Proton Transfer Charge Reduction Enables High-Throughput Top-Down Analysis of Large Proteoforms
Open accessAbstract
region of analytes is subjected to collisional dissociation to obtain proteoform sequence information, which used in combination with intact mass information leads to proteoform identification through an off-line database search. The newly proposed method was benchmarked against the previously developed "medium/high" data-dependent acquisition strategy and doubled the number of UniProt entries and proteoforms >30 kDa identified on the liquid chromatography time scale.
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- Findingown data
The tPTCR approach yielded twice as many UniProt entries and proteoforms above 30 kDa as the medium/high DDA strategy on the LC time scale.
“The newly proposed method was benchmarked against the previously developed “medium/high” data-dependent acquisition strategy and doubled the number of UniProt entries and proteoforms >30 kDa identified on the liquid chromatography time scale.”
Quote in the paperSubstantial claim- Rests on an assumption: Ion–ion proton transfer had not become a routine technique for high-throughput proteomics of highly complex samples.
- Findingown data
The tPTCR-based acquisition returned more identifications than DDA med/hi across the entire mass range of identified proteoforms (6.9-56.9 kDa).
“while the tPTCR-based acquisition strategy returned more identifications of the DDA counterpart across the entire mass range of the identified proteoforms (6.9–56.9 kDa)”
Quote in the paperSubstantial claim - Findingown data
The PTCR-based acquisition increased UniProt entries by 74% compared to med/hi (67 vs 117) at 1% FDR.
“leading to an increase of +74% in UniProt entries (67 vs 117 for med/hi and PTCR, respectively)”
Quote in the paperSubstantial claim - Findingown data
The number of new identifications from tPTCR grows almost linearly across the nine total experiments.
“with the number of new identifications growing almost linearly across the nine total experiments”
Quote in the paperSubstantial claim - Findingown data
Many proteomes of interest, including the human proteome, consist primarily of proteins larger than 30 kDa.
“many proteomes of interest, including the human one, are primarily composed of proteins larger than 30 kDa (Figure S1).”
Quote in the paperSubstantial claim
- Findingown data
The tPTCR data acquisition cycle was substantially slower than the DDA med/hi cycle.
“tPTCR data acquisition cycle was found to be substantially slower than DDA med/hi one”
Quote in the paperNot a substantial claim - Findingown data
The tPTCR method was particularly more effective than med/hi for identifying larger proteins (>25 kDa).
“the new method was particularly more effective than med/hi for identifying larger proteins (>25 kDa).”
Quote in the paperSubstantial claim - Findingown data
The tPTCR method returned more identifications across the whole mass range considered.
“the tPTCR method returned more identifications across the whole mass range considered (Figure 4B)”
Quote in the paperSubstantial claim - Findingown data
CID resulted as the best fragmentation technique for large proteoforms in high-throughput TDP.
“CID resulted as the best fragmentation technique.”
Quote in the paperSubstantial claim - Findingown data
Even using CID MS2, a large fraction (~50%) of PTCR-determined intact masses could not be associated with a confident proteoform identification due to poor quality of related fragmentation spectra.
“Even using CID MS2, a large fraction (~50%) of PTCR-determined intact masses could not be associated with a confident proteoform identification due to poor quality of related fragmentation spectra.”
Quote in the paperSubstantial claim - Findingown data
The CID-PTCR MS3 method returned fewer identifications than the CID MS2 method.
“The CID-PTCR MS3 method likely returned fewer identifications than the CID MS2 one”
Quote in the paperNot a substantial claim - Findingown data
Off-line deconvolution of the medium-resolution MS1 spectrum yielded a single proteoform mass.
“Off-line deconvolution of this medium-resolution MS1 spectrum returned one proteoform mass.”
Quote in the paperSubstantial claim - Findingown data
After PTCR, multiple charge state distributions were clearly distinguishable in the PTCR MS2 spectra.
“In these PTCR MS2 spectra, multiple charge state distributions were clearly distinguishable after PTCR”
Quote in the paperSubstantial claim - Findingown data
Theoretical calculations indicate that for large proteins about 25 m/z units must be sampled when isolation windows are centered around 850-900 m/z.
“Theoretical calculations suggest that for large proteins it is necessary to sample about 25 m/z units when centering the isolation windows around 850–900 m/z, Figure 1B.”
Quote in the paperSubstantial claim - Findingown data
A single tPTCR cycle takes about 10 seconds.
“the time required to complete a single cycle, which is ~10 s (vide infra).”
Quote in the paperSubstantial claim - Findingcitation
The Advanced Peak Determination algorithm was able to assign charge states of the most abundant proteoforms on-the-fly in the PTCR MS2 spectra.
“the Advanced Peak Determination algorithm44 was able to assign the charge states of the most abundant proteoforms on-the-fly.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [44] source
Not checked in the free run.
- Findingown data
Shifting the center of the m/z selection windows for PTCR MS2 enabled detection of proteoforms that were otherwise not clearly distinguishable.
“Shifting the center of the m/z selection windows used for PTCR MS2 allowed for the detection of proteoforms otherwise not clearly distinguishable.”
Quote in the paperSubstantial claim - Findingown data
The PTCR-based acquisition increased unique proteoforms by 47% compared to med/hi (94 vs 138) at 1% FDR.
“and +47% in unique proteoforms (94 vs 138), both identified at 1% FDR.”
Quote in the paperSubstantial claim - Findingown data
The tPTCR method returns fewer protein identifications per run than med/hi.
“the tPTCR method returns fewer protein identifications per run”
Quote in the paperNot a substantial claim - Findingown data
The CID-PTCR MS3 method had a ~35% average reduction in signal intensity of fragment spectra compared to CID MS2.
“due to a ~35% average reduction in signal intensity of fragment spectra.”
Quote in the paperSubstantial claim - Findingown data
The data acquisition method allowed analysis of large biomolecules >30 kDa in a large-scale fashion.
“Our data acquisition method allowed the analysis of large biomolecules >30 kDa in a large-scale fashion”
Quote in the paperSubstantial claim - Findingown data
Off-line deconvolution of the three PTCR MS2 spectra returned four, three, and three unique masses, respectively.
“The off-line deconvolution of the three PTCR MS2 spectra depicted in panels B, C, and D returned four, three, and three unique masses, respectively.”
Quote in the paperSubstantial claim - Findingown data
The simulation result is substantially confirmed when all theoretical charge states between 5+ and 60+ within a 700-1500 m/z window are considered for the same 3001 theoretical proteins.
“Such results are substantially confirmed when the simulation was repeated by simply considering all the theoretical charge states between 5+ and 60+ that the same 3001 theoretical proteins could produce within a 700–1500 m/z window (see Figure S3 for details).”
Quote in the paperNot a substantial claim - Premisecitation
Top-down proteomics has the theoretical capacity to bypass the protein inference issue that affects bottom-up proteomics.
“TDP can theoretically overcome5 the well-known “protein inference” problem afflicting bottom-up proteomics (BUP),6”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [5] source
Not checked in the free run.
- Interpretationown data
Each successive tPTCR LC-MS run interrogates a new region of the proteoform m/z space.
“because each successive LC–MS run interrogates a new region of the proteoform (i.e., m/z) space”
Quote in the paperSubstantial claim - Interpretationnone given
The tPTCR strategy could be implemented in many top-down capable MS platforms (e.g., selected q-TOFs and FT-ICR instruments) with a reagent source and an ion trapping device as the only hardware modifications/requirements.
“With a reagent source and an ion trapping device as the only hardware modifications/requirements, the tPTCR strategy could be implemented in many top-down capable MS platforms (e.g., selected q-TOFs and FT-ICR instruments)”
Quote in the paperSubstantial claim - Interpretationreasoning
Because a single tPTCR run covers only a limited m/z space, multiple experiments are required to theoretically obtain chemical information for all proteins in the 30-60 kDa range.
“Due to the very limited m/z space investigated in a single tPTCR run, multiple experiments have to be performed to theoretically obtain chemical information (i.e., to encounter at least one charge state per proteoform) for all the proteins falling in the MW range of interest (i.e., 30–60 kDa).”
Quote in the paperSubstantial claim - Interpretationreasoning
In high-resolution FTMS experiments, the reduction in spectral S/N for proteins larger than 30 kDa is so pronounced that it practically prevents large-scale top-down proteomics.
“when running high-resolution FTMS experiments (i.e., generating isotopically resolved spectra), the reduction in spectral signal-to-noise ratio (S/N) observed for large proteins (i.e., >30 kDa) is so pronounced as to practically impede large scale TDP.”
Quote in the paperSubstantial claim - Interpretationreasoning
The results of this study were obtained by implementing an ad hoc data acquisition method for TDP based on sophisticated manipulation of ions in the gas phase, not simply by increasing the capabilities and performance of high-resolution and m/z accuracy instrumentation.
“the results of this study were not obtained by “simply” increasing the capabilities and performance of high-resolution and m/z accuracy instrumentation, certainly an aspect of pivotal importance that is leveraged particularly by bottom-up proteomics, but by implementing an ad hoc data acquisition method for TDP based on sophisticated manipulation of ions in the gas phase.”
Quote in the paperSubstantial claim - Premisecitation
The 850-900 m/z window center was chosen because previous experimental data showed that the highest intensity charge states for most nanoflow electrospray-ionized proteins localize in that m/z region.
“The 850–900 m/z window center was selected for tPTCR runs based on the analysis of experimental data from previous studies23 that showed that the highest intensity charge states for most proteins ionized by nanoflow electrospray were localized in that m/z region.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] source
Not checked in the free run.
- Interpretationown data
tPTCR unveils the true complexity of intact proteomes beyond the 30 kDa barrier, which until now could only be speculated.
“tPTCR has the merit of unveiling the true complexity (that until now could only be speculated) of intact proteomes beyond the 30 kDa barrier.”
Quote in the paperSubstantial claim - Interpretationown data
CID, alone or followed by PTCR, outperformed HCD particularly when characterizing large proteoforms.
“suggests that CID, alone or followed by PTCR, outperformed HCD particularly when characterizing large proteoforms.”
Quote in the paperSubstantial claim- Rests on an assumption: The HCD algorithm in Tune 3.0 does not compensate for high charge states when calculating axial acceleration in the HCD cell, so overfragmentation of protein cations is more likely than in slow-heating CID even at low normalized collision energy.
- Interpretationown data
The tPTCR strategy heavily outperforms the previous state-of-the-art for TDP of large proteoforms represented by medium/high DDA.
“The described tPTCR strategy heavily outperforms the previous state-of-the-art for TDP of large proteoforms represented by medium/high DDA”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [46] source
Not checked in the free run.
- Interpretationown data
Different proteoforms were selected and detected in the six PTCR MS2 experiments, as suggested by the unique TIC traces.
“The TIC traces all look unique, suggesting that different proteoforms were selected and subsequently detected in the six PTCR MS2 experiments.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Lowering broadband spectral resolution alone might still fail to resolve the separate proteoforms in a mass spectrum.
“even reducing the resolution of broadband spectra might not be sufficient to distinguish the single components (proteoforms) present in a mass spectrum.”
Quote in the paperSubstantial claim- Rests on an assumption: On average, larger proteins carry more modifications, whether chemical such as PTMs or genetic such as SNPs or isoforms, which increases the complexity of proteoform mixtures as protein mass rises.
- Rests on an assumption: Multiple proteoforms from the same gene usually coelute and are ionized together in LC–MS experiments.
- Rests on an assumption: When ionized by electrospray, larger proteins occupy a wider charge state distribution than smaller proteins, raising the chance of signal overlap when multiple species are present.
- Interpretationreasoning
The difference in acquisition cycle time is explained by the injection time required for accumulating a large number of charges using a very narrow m/z selection window in tPTCR experiments.
“This difference, which is readily explained by the injection time required for accumulating a large number of charges using a very narrow m/z selection window in tPTCR experiments”
Quote in the paperSubstantial claim - Premisecitation
The medium/high DDA approach yielded hundreds of identifications of large proteoforms in the 30-60 kDa range from human fibroblasts.
“The medium/high data acquisition brought the identification of hundreds of large proteoforms (between 30 and 60 kDa) from human fibroblasts.23”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] source
Not checked in the free run.
- Interpretationreasoning
GPF can contribute to top-down proteomics in a similar manner to sophisticated multidimensional liquid phase separations.
“demonstrating that GPF can contribute to top-down proteomics in a similar manner to sophisticated multidimensional liquid phase separations.49-51”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Data-independent fragmentation in past top-down MS studies relied on in-source fragmentation of all intact proteoforms ionized simultaneously after LC elution, with no m/z filtering and limited possibility of obtaining precursor information.
“those works relied on the in-source fragmentation of all intact proteoforms ionized simultaneously after LC elution, with no m/z filtering and limited possibility of obtaining precursor information.”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationnone given
The experiments can be directly reproduced using the latest generation of Tribrid Orbitrap mass spectrometers (Orbitrap Eclipse Tribrid), which includes the described PTCR source and a redesigned linear ion trap optimized for such ion-ion reactions.
“our experiments can be directly reproduced using the latest generation of Tribrid Orbitrap mass spectrometers (Orbitrap Eclipse Tribrid), which includes the here described PTCR source along with a redesigned linear ion trap optimized for such ion–ion reactions.”
Quote in the paperSubstantial claim - Interpretationnone given
This work presents the first application of PTCR specifically designed for facilitating high-throughput top-down analysis of large proteoforms by Orbitrap FTMS.
“We presented here the first application of PTCR specifically designed for facilitating the high-throughput top-down analysis of large proteoforms by Orbitrap FTMS.”
Quote in the paperSubstantial claim
- May combine two claims. 14
- Classified as probably not a substantial claim. 7
May combine two claims.
Findingown dataThe tPTCR method identified 230 unique proteoforms at 1% FDR, compared to 102 by med/hi, a 125% increase.
“it allowed to pass from the 102 unique proteoforms identified by med/hi at 1% FDR to 230 (+125% increase).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn the med/hi DDA method, 89.5% of total protein identifications were generated within three runs, and the last two runs added no new UniProt entry.
“89.5% of the total protein identifications were generated within three runs, with the last two of this series not adding a single new UniProt entry”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe DDA med/hi method rapidly reaches a plateau, with the first three technical replicates producing 60 out of 67 total identifications.
“the DDA med/hi method rapidly reaches a plateau (the first three technical replicates produced 60 out of the 67 total identifications).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn tPTCR experiments, 123 identified proteoforms had mass >30 kDa, which is 54% of the total.
“In tPTCR experiments, 123 identified proteoforms had mass >30 kDa (54% of the total).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe DDA med/high method identified 85 UniProt entries, while the tPTCR method identified 192 at 1% FDR, a 125% increase.
“The DDA med/high method led to the identification of 85 UniProt entries, while the tPTCR method to 192 identifications at 1% FDR (a + 125% increase).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOf the total 217 UniProt entries collectively identified, 25 were identified uniquely by DDA med/hi, corresponding to 29% of those identified by med/hi and 12% of the total.
“of the total 217 UniProt entries collectively identified, only a small group (25, corresponding to 29% of those identified by the med/hi method and 12% of the total) was identified uniquely by DDA med/hi”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationTop-down proteomics is currently applied mainly to proteoforms smaller than 30 kDa, because high-resolution FTMS performs poorly for larger proteoforms and intact proteomes in the 30-60 kDa range are highly complex.
“top-down proteomics (TDP) is currently mostly applied to the characterization of proteoforms <30 kDa due to the poor performance of high-resolution FTMS for the analysis of larger proteoforms and the high complexity of intact proteomes in the 30–60 kDa mass range.”
- Also stated in: § Abstract · plain
“so far high-throughput TDP has been applied mainly to proteins <30 kDa.17-19”
Quote in the paperSubstantial claim0 of 3 sources checked- Also stated in: § Abstract · plain
Classified as probably not a substantial claim.
PremisecitationThe proteoform hypothesis holds that direct analysis of actual proteins in a living system has a tighter mechanistic connection to biological processes than analysis of proteolytic peptides.
“the so-called “proteoform hypothesis” posits that the direct analysis of the actual proteins present in a living system holds a much tighter mechanistic connection with biological processes than the analysis of their surrogates (i.e., proteolytic peptides).7,8”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationMass spectrometry of intact proteins cannot achieve the throughput of bottom-up proteomics, which may identify thousands of protein families in one experiment.
“intact protein MS cannot match the analysis throughput typically obtainable through BUP (i.e., thousands of protein families identified in a single experiment).15”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] source
Not checked in the free run.
May combine two claims.
InterpretationcitationSIM cannot serve as a gas-phase fractionation method for large proteins because only one to three charge states per proteoform fall within a narrow SIM window, and determining charge from isotope spacing would require high resolution and reintroduce S/N problems; it also does not reduce overlap from coeluted analytes.
“Selected ion monitoring (SIM) cannot be applied as a GPF method for characterizing large proteins, because only a few charge states (typically 1 to 3, depending on SIM window width and protein mass) of each proteoform can be detected within a narrow SIM window: if charge states (and hence mass) cannot be determined using a charge state envelope, high resolution would be needed (to determine charge”
- Also stated in: § Abstract · hedged
“Furthermore, this method would not mitigate the problem of overlapping signals due to coeluted analytes.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] source
Not checked in the free run.
- Rests on an assumption: Multiple proteoforms from the same gene usually coelute and are ionized together in LC–MS experiments.
- Also stated in: § Abstract · hedged
May combine two claims.
Interpretationown dataUnlike DDA med/hi, which reaches the vast majority of its total identifications after only a few technical replicates, tPTCR returns new identifications through each LC-MS experiment by shifting the applied m/z selection windows.
“unlike DDA med/hi acquisition, which reaches the vast majority of the total identifications it is capable of after only a few technical replicates, tPTCR returns new identifications through each LC–MS experiment by shifting the applied m/z selection windows”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationSingle-dimension nanoflow reversed-phase LC under MS-compatible conditions with formic acid instead of trifluoroacetic acid has reduced performance for separating large biomolecules, which worsens spectral complexity.
“the reduced performance offered by singledimension nanoflow reversed-phase liquid chromatography (LC) for the separation of large biomolecules under MScompatible conditions (i.e., with formic acid replacing trifluoroacetic acid)24 further exacerbates the spectral complexity issue”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationThe ion-ion proton transfer reaction involves a multiply charged cation reacting with a singly charged anion to produce a cation of reduced charge state and a neutral molecule.
“a multiply charged cation is let to react with a singly charged anion (typically originated from a perfluorinated molecule) to generate a cation with reduced charge state and a neutral molecule (that produces no signal during m/z analysis)”
Quote in the paperSubstantial claim0 of 4 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationProteoforms passing a 1% false-discovery rate cutoff were associated with p-score, E-value, and C-score.
“Proteoforms passing the 1% false-discovery rate (FDR) cutoff41 were associated with a p-score, an E-value, and a C-score.42”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisereasoningThe medium/high DDA method collects MS1 spectra by averaging 10-15 short transients before Fourier transform, improving S/N at the cost of resolving power and yielding average rather than monoisotopic proteoform masses.
“broadband spectra (MS1) are collected by averaging a large number (i.e., 10–15) of short time-domain transients (i.e., microscans) prior to Fourier transform. In this way, the S/N of MS1 spectra is substantially improved at the expense of resolving power, with the resulting non-isotopically resolved spectra leading to the determination of an average proteoform mass rather than the monoisotopic one”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHCD was used when the med/hi strategy was originally developed to investigate 30-60 kDa proteoforms because it was the only ion activation technique available on a Q Exactive mass spectrometer.
“HCD was used when the med/hi strategy was originally developed to investigate 30–60 kDa proteoforms as it was the only ion activation technique available on a Q Exactive mass spectrometer.23”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [23] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIon-ion proton transfer reactions have been used mainly to reduce the complexity of ETD fragmentation spectra by shifting charge-reduced product ions to higher m/z values where signal overlap is limited.
“ion–ion proton transfer reactions have found several applications, most importantly to reduce the complexity of fragmentation spectra generated by electron transfer dissociation (ETD) by distributing charge-reduced product ions toward higher m/z values, where signal overlap is limited.32-34”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Premisenone givenPseudomonas aeruginosa can theoretically express about 5500 gene products, one-third of which fall in the 30-60 kDa molecular weight window.
“which can theoretically express ~5500 different gene products one-third of which fall into the molecular weight (MW) window of interest (30–60 kDa, Figure S1).”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningThe tPTCR method applies two sequential gas-phase fractionation steps-narrow quadrupole selection and PTCR charge reduction-to yield mass spectra with little m/z peak overlap and charge state distributions that are easy to interpret, thereby simplifying mass calculation.
“We designed a data acquisition strategy, named tPTCR, which applies two consecutive gas phase fractionation steps for obtaining intact precursor masses: first, a narrow (1.5 m/z-wide) quadrupole filter m/z transmission window is used to select a subset of charge states from all ionized proteoform cations; second, this aliquot of protein cations is subjected to PTCR in order to reduce their average”
Quote in the paperSubstantial claim- Rests on an assumption: Ion–ion proton transfer had not become a routine technique for high-throughput proteomics of highly complex samples.
Classified as probably not a substantial claim.
PremisecitationTribrid Orbitrap instruments offer a variety of ion activation methods.
“tribrid Orbitrap instruments offer a variety of ion activation methods,45”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [45] source
Not checked in the free run.
The paper relies on this without support.
On average, larger proteins carry more modifications, whether chemical such as PTMs or genetic such as SNPs or isoforms, which increases the complexity of proteoform mixtures as protein mass rises.
“larger proteins can, on average, carry a higher number of modifications, either chemical (such as post-translational modifications, PTMs) or genetic (arising from single nucleotide polymorphisms, presence of multiple isoforms, etc).”
The paper relies on this without support.
Multiple proteoforms from the same gene usually coelute and are ionized together in LC–MS experiments.
“multiple proteoforms derived from the same gene typically coelute to then be ionized together in LC–MS experiments.”
The paper relies on this without support.
Ion–ion proton transfer had not become a routine technique for high-throughput proteomics of highly complex samples.
“However, this technique never became routinely applied to high-throughput proteomics of highly complex samples.”
The paper relies on this without support.
When ionized by electrospray, larger proteins occupy a wider charge state distribution than smaller proteins, raising the chance of signal overlap when multiple species are present.
“larger proteins are represented in the mass-over-charge (m/z) domain by a wider charge state distribution than smaller proteins when ionization is performed by electrospray (which increases the probability of signal overlap in the presence of multiple species)”
The paper relies on this without support.
The HCD algorithm in Tune 3.0 does not compensate for high charge states when calculating axial acceleration in the HCD cell, so overfragmentation of protein cations is more likely than in slow-heating CID even at low normalized collision energy.
“the HCD algorithm implemented in the version of the instrument control software used for those experiments (Tune 3.0) does not compensate for high charge states when calculating the actual axial acceleration in the HCD cell, therefore overfragmentation of protein cations is more likely than in slow-heating CID even when the normalized collision energy for HCD is kept low”
The authors state this as an assumption.
The sample contains an extremely complex mixture of different proteoforms.
“Although the presence of an extremely complex mixture of different proteoforms can be presumed”
The paper relies on this without support.
The highest intensity charge states for most proteins ionized by nanoflow electrospray are localized in the m/z region analyzed.
“that showed that the highest intensity charge states for most proteins ionized by nanoflow electrospray were localized in that m/z region.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
PTR MS reduces the average number of charge states for improved signal-to-noise and reduced spectral complexity for identification of protein complex mixtures.
“Similarly, proton transfer reaction (PTR) MS has been used to reduce the average number of charge states for improved signal-to-noise and reduced spectral complexity for the identification of protein complex mixtures [106].”
From Top-down proteomics: challenges, innovations, and applications in basic and clinical research (2020) · cites this paper as [106]
Proton transfer reaction methods recently introduced in top-down proteomics lower charge states and simplify mass spectra, which improves analysis of complex intact protein mixtures.
“Recent implementations of proton transfer reaction in top-down proteomics have allowed to reduce the charge states and simplify mass spectra, leading to significant improvements in analysis of complex intact protein mixtures.12,44,45”
From Sensitive Top-Down Proteomics Analysis of a Low Number of Mammalian Cells Using a Nanodroplet Sample Processing Platform (2020) · cites this paper as [44]
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Self-citationIon/Ion Proton Transfer Reactions for Protein Mixture Analysis
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Self-citationEvaluation of the Compact High-Field Orbitrap for Top-Down Proteomics of Human Cells
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Accurate Estimation of Context-Dependent False Discovery Rates in Top-Down Proteomics
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Self-citationTop-down Mass Spectrometry Analysis of Human Serum Autoantibody Antigen-Binding Fragments
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Optimal Dissociation Methods Differ for N - and O -Glycopeptides
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Self-citationDeep Profiling of Plasma Proteoforms with Engineered Nanoparticles for Top-Down Proteomics
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Top-Down Proteomics Identifies Plasma Proteoform Signatures of Liver Cirrhosis Progression
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Self-citationIon–Ion Charge Reduction Addresses Multiple Challenges Common to Denaturing Intact Mass Analysis
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Rapid MRSA detection via tandem mass spectrometry of the intact 80 kDa PBP2a resistance protein
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Self-citationTop-Down Identification and Sequence Analysis of Small Membrane Proteins Using MALDI-MS/MS
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Asymmetric N-Glycosylation in the Tailpiece of Recombinant IgA1
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Imaging of Protein Assemblies up to 231 kDa in Tissues with Nano-DESI Mass Spectrometry
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Discovery top-down proteomics in symbiotic soybean root nodules
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Shaping Nanobodies and Intrabodies against Proteoforms
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- Authors
- Huguet, R., Mullen, C., Srzentić, K., Greer, J. B., Fellers, R. T., Zabrouskov, V., Syka, J. E. P., Kelleher, N. L., & Fornelli, L.
- Affiliations
- Thermo Fisher Scientific (United States) (US)
- Northwestern University (US)
- University of Oklahoma (US)
- Corresponding author
- Fornelli, Luca
- ORCID
- Venue
- Analytical Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-11-12
- Volume
- 91
- Issue
- 24
- Pages
- 15732-15739
- ISSN
- 0003-2700 (ISSN-L)
- 1520-6882
- PMC
- PMC7008508
- OpenAlex
- W2987849054
- Cited by
- 94
- References
- 52
- Citations by year
- 2026: 15 · 2025: 14 · 2024: 22 · 2023: 9 · 2022: 15 · 2021: 11 · 2020: 8
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Analytical Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (P41 GM108569)
- Topics
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- top-down proteomics, proteoform identification, collision-induced dissociation, high-throughput proteomics
- MeSH terms
- Bacterial Proteins, Chromatography, Liquid, Protons, Pseudomonas aeruginosa, Software, Protein Isoforms, Proteome, Tandem Mass Spectrometry
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