Merge pull request #88 from agduboff/patch-5

Update 13.Peptide-Fragmentation.md
jessegmeyerlab · Oct 18, 2023 · 64aad8b · 64aad8b
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Showing 1 changed file with 15 additions and 15 deletions.
diff --git a/content/13.Peptide-Fragmentation.md b/content/13.Peptide-Fragmentation.md
@@ -11,9 +11,9 @@ True MS1-only methods that use only accurate mass and retention time for identif
 The value of MS/MS spectra for peptide identification comes from predictable fragmentation behavior of peptide ions to generate sequence-informative fragments [@DOI:10.1073/pnas.83.17.6233; @DOI:10.1021/acs.jproteome.2c00838].
 Multiple dissociation methods exist to generate product ions in MS/MS spectra through various mechanisms (**Figure 13**).
 In non-modified peptides, the most labile bonds are typically peptide bonds (i.e., amide bonds) between amino acids.
-Depending on where peptides dissociate along the peptide backbone, the fragments are assigned different ion types (Figure XA). 
+Depending on where peptides dissociate along the peptide backbone, the fragments are assigned different ion types (**Figure 13A**). 
 Fragment ion nomenclature was first developed by Roepstorff and Fohlman in 1984 [@DOI:10.1002/bms.1200111109] and then refined by Biemann in 1990 [@ISBN:978-0121820947].
-The main ion types are the peptides that contain the original peptide n-terminus (i.e. a, b, and c ions), or the original peptide c-terminus (i.e. x, y, and z ions). 
+The main ion types are the peptides that contain the original peptide N-terminus (i.e., a, b, and c ions), or the original peptide C-terminus (i.e., x, y, and z ions). 
 The number associated with each fragment ion indicates how many amino acids from each end are included. 
 The most common ions from collisional methods are the b and y ions, which result from fragmentation of the amide between the carbonyl and nitrogen.
 The most common ions from electron transfer methods are c and z ions, which occur between the nitrogen and the alpha-carbon of the peptide backbone. 
@@ -24,7 +24,7 @@ Fragments that explain the intact N-terminus of the peptide are a-, b-, and c-ty
 Other panels show common dissociation methods, including collision, electron, and photon-based fragmentation. 
 (B) Resonant collision-induced dissociation (resCID) and beam-type CID (beamCID) both produce mainly b/y-type sequencing ions through collisions with background gases like helium and nitrogen that increase the internal energy of peptide cations. 
 (C) Electron capture and electron transfer dissociation (ECD and ETD) generate mainly c/z-type fragments through electron-mediated radical driven cleavage of the peptide backbone. 
-(D) Infrared multiphoton dissociation (IRMPD) is a slow heating method similar in dissociation mechanism to resCID, but very different in implementation due to the IR lasers required (often with lower energy 10.6 micron photons). 
+(D) Infrared multi-photon dissociation (IRMPD) is a slow heating method similar in dissociation mechanism to resCID, but very different in implementation due to the IR lasers required (often with lower energy 10.6 micron photons). 
 Ultraviolet photodissociation (UVPD) can use a range of wavelengths (popular options shown) to introduce higher energy photons to peptide cations, causing vibrational and electronic excitation that can generate all major fragment ion types depending on wavelength used.
 ](images/Tandem_MS.svg){#fig:SPE tag="13" width="100%"}
 
@@ -36,7 +36,7 @@ Two main versions of CID are used in proteomics, with the most common being beam
 BeamCID typically uses nitrogen or argon as a collision gas, and peptide ions are accelerated into a collision cell filled with several mTorr of bath gas.
 The kinetic energy used to accelerate precursor ions (often generated using direct current voltage differentials between the source of the ions and the collision cell) determines the energy imparted through collisions with the bath gas, which in turn governs their fragmentation behavior.
 
-In non-modified peptides, the most labile bonds are typically peptide bonds (i.e., amide bonds) between amino acids, so the increase in internal energy from beamCID generates b- and y-type ions that represent this peptide bond cleavage, as shown in Biemann fragment ion nomenclature (Figure X).
+Since in non-modified peptides the most labile bonds are typically peptide bonds (i.e., amide bonds) between amino acids, the increase in internal energy from beamCID generates b- and y-type ions that represent this peptide bond cleavage, as shown in Biemann fragment ion nomenclature (**Figure 13A**).
 b-type ions provide sequence information for fragments that have an intact N-terminus, while y-type ions denote fragment ions with an intact C-terminus.
 Collisions in beamCID cause near instantaneous generation of primary fragment ions.
 Because the increase in internal energy happens rapidly before energy can be redistributed, beamCID can generate fragments that are not necessarily derived from cleavage of the most labile bonds (e.g., PTM-modified peptides, discussed below), but spectra are often dominated by b/y-type ions from amide bond cleavage.
@@ -51,13 +51,13 @@ The increased kinetic energy creates more collisions with the background helium
 Once ions dissociate, the fragments have different m/z values than the precursor ions, meaning they fall out of resonance with the supplemental rf and are no longer activated.
 Thus, resCID typically fragments only the most labile bonds in precursor ions and does not have secondary fragmentation behavior.
 As above, for non-modified peptide ions, this typically generates sequence-informative b- and y-type product ions.
-For modified peptides where the bonds connecting the modification to an amino acid are more labile than peptide bonds, e.g., phosphopeptides and glycopeptides, resCID MS/MS spectra can be dominated by products ions only of the PTM-loss rather than sequence informative fragment ions, although many factors govern this behavior [@DOI:10.1021/pr0705136; @DOI:10.1021/ac0497104].
+For modified peptides where the bonds connecting the modification to an amino acid are more labile than peptide bonds (e.g., phosphopeptides and glycopeptides), resCID MS/MS spectra can be dominated by product ions only of the PTM-loss rather than sequence-informative fragment ions, although many factors govern this behavior [@DOI:10.1021/pr0705136; @DOI:10.1021/ac0497104].
 Because of this, and because this method requires an ion trap device with the ability to apply supplemental rfs, resCID is less used than beamCID.
 For both beamCID and resCID, the mobile proton model has been widely accepted to explain fragmentation behavior [@PMID:11180630], and this largely predictable behavior has greatly helped in manual and algorithm-assisted spectral interpretation.
 
 Despite the utility and broad adoption of CID, there are alternative dissociation methods that have been explored for a variety of uses, including applications where CID is inadequate for the experimental question [@DOI:10.1021/ac802330b; @DOI:10.1038/nprot.2008.159; @DOI:10.1007/s00726-014-1726-y].
 The most popular of these alternative dissociation methods are electron-based dissociation (ExD) approaches, which include electron capture dissociation (ECD) and electron transfer dissociation (ETD).
-In both of these, peptide cations capture thermal electrons (ECD, [@DOI:10.1021/ja973478k]) or abstract an electron from a reagent anion (ETD, [@DOI:10.1073/pnas.0402700101]) to generate radical-driven dissociation of the N-Ca bond that predominantly generates sequence-informative c- and z-type product ions (**Figure 13C**).
+In both of these, peptide cations capture thermal electrons (ECD [@DOI:10.1021/ja973478k]) or abstract an electron from a reagent anion (ETD [@DOI:10.1073/pnas.0402700101]) to generate radical-driven dissociation of the N-Ca bond that predominantly generates sequence-informative c- and z-type product ions (**Figure 13C**).
 The mechanisms of ExD methods have been widely explored [@DOI:10.1021/ja8019005; @DOI:10.1016/j.jasms.2004.11.001], and the preferential cleavage of N-Ca bonds along the peptide backbone have been particularly useful for PTM-modified species because the modifications remain largely intact even during peptide backbone bond fragmentation.
 ExD methods have shown promise for analysis of numerous PTMs, including phosphorylation, glycosylation, ADP-ribosylation, and more [@DOI:10.1021/acs.analchem.7b04810; @DOI:10.1002/mas.21560].
 
@@ -66,17 +66,17 @@ First, ExD implementation requires instruments that can manipulate cations and a
 This has been successfully accomplished on a number of instruments, including FT-ICR, ion trap, ToFs with quadrupole ion traps, and hybrid Orbitrap instruments, but it is not a ubiquitous feature of all platforms.
 That said, several exciting advances in recent years have made ExD methods more accessible on numerous instrument configurations [@DOI:10.1021/acs.analchem.7b04810; @DOI:10.1002/mas.21560; @DOI:10.1021/acs.analchem.8b01901; @DOI:10.1021/acs.jproteome.7b00622; @DOI:10.1021/jasms.0c00425].
 A second challenge is the dependence of ExD dissociation efficiency on precursor ion charge density [@DOI:10.1074/mcp.M700073-MCP200].
-ExD methods generally produce robust fragmentation for charge dense precursor ions, i.e., those with relatively low m/z values and higher z. 
-Alternatively, precursors with low charge density, i.e., higher m/z values, have relatively condensed secondary gas-phase structure that leads to non-covalent interactions.
-Even when ExD methods drive peptide backbone cleavage in these cases, product ions (i.e. c- and z-type fragments) are held together by the non-covalent interactions so that few (or no) sequence-informative product ions are produced.
-This process is called non-dissociative electron-capture/transfer (ECnoD/ETnoD)[@DOI:10.1021/ac050666h].
-Several strategies to mitigate ECnoD/ETnoD have been successfully explored, including supplemental activation of product ions with resCID (ETcaD [@DOI:10.1021/ac061457f]) or beamCID (EThcD [@DOI:10.1016/j.jasms.2009.05.009; @DOI:10.1021/ac3025366]), supplemental activation with infrared photons (AI-ECD [@DOI:10.1016/j.jasms.2008.12.015; @DOI:10.1021/ac000494i] and AI-ETD [@DOI:10.1021/acs.analchem.5b00881; @DOI:10.1002/anie.200903557; @DOI:10.1021/acs.analchem.0c02087; @DOI:10.1021/jasms.1c00284]) or ultraviolet photons (ETuvPD[@DOI:10.1021/ac5036082]), and use of higher energy electrons [@URL:https://www.sciencedirect.com/science/article/abs/pii/S0009261402001495; @DOI:10.1021/ja8087407; @DOI:10.1021/jasms.0c00425].
-Despite their successes, these methods still require instrumentation capable of ExD in addition to extra hardware needed for a given strategy (e.g., a CO2 laser in AI-ETD [@DOI:10.1021/acs.analchem.7b00213]).
+ExD methods generally produce robust fragmentation for charge dense precursor ions (i.e., those with relatively low m/z values and higher z). 
+Alternatively, precursors with low charge density (i.e., higher m/z values) have relatively condensed secondary gas-phase structure that leads to non-covalent interactions.
+Even in the cases when ExD methods drive peptide backbone cleavage, product ions (i.e., c- and z-type fragments) are held together by the non-covalent interactions so that few (or no) sequence-informative product ions are produced.
+This process is called non-dissociative electron-capture/transfer (ECnoD/ETnoD) [@DOI:10.1021/ac050666h].
+Several strategies to mitigate ECnoD/ETnoD have been successfully explored, including supplemental activation of product ions with resCID (ETcaD [@DOI:10.1021/ac061457f]) or beamCID (EThcD [@DOI:10.1016/j.jasms.2009.05.009; @DOI:10.1021/ac3025366]), supplemental activation with infrared photons (AI-ECD [@DOI:10.1016/j.jasms.2008.12.015; @DOI:10.1021/ac000494i] and AI-ETD [@DOI:10.1021/acs.analchem.5b00881; @DOI:10.1002/anie.200903557; @DOI:10.1021/acs.analchem.0c02087; @DOI:10.1021/jasms.1c00284]) or ultraviolet photons (ETuvPD [@DOI:10.1021/ac5036082]), and use of higher energy electrons [@URL:https://www.sciencedirect.com/science/article/abs/pii/S0009261402001495; @DOI:10.1021/ja8087407; @DOI:10.1021/jasms.0c00425].
+Despite their successes, these methods still require instrumentation capable of ExD in addition to extra hardware needed for a given strategy (e.g., a CO<sub>2</sub> laser in AI-ETD [@DOI:10.1021/acs.analchem.7b00213]).
 As with ExD in general, recent advances in supplemental activation strategies for ExD are making these tools more accessible [@DOI:10.1021/acs.analchem.7b04810; @DOI:10.1002/mas.21560].
 
-Photoactivation is another family of alternative dissociation strategies that have been steadily gaining popularity [@DOI:10.1021/acs.analchem.9b04859; @DOI:10.1039/c3cs60444f].
+Photoactivation is another family of alternative dissociation strategies that has been steadily gaining popularity [@DOI:10.1021/acs.analchem.9b04859; @DOI:10.1039/c3cs60444f].
 Infrared multi-photon dissociation (IRMPD) is canonically the photodissociation method used in early proteomic applications [@DOI:10.1039/c3cs60444f], but ultraviolet photodissociation (UVPD) has been the more widely used approach in the recent decade [@DOI:10.1021/acs.chemrev.9b00440].
-IRMPD functions similarly to resCID; it is a slow heating approach that causes vibrational excitation due to absorption of low energy photons, generally 10.6 um photons from a CO2 laser [@DOI:10.1021/acs.chemrev.9b00395; @DOI:10.1016/j.jasms.2004.07.016].
+IRMPD functions similarly to resCID; it is a slow heating approach that causes vibrational excitation due to absorption of low energy photons, generally 10.6 μm photons from a CO<sub>2</sub> laser [@DOI:10.1021/acs.chemrev.9b00395; @DOI:10.1016/j.jasms.2004.07.016].
 Predominant fragments are b- and y-type fragments, although secondary fragmentation occurs because fragment ions remain in the photon path after the initial dissociation event (**Figure 13D**).
 Despite limited use in the past decade, recent work shows that IRMPD, or more generally activation with IR photons, may still have value in the proteomics toolkit [@DOI:10.1021/acs.analchem.1c05398; @DOI:10.1021/acs.analchem.0c02087].
 UVPD has been explored with a number of wavelengths, including 157 nm, 193 nm, 213 nm, 266 nm, and 355 nm [@DOI:10.1002/anie.200460788; @DOI:10.1021/pr100515x; @DOI:10.1074/mcp.TIR119.001638; @DOI:10.1016/j.jasms.2008.10.019; @DOI:10.1002/rcm.4184; @DOI:10.1021/ac071241t].
@@ -86,4 +86,4 @@ UVPD has been explored for bottom-up proteomic applications, but its more impact
 The laser needed for UVPD (i.e., the photon wavelength desired) determines much about its implementation.
 193 nm photons are typically generated using an Excimer laser with ArF gas [@DOI:10.1021/ja4029654], while 213 nm photons can be generated with a solid-state laser that is easier to integrate into an instrument platform and maintain [@DOI:10.1021/jasms.0c00106; @DOI:10.1074/mcp.TIR119.001638].
 That said, 213 nm photons tend to provide more directed, preferential cleavage pathways compared to 193 nm photons that cleave more broadly in non-directed fashion [@DOI:10.1021/jasms.2c00288].
-Outside of ExD and photoactivation approaches, other alternative dissociation methods have been explored for various proteomic applications, although they are not as widely adopted at ExD and UVPD methods[@DOI:10.1021/acs.analchem.9b04859].
+Outside of ExD and photoactivation approaches, other alternative dissociation methods have been explored for various proteomic applications, although they are not as widely adopted at ExD and UVPD methods [@DOI:10.1021/acs.analchem.9b04859].