical to MALDI but does not require laser ablation to produce analyte ions of volatile or nonvolatile compounds. Simply exposing the matrix [e.g. 3-nitrobenzonitrile] with analyte to the vacuum of the mass spectrometer creates ions with nearly identical charge states to electrospray ionization. It is suggested that there are likely mechanistic commonality between this process and MALDI.
Time of Flight
The type of a mass spectrometer most widely used with MALDI is the TOF (time-of-flight mass spectrometer), mainly due to its large mass range. The TOF measurement procedure is also ideally suited to the MALDI ionization process since the pulsed laser takes individual 'shots' rather than working in continuous operation. MALDI-TOF instrument or reflectron is equipped with an "ion mirror" that reflects ions using an electric field, thereby doubling the ion flight path and increasing the resolution. Today, commercial reflectron TOF instruments reach a resolving power m/Δm of well above 20,000 FWHM (full-width half-maximum, Δm defined as the peak width at 50% of peak height).
Atmospheric pressure matrix-assisted laser desorption/ionization
Atmospheric pressure (AP) matrix-assisted laser desorption/ionization (MALDI) is an ionization technique (ion source) that in contrast to vacuum MALDI operates at normal atmospheric environment. The main difference between vacuum MALDI and AP-MALDI is the pressure in which the ions are created. In vacuum MALDI, ions are typically produced at 10 mTorr or less while in AP-MALDI ions are formed in atmospheric pressure. In the past the main disadvantage of AP MALDI technique compared to the conventional vacuum MALDI has been its limited sensitivity; however, ions can be transferred into the mass spectrometer with high efficiency and attomole detection limits have been reported. AP-MALDI is used in mass spectrometry (MS) in a variety of applications ranging from proteomics to drug discovery. Popular topics that are addressed by AP-MALDI mass spectrometry include: proteomics; mass analysis of DNA, RNA, PNA, lipids, oligosaccharides, phosphopeptides, bacteria, small molecules and synthetic polymers, similar applications as available also for vacuum MALDI instruments. The AP-MALDI ion source is easily coupled to an ion trap mass spectrometer or any other MS system equipped with ESI (electrospray ionization) or nanoESI source.
In proteomics, MALDI is used for the rapid identification of proteins isolated by using gel electrophoresis: SDS-PAGE, size exclusion chromatography, affinity chromatography, strong/weak ion exchange, isotope coded protein labelling (ICPL),and two-dimensional gel electrophoresis. Peptide mass fingerprinting is the most popular analytical application of MALDI-TOF mass spectrometers. MALDI TOF/TOF mass spectrometers are used to reveal amino acid sequence of peptides using post-source decay or high energy collision-induced dissociation (further use see mass spectrometry).
Loss of sialic acid has been identified in papers when DHB has been used as a matrix for MALDI MS analysis of glycosylated peptides. Using sinapinic acid, 4-HCCA and DHB as matrices, S. Martin studied loss of sialic acid in glycosylated peptides by metastable decay in MALDI/TOF in linear mode and reflector mode. A group at Shimadzu Corporation derivatized the sialic acid by an amidation reaction as a way to improve detection sensitivity and also demonstrated that ionic liquid matrix reduces a loss of sialic acid during MALDI/TOF MS analysis of sialylated oligosaccharides. THAP, DHAP, and a mixture of 2-aza-2-thiothymine and phenylhydrazine  have been identified as matrices that could be used to minimize loss of sialic acid during MALDI MS analysis of glycosylated peptides.
It has been reported that a reduction in loss of some post-translational modifications can be accomplished if IR MALDI is used instead of UV MALDI 
In molecular biology, a mixture of 5-methoxysalicylic acid and spermine can be used as a matrix for oligonucleotides analysis in MALDI mass spectrometry, for instance after oligonucleotide synthesis.
Some synthetic macromolecules, such as catenanes and rotaxanes, dendrimers and hyperbranched polymers, and other assemblies, have molecular weights extending into the thousands or tens of thousands, where most ionization techniques have difficulty producing molecular ions. MALDI is a simple and fast analytical method that can allow chemists to rapidly analyze the results of such syntheses and verify their results.
In polymer chemistry MALDI can be used to determine the molar mass distribution. Polymers with polydispersity greater than 1.2 are difficult to characterize with MALDI due to the signal intensity discrimination against higher mass oligomers.
MALDI/TOF spectra are used for the identification of microorganisms such as bacteria or fungi. A colony of the microbe in question is smeared directly on the sample target and overlaid with matrix. The mass spectra generated are analyzed by dedicated software and compared with stored profiles. Species diagnosis by this procedure is much faster, more accurate and cheaper than other procedures based on immunological or biochemical tests. MALDI/TOF may become the standard method for species identification in medical microbiological laboratories over the next few years.
MALDI/TOF spectra are often utilized in tandem with other analysis and spectroscopy techniques in the diagnosis of diseases. MALDI/TOF is a diagnostic tool with much potential because it allows for the rapid identification of proteins and changes to proteins without the cost or computing power of sequencing nor the skill or time needed to solve a crystal structure in X-ray crystallography.
One of example of this is necrotizing enterocolitis (NEC), which is a devastating disease that affects the bowels of premature infants. The symptoms of NEC are very similar to those of sepsis, and many infants die awaiting diagnosis and treatment. MALDI/TOF was used to quickly analyze fecal samples and find differences between the mutant and the functional protein responsible for NEC. There is hope that a similar technique could be used as a quick, diagnostic tool that would not require sequencing.
Another example of the diagnostic power of MALDI/TOF is in the area of cancer. Pancreatic cancer remains one of the most deadly and difficult to diagnose cancers. Impaired cellular signaling due to mutations in membrane proteins has been long suspected to contribute to pancreatic cancer. MALDI/TOF has been used to identify a membrane protein associated with pancreatic cancer and at one point may even serve as an early detection technique.
MALDI/TOF can also potentially be used to dictate treatment as well as diagnosis. Since the use of antibacterial hand-creams and soaps has becoming popular, the question of “super bugs” and increased bacterial drug resistance has been raised. MALDI/TOF serves as a method for determining the drug resistance of bacteria, especially to β-lactamases (Penicillin family). The MALDI/TOF detects the presence of carbapenemases, which indicates drug resistance to standard antibiotics. It is predicted that this could serve as a method for identifying a bacteria as drug resistant in as little as three hours. This technique could help physicians decide whether to prescribe more aggressive antibiotics initially.
Reproducibility and improving performance
Reproducibility is a known weakness of MALDI where the same analysis protocol can potentially yield different results, especially over time. Two key aspects are sample preparation and calibration. It is important for both sensitivity, reproducibility, and quantification of mass analysis. As MALDI is an invaluable technique for providing characterization data (e.g. the overall molecular weight, the mass of repeating units/amino acid sequences, and the identity of end groups) of high-mass synthetic or biological macromolecules; the technique requires regular calibration of the mass scale to assure mass accuracy. Traditionally, calibration systems have fallen into two categories: polydisperse systems (synthetic polymers   or ion clusters      ) or monodisperse biomolecules (typically peptides or proteins). Of these, peptides and proteins had become the preferred calibrant because they were monodisperse and widely available. While these biomacromolecules fulfill the calibration requirements, their poor stability at ambient conditions and the high cost of their purification has complicated their regular use.
With the announcement by Bruker on the FDA approval of the use of MALDI Biotyper CA   for the indentation of Gram negative bacterial colonies cultured from human specimens in clinical microbiology diagnostics the need of more robust and user-friendly calibrants is of outmost importance. A versatile synthetic analog, marketed under the brand name SpheriCal, is one available high-throughput MALDI calibrant.  Prepared as sets of discrete, monodisperse dendrimers, these calibrants exhibit an extended shelf-life and exceptional compatibility with a wide range of solvents and matrices, when compared to protein analogs. Their stability enables the calibrations samples to be premixed (matrix, cation, calibrant) and are available as 20 discrete calibration masses up to 30,000 Da. Standard peptide and protein calibration kits, on the other hand, only contain a few masses above 10 000 Da. Most notably Trypsinogen and Albumin-Bovine. The latter is usually seen as both [M+H] and [M+2H]2+ where Albumin-Bovine is not recommended for calibration purposes as it has been seen shifting to higher masses due to unspecific adduct formations.
In analysis of biological systems, Inorganic salts, which are also part of protein extracts, interfere with the ionization process. The salts can be removed by solid phase extraction or by washing the dried-droplet MALDI spots with cold water. Both methods can also remove other substances from the sample. The matrix-protein mixture is not homogenous because the polarity difference leads to a separation of the two substances during co-crystallization. The spot diameter of the target is much larger than that of the laser, which makes it necessary to make many laser shots at different places of the target, to get the statistical average of the substance concentration within the target spot. The matrix chemical composition, the addition of trifluoroacetic acid, formic acid, fructose, delay time between the end of laser pulse and start of ion acceleration in the ion source (in vacuum MALDI sources), laser wavelength, UV energy (as well as its density and homogeneity)in a focused light spot produced by pulsed laser, and the impact angle of the laser on the target are among critical parameters for the quality and reproducibility of the MALDI-TOF MS method.
Additionally, the thickness of the MALDI plate can affect the TOF measurements. The smaller plates (less thick) will have longer TOF measurements. This can potentially shift peaks in the spectra and make it difficult to compare to other published results.
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