Pub Date : 2025-02-01DOI: 10.1016/j.ijms.2024.117386
Annabel S.J. Eardley-Brunt , Anna Jones , Thomas Mills , Liwen Song , Rafail Kotronias , Pierfrancesco Lapolla , Oxford Acute Myocardial Infarction (OxAMI) Study , Oxford Abdominal Aortic Aneurysm (OxAAA) Study , Ashok Handa , Regent Lee , Keith Channon , Giovanni Luigi de Maria , Claire Vallance
Analysis of small-molecule metabolites in plasma has the potential for development as a clinical diagnostic and prognostic tool. Atmospheric solids analysis probe mass spectrometry (ASAP-MS) is capable of performing rapid metabolite and small molecule fingerprinting, and has the potential for use in a clinical setting. Combining ASAP-MS data with a predictive model could provide clinicians with a rapid patient risk metric, anticipating disease progression and response to treatment, and thereby aiding in treatment decisions. In order to develop predictive models, experimental errors and uncertainties must be minimised, requiring a robust experimental protocol. In the present study we have performed ASAP-MS measurements on plasma samples from patients recruited for two prospective clinical studies: the Oxford Acute Myocardial Infarction (OxAMI) study; and the Oxford Abdominal Aortic Aneurysm (OxAAA) study. Through a carefully designed series of measurements, we have optimised the method of sample introduction, together with a number of key instrument and data acquisition parameters. Following the optimisation process, we are consistently able to record high quality mass spectra for plasma samples. Typical coefficients of variation for individual mass peaks are in the range from 20%–50%, overlapping with those obtained using more sophisticated LC-MS approaches. The measurement protocol optimises mass spectral quality and reproducibility, while retaining the simplicity of measurement required for use in a clinical setting. While the protocol was developed using plasma samples from two specific patient cohorts, the method can be generalised to any plasma measurements.
{"title":"Development of an optimised method for the analysis of human blood plasma samples by atmospheric solids analysis probe mass spectrometry","authors":"Annabel S.J. Eardley-Brunt , Anna Jones , Thomas Mills , Liwen Song , Rafail Kotronias , Pierfrancesco Lapolla , Oxford Acute Myocardial Infarction (OxAMI) Study , Oxford Abdominal Aortic Aneurysm (OxAAA) Study , Ashok Handa , Regent Lee , Keith Channon , Giovanni Luigi de Maria , Claire Vallance","doi":"10.1016/j.ijms.2024.117386","DOIUrl":"10.1016/j.ijms.2024.117386","url":null,"abstract":"<div><div>Analysis of small-molecule metabolites in plasma has the potential for development as a clinical diagnostic and prognostic tool. Atmospheric solids analysis probe mass spectrometry (ASAP-MS) is capable of performing rapid metabolite and small molecule fingerprinting, and has the potential for use in a clinical setting. Combining ASAP-MS data with a predictive model could provide clinicians with a rapid patient risk metric, anticipating disease progression and response to treatment, and thereby aiding in treatment decisions. In order to develop predictive models, experimental errors and uncertainties must be minimised, requiring a robust experimental protocol. In the present study we have performed ASAP-MS measurements on plasma samples from patients recruited for two prospective clinical studies: the Oxford Acute Myocardial Infarction (OxAMI) study; and the Oxford Abdominal Aortic Aneurysm (OxAAA) study. Through a carefully designed series of measurements, we have optimised the method of sample introduction, together with a number of key instrument and data acquisition parameters. Following the optimisation process, we are consistently able to record high quality mass spectra for plasma samples. Typical coefficients of variation for individual mass peaks are in the range from 20%–50%, overlapping with those obtained using more sophisticated LC-MS approaches. The measurement protocol optimises mass spectral quality and reproducibility, while retaining the simplicity of measurement required for use in a clinical setting. While the protocol was developed using plasma samples from two specific patient cohorts, the method can be generalised to any plasma measurements.</div></div>","PeriodicalId":338,"journal":{"name":"International Journal of Mass Spectrometry","volume":"508 ","pages":"Article 117386"},"PeriodicalIF":1.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143135483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.ijms.2024.117392
Akash Srivastav, Vishnu P, Bhas Bapat
Ion momentum spectrometers, which are commonly used devices for studying molecular dissociation, are lossy devices in that not all charged fragments are assuredly detected. Combined with the fact that neutrals are always undetected, this can result in a mixing of distinct dissociation channels. A dissociation event with all charged fragments may mimic an event where at least one fragment is neutral. As a result, an analysis of the dissociation channels identified using an ion pair coincidence map may result in misleading interpretations, especially when analyzing channels with both charged and neutral fragments. In this study, we present a method to rectify the distributions of kinematic parameters for such cases. The rectification method is discussed in the context of the (O, C, O) breakup channel of the CO molecular ion. The distribution of the kinematic parameters after rectification exhibit stark differences from the raw distributions, emphasizing the need for rectification. A comparison of the rectified data with cases in the literature where such losses are estimated to be negligible, underline the efficacy of the method.
{"title":"Rectification of kinematic parameters of dissociative ionization derived from ion momentum spectra","authors":"Akash Srivastav, Vishnu P, Bhas Bapat","doi":"10.1016/j.ijms.2024.117392","DOIUrl":"10.1016/j.ijms.2024.117392","url":null,"abstract":"<div><div>Ion momentum spectrometers, which are commonly used devices for studying molecular dissociation, are lossy devices in that not all charged fragments are assuredly detected. Combined with the fact that neutrals are always undetected, this can result in a mixing of distinct dissociation channels. A dissociation event with all charged fragments may mimic an event where at least one fragment is neutral. As a result, an analysis of the dissociation channels identified using an ion pair coincidence map may result in misleading interpretations, especially when analyzing channels with both charged and neutral fragments. In this study, we present a method to rectify the distributions of kinematic parameters for such cases. The rectification method is discussed in the context of the (O<span><math><msup><mrow></mrow><mrow><mo>+</mo></mrow></msup></math></span>, C<span><math><msup><mrow></mrow><mrow><mo>+</mo></mrow></msup></math></span>, O) breakup channel of the CO<span><math><msubsup><mrow></mrow><mrow><mn>2</mn></mrow><mrow><mn>2</mn><mo>+</mo></mrow></msubsup></math></span> molecular ion. The distribution of the kinematic parameters after rectification exhibit stark differences from the raw distributions, emphasizing the need for rectification. A comparison of the rectified data with cases in the literature where such losses are estimated to be negligible, underline the efficacy of the method.</div></div>","PeriodicalId":338,"journal":{"name":"International Journal of Mass Spectrometry","volume":"508 ","pages":"Article 117392"},"PeriodicalIF":1.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143135567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.ijms.2024.117395
Anatoly N. Verenchikov , Sergey N. Kirillov , Aleksey V. Vorobyev , Vasily V. Makarov , Mikhail I. Yavor , Robert P. Tonge , James I. Langridge
Time-of-flight mass spectrometry (TOFMS) is a cornerstone of analytical chemistry, renowned for its exceptional combination of speed, sensitivity, resolution, and mass accuracy. Multi-reflecting TOFMS (MRT) instruments significantly enhance TOFMS resolution by repeatedly folding and extending the ion trajectory. Historically, MRT instruments have achieved resolutions of up to 200,000 across a wide mass range. While higher resolutions (reaching 1 million) have been demonstrated in trajectory looping configurations, these are associated with a narrower mass range that shrinks inversely with the number of loops. This research presents an advanced MRT instrument that overcomes these limitations by achieving both a resolving power of approximately 1 million (R ≈ 1,000,000) and a wide mass range, not limited by the analyzer design. This was achieved through numerous instrumental enhancements, and primarily by extending the flight path to approximately 100 m, corresponding to a flight time of 2.55 ms for m/z = 1000 Th ions. Prolonged flight times inevitably reduce the duty cycle of the orthogonal accelerator. In one practical acquisition method, encoded frequent pulsing (EFP) at an average pulsing rate of 50 kHz, recovered the OA duty cycle to 10 %. This enabled the instrument to record high-resolution MS/MS spectra at a rate of 10 Hz and identifying peptides in a concentration range of 10−8 to 10−4 M, enabling high-throughput MS/MS analysis. At higher sample concentrations, the instrument is sensitive to space charge effects within the analyzer, which start affecting resolution as early as 20 ions per packet. At 50 kHz EFP method, this limit corresponds to 106 ion/peak/s and allows ion fluxes up to 108 ion/s in the case of complex spectra containing numerous peaks. The major part of this publication is focused on characterizing the ultimate performance of the prototype MRT. To minimize spectral artifacts, most characterization experiments were conducted using a rare pulsing method (push and wait) at a pulsing rate of 500 Hz. Extended spectral acquisition times allowed for the accumulation of sufficient ion statistics, enabling the exploration of fine details within MS/MS spectra of peptides. The achieved standard deviation of mass accuracy was approximately 100 ppb over a dynamic range of 105. This research comprehensively characterizes the high-resolution MRT instrument, focusing on its capabilities and limitations. While analytical applications are not discussed in this paper, the presented data provides a solid foundation for understanding the instrument's potential.
{"title":"Multi reflecting TOF MS approaching resolution of 1,000,000 in a wide mass range","authors":"Anatoly N. Verenchikov , Sergey N. Kirillov , Aleksey V. Vorobyev , Vasily V. Makarov , Mikhail I. Yavor , Robert P. Tonge , James I. Langridge","doi":"10.1016/j.ijms.2024.117395","DOIUrl":"10.1016/j.ijms.2024.117395","url":null,"abstract":"<div><div>Time-of-flight mass spectrometry (TOFMS) is a cornerstone of analytical chemistry, renowned for its exceptional combination of speed, sensitivity, resolution, and mass accuracy. Multi-reflecting TOFMS (MRT) instruments significantly enhance TOFMS resolution by repeatedly folding and extending the ion trajectory. Historically, MRT instruments have achieved resolutions of up to 200,000 across a wide mass range. While higher resolutions (reaching 1 million) have been demonstrated in trajectory looping configurations, these are associated with a narrower mass range that shrinks inversely with the number of loops. This research presents an advanced MRT instrument that overcomes these limitations by achieving both a resolving power of approximately 1 million (R ≈ 1,000,000) and a wide mass range, not limited by the analyzer design. This was achieved through numerous instrumental enhancements, and primarily by extending the flight path to approximately 100 m, corresponding to a flight time of 2.55 ms for <em>m/z</em> = 1000 Th ions. Prolonged flight times inevitably reduce the duty cycle of the orthogonal accelerator. In one practical acquisition method, encoded frequent pulsing (EFP) at an average pulsing rate of 50 kHz, recovered the OA duty cycle to 10 %. This enabled the instrument to record high-resolution MS/MS spectra at a rate of 10 Hz and identifying peptides in a concentration range of 10<sup>−8</sup> to 10<sup>−4</sup> M, enabling high-throughput MS/MS analysis. At higher sample concentrations, the instrument is sensitive to space charge effects within the analyzer, which start affecting resolution as early as 20 ions per packet. At 50 kHz EFP method, this limit corresponds to 10<sup>6</sup> ion/peak/s and allows ion fluxes up to 10<sup>8</sup> ion/s in the case of complex spectra containing numerous peaks. The major part of this publication is focused on characterizing the ultimate performance of the prototype MRT. To minimize spectral artifacts, most characterization experiments were conducted using a rare pulsing method (push and wait) at a pulsing rate of 500 Hz. Extended spectral acquisition times allowed for the accumulation of sufficient ion statistics, enabling the exploration of fine details within MS/MS spectra of peptides. The achieved standard deviation of mass accuracy was approximately 100 ppb over a dynamic range of 10<sup>5</sup>. This research comprehensively characterizes the high-resolution MRT instrument, focusing on its capabilities and limitations. While analytical applications are not discussed in this paper, the presented data provides a solid foundation for understanding the instrument's potential.</div></div>","PeriodicalId":338,"journal":{"name":"International Journal of Mass Spectrometry","volume":"508 ","pages":"Article 117395"},"PeriodicalIF":1.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143135926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.ijms.2024.117384
Brendan C. Sweeny, Shaun G. Ard, Albert A. Viggiano, Nicholas S. Shuman
The kinetics of Al2O2+ + CH4 and Al2O2+ + C2H6 are measured from 300 to 600 K at pressures near ∼0.35 Torr in a Selected-Ion Flow Tube apparatus. The reaction with CH4 proceeds by hydrogen abstraction to yield an open chain AlOAlOH+ +CH3. The rate constant is nearly temperature-independent at 7 ± 2 × 10−11 cm3 s−1. This competes with association, which decreases sharply with temperature (k = 3.3 ± 0.8 × 10−10 (T/300 K)−3.1±0.2 cm3 s−1). The reaction with C2H6 primarily yields Al2O2H2+ + C2H4. The rate constant for this channel k300K = 4 ± 1 × 10−10 cm3 s−1 with a very slight negative temperature dependence. A second channel producing C2H5 + Al2O2H+ rises steeply with temperature (k = 10 ± 2 × 10−10 e−0.12 eV/kT cm3 s−1), and finally association decreases steeply with temperature (k = 6 ± 1.5 × 10−10 (T/300 K)−3.2±0.2 cm3 s−1). The reaction with methane is well-described using statistical theory based on reaction coordinates calculated using density functional theory. The total rate constant for the ethane reaction is also well-described using statistical theory, but the product branching is not, suggesting post-transition state non-statistical dynamics. One possibility is that the ethane reaction unexpectedly produces a higher energy C2v isomer of Al2O2H+. The results support the prior interpretation that Al2O2+ activates hydrocarbons via a proton-coupled electron transfer (PCET) mechanism and not a hydrogen-atom transfer (HAT) mechanism.
{"title":"Activation of CH4 and C2H6 by Al2O2+ from 300 to 600 K","authors":"Brendan C. Sweeny, Shaun G. Ard, Albert A. Viggiano, Nicholas S. Shuman","doi":"10.1016/j.ijms.2024.117384","DOIUrl":"10.1016/j.ijms.2024.117384","url":null,"abstract":"<div><div>The kinetics of Al<sub>2</sub>O<sub>2</sub><sup>+</sup> + CH<sub>4</sub> and Al<sub>2</sub>O<sub>2</sub><sup>+</sup> + C<sub>2</sub>H<sub>6</sub> are measured from 300 to 600 K at pressures near ∼0.35 Torr in a Selected-Ion Flow Tube apparatus. The reaction with CH<sub>4</sub> proceeds by hydrogen abstraction to yield an open chain AlOAlOH<sup>+</sup> +CH<sub>3</sub>. The rate constant is nearly temperature-independent at 7 ± 2 × 10<sup>−11</sup> cm<sup>3</sup> s<sup>−1</sup>. This competes with association, which decreases sharply with temperature (k = 3.3 ± 0.8 × 10<sup>−10</sup> (T/300 K)<sup>−3.1±0.2</sup> cm<sup>3</sup> s<sup>−1</sup>). The reaction with C<sub>2</sub>H<sub>6</sub> primarily yields Al<sub>2</sub>O<sub>2</sub>H<sub>2</sub><sup>+</sup> + C<sub>2</sub>H<sub>4</sub>. The rate constant for this channel k<sub>300K</sub> = 4 ± 1 × 10<sup>−10</sup> cm<sup>3</sup> s<sup>−1</sup> with a very slight negative temperature dependence. A second channel producing C<sub>2</sub>H<sub>5</sub> + Al<sub>2</sub>O<sub>2</sub>H<sup>+</sup> rises steeply with temperature (k = 10 ± 2 × 10<sup>−10</sup> e<sup>−0.12 eV/kT</sup> cm<sup>3</sup> s<sup>−1</sup>), and finally association decreases steeply with temperature (k = 6 ± 1.5 × 10<sup>−10</sup> (T/300 K)<sup>−3.2±0.2</sup> cm<sup>3</sup> s<sup>−1</sup>). The reaction with methane is well-described using statistical theory based on reaction coordinates calculated using density functional theory. The total rate constant for the ethane reaction is also well-described using statistical theory, but the product branching is not, suggesting post-transition state non-statistical dynamics. One possibility is that the ethane reaction unexpectedly produces a higher energy C<sub>2v</sub> isomer of Al<sub>2</sub>O<sub>2</sub>H<sup>+</sup>. The results support the prior interpretation that Al<sub>2</sub>O<sub>2</sub><sup>+</sup> activates hydrocarbons via a proton-coupled electron transfer (PCET) mechanism and not a hydrogen-atom transfer (HAT) mechanism.</div></div>","PeriodicalId":338,"journal":{"name":"International Journal of Mass Spectrometry","volume":"508 ","pages":"Article 117384"},"PeriodicalIF":1.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143135481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.ijms.2024.117393
Bin Yan , Koen K.W. van Asseldonk , Baptiste Schindler , Isabelle Compagnon , Anouk M. Rijs
The nucleotide adenosine-5′-triphosphate (ATP) is the coenzyme selected by nature to provide energy for its cellular processes through the ATP hydrolysis reaction. Although the crystal structures and the general working principles of numerous ATP hydrolases (ATPases) are generally known, this omnipresent ATP conversion reaction is not fully understood at the level of local interactions. Questions such as “How does the peptide environment of the active sites of ATPases affect their association with ATP and the consecutive reaction of ATP?” and “Why is the conversion of ATP to ADP preferred over other reactions at the active site?” await detailed answers at the molecular level. Here, tandem mass spectrometry (MS) based techniques are applied to answer these questions. Gas phase studies indicate that the conversion of ATP to ADP is a charge state driven process of which the behaviour varies dramatically with subtle changes in the ATP binding peptide. Of the peptides and peptide mimics studied, only the Ac-Arg-NH2 form of arginine actively regulates the hydrolysis of ATP, which proceeds through the sequential release of the ADP peptide complex and ADP. Relative ion activation studies of the fragmentation patterns of the ATP Ac-Arg-NH2 complex show that phosphate bond dissociation is preferred over breakage of the non-covalent bond between ATP and the peptide mimic, which coincidentally agrees with the behaviour of catalysed ATP hydrolysis reaction in solution.
{"title":"Exploring the catalytic mechanism of ATPase at the molecular level by tandem mass spectrometry","authors":"Bin Yan , Koen K.W. van Asseldonk , Baptiste Schindler , Isabelle Compagnon , Anouk M. Rijs","doi":"10.1016/j.ijms.2024.117393","DOIUrl":"10.1016/j.ijms.2024.117393","url":null,"abstract":"<div><div>The nucleotide adenosine-5′-triphosphate (ATP) is the coenzyme selected by nature to provide energy for its cellular processes through the ATP hydrolysis reaction. Although the crystal structures and the general working principles of numerous ATP hydrolases (ATPases) are generally known, this omnipresent ATP conversion reaction is not fully understood at the level of local interactions. Questions such as “How does the peptide environment of the active sites of ATPases affect their association with ATP and the consecutive reaction of ATP?” and “Why is the conversion of ATP to ADP preferred over other reactions at the active site?” await detailed answers at the molecular level. Here, tandem mass spectrometry (MS) based techniques are applied to answer these questions. Gas phase studies indicate that the conversion of ATP to ADP is a charge state driven process of which the behaviour varies dramatically with subtle changes in the ATP binding peptide. Of the peptides and peptide mimics studied, only the Ac-Arg-NH<sub>2</sub> form of arginine actively regulates the hydrolysis of ATP, which proceeds through the sequential release of the ADP <span><math><mrow><mo>•</mo></mrow></math></span> peptide complex and ADP. Relative ion activation studies of the fragmentation patterns of the ATP <span><math><mrow><mo>•</mo></mrow></math></span> Ac-Arg-NH<sub>2</sub> complex show that phosphate bond dissociation is preferred over breakage of the non-covalent bond between ATP and the peptide mimic, which coincidentally agrees with the behaviour of catalysed ATP hydrolysis reaction in solution.</div></div>","PeriodicalId":338,"journal":{"name":"International Journal of Mass Spectrometry","volume":"508 ","pages":"Article 117393"},"PeriodicalIF":1.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143135563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.ijms.2024.117396
Kemi E. Osho, Keshari Kunwor, Nicholas B. Borotto
Free radical-initiated peptide sequencing (FRIPS) is a tandem mass spectrometry technique (MS/MS) that enables radical-based dissociation on instruments only capable of collisional activation. In FRIPS, peptides are chemically-derivatized with a compound that undergoes homolytic cleavage and generates radicals upon collisional activation. These radicals then propagate through the peptide backbone enabling the sequencing of peptide ions. This MS/MS technique has shown promise in sequencing post-translationally modified peptides, but it is typically performed in an MS3 workflow and single-step MS/MS approaches result in the generation of both collisional- and radical-driven dissociation products and highly complex spectra. Recently, our group developed a method to dissociate peptide ions prior to ion mobility analysis within a trapped-ion mobility spectrometry (TIMS) device. In this work, we examine if this “CIDtims” technique can initiate the homolytic cleavage of the FRIPS precursor. We then examine if the resultant ion mobility separation results in additional assignments of product ions and improved sequence coverage. We demonstrate that activation within the TIMS device does indeed promote robust radical initiation and fragmentation of peptide cations and that the generated product ions are mobility separated enabling facile assignment and increased sequence coverage.
{"title":"Ion mobility-assisted free radical-initiated peptide sequencing","authors":"Kemi E. Osho, Keshari Kunwor, Nicholas B. Borotto","doi":"10.1016/j.ijms.2024.117396","DOIUrl":"10.1016/j.ijms.2024.117396","url":null,"abstract":"<div><div>Free radical-initiated peptide sequencing (FRIPS) is a tandem mass spectrometry technique (MS/MS) that enables radical-based dissociation on instruments only capable of collisional activation. In FRIPS, peptides are chemically-derivatized with a compound that undergoes homolytic cleavage and generates radicals upon collisional activation. These radicals then propagate through the peptide backbone enabling the sequencing of peptide ions. This MS/MS technique has shown promise in sequencing post-translationally modified peptides, but it is typically performed in an MS<sup>3</sup> workflow and single-step MS/MS approaches result in the generation of both collisional- and radical-driven dissociation products and highly complex spectra. Recently, our group developed a method to dissociate peptide ions prior to ion mobility analysis within a trapped-ion mobility spectrometry (TIMS) device. In this work, we examine if this “CIDtims” technique can initiate the homolytic cleavage of the FRIPS precursor. We then examine if the resultant ion mobility separation results in additional assignments of product ions and improved sequence coverage. We demonstrate that activation within the TIMS device does indeed promote robust radical initiation and fragmentation of peptide cations and that the generated product ions are mobility separated enabling facile assignment and increased sequence coverage.</div></div>","PeriodicalId":338,"journal":{"name":"International Journal of Mass Spectrometry","volume":"508 ","pages":"Article 117396"},"PeriodicalIF":1.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.ijms.2024.117388
Chaofu Wang , Ping Xu , Lingyun Xue , Yian Liu , Ming Yan , Anqi Chen , Shundi Hu , Luhong Wen
Metabolite annotation plays a key role in metabolomics. To enable structural annotation of unknown tandem mass spectra, the prediction of molecular fingerprints using MS/MS is currently of great interest. However, current methods still present challenges in terms of redundancy and high dimensionality of fingerprint features, which can affect the accuracy and speed of annotation results. Therefore, we propose a dual-tower model structure consisting of an MS/MS feature extractor and a fingerprint feature extractor, which can directly compute the correlation between MS/MS and molecular fingerprints without needing to predict molecular fingerprints. Moreover, the fingerprint feature extractor, consisting of two MLPs, effectively reduces fingerprint redundancy. Both feature extractors are simultaneously optimized by contrastive learning. We trained and tested our method using data downloaded from the GNPS. The trained model was then used to search molecular structure databases such as PubChem. Experimental results show that our method outperforms MetFID, FingerScorer, MatFrag, DeepMass and CFM-ID in top-k evaluation.
{"title":"Deep cross-modal learning between tandem mass spectrometry and molecular fingerprints for metabolite identification","authors":"Chaofu Wang , Ping Xu , Lingyun Xue , Yian Liu , Ming Yan , Anqi Chen , Shundi Hu , Luhong Wen","doi":"10.1016/j.ijms.2024.117388","DOIUrl":"10.1016/j.ijms.2024.117388","url":null,"abstract":"<div><div>Metabolite annotation plays a key role in metabolomics. To enable structural annotation of unknown tandem mass spectra, the prediction of molecular fingerprints using MS/MS is currently of great interest. However, current methods still present challenges in terms of redundancy and high dimensionality of fingerprint features, which can affect the accuracy and speed of annotation results. Therefore, we propose a dual-tower model structure consisting of an MS/MS feature extractor and a fingerprint feature extractor, which can directly compute the correlation between MS/MS and molecular fingerprints without needing to predict molecular fingerprints. Moreover, the fingerprint feature extractor, consisting of two MLPs, effectively reduces fingerprint redundancy. Both feature extractors are simultaneously optimized by contrastive learning. We trained and tested our method using data downloaded from the GNPS. The trained model was then used to search molecular structure databases such as PubChem. Experimental results show that our method outperforms MetFID, FingerScorer, MatFrag, DeepMass and CFM-ID in top-k evaluation.</div></div>","PeriodicalId":338,"journal":{"name":"International Journal of Mass Spectrometry","volume":"508 ","pages":"Article 117388"},"PeriodicalIF":1.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143135564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-23DOI: 10.1016/j.ijms.2025.117408
Xianglong Yuan , Xiaopan Shen , Lubaiyang Liu , Feiteng Li , Lili Jiang , Lihua Zhai , Hu Deng , Leixin Yan , Zhiming Li
Unlike traditional Thermal Ionization Mass Spectrometers (TIMS) with single-focusing magnetic mass analyzers (such as Triton, Phoenix, Nu TIMS, etc.), a newly developed Double-Focusing Thermal Ionization Mass Spectrometer (DF-TIMS) enhances the system stability by mitigating accelerating high-voltage noise and drift. Featuring a Nier-Johnson type double-focusing mass analyzer, the instrument includes a laminated magnet with a 250 mm radius and a cylindrical Electrostatic Analyzer (ESA) with a 350 mm radius, achieving a mass dispersion of 560 mm. It is equipped with of 16 Faraday cups and 4 full-size discrete dynode secondary electron multipliers (SEM), combined with variable dispersion double quadrupole zoom optics, allowing for multi-collection of isotopes with up to 20 % mass dispersion, such as isotopes of Lithium, Boron and Calcium. Additionally, a compact and advanced Retarding Filter enhances abundance sensitivity from < 2 ppm to < 5 ppb. Automated tuning and measurement improve efficiency for both positive and negative ions. With a 0.2 mm source slit and a 1 mm receiving slit, DF-TIMS achieves a resolution over 470 and a peak shape factor below 0.3. System stability is less than 15 ppm/30 min credit to the double-focusing design. Each Faraday cup operates with a dynamic range of 0–50 V, featuring Root Mean Square (RMS) noise (4s integration, 1011 Ω high resistance) under 20 μV and baseline drift below 1 × 10−16 A/h. The instrument has been applied extensively, delivering internal precision and external precision for Strontium and Neodymium measurements under 5 ppm, meeting stringent isotopic ratio analysis requirements in nuclear science and geoscience.
与传统的单聚焦磁质分析仪（如Triton， Phoenix， Nu TIMS等）不同，新开发的双聚焦热电离质谱仪（DF-TIMS）通过减轻加速高压噪声和漂移来提高系统的稳定性。该仪器采用尼尔-约翰逊型双聚焦质量分析仪，包括一个半径为250毫米的层压磁铁和一个半径为350毫米的圆柱形静电分析仪（ESA），可实现560毫米的质量弥散。它配备了16个法拉第杯和4个全尺寸离散dynode二级电子倍增器（SEM），结合可变色散双四极变焦光学，允许多次收集高达20%质量色散的同位素，如锂，硼和钙的同位素。此外，一个紧凑和先进的缓速过滤器提高了丰度的灵敏度，从<；2 ppm至<；5磅。自动调谐和测量提高了正离子和负离子的效率。DF-TIMS的源狭缝为0.2 mm，接收狭缝为1 mm，分辨率超过470，峰值形状因子低于0.3。由于双聚焦设计，系统稳定性低于15 ppm/30分钟。每个法拉第杯的工作动态范围为0-50 V， RMS噪声（4s积分，1011 Ω高电阻）低于20 μV，基线漂移低于1 × 10−16 a /h。该仪器已被广泛应用，为5 ppm以下的锶和钕测量提供内部精度和外部精度，满足核科学和地球科学中严格的同位素比分析要求。
{"title":"The development of a novel double-focusing thermal ionization mass spectrometer","authors":"Xianglong Yuan , Xiaopan Shen , Lubaiyang Liu , Feiteng Li , Lili Jiang , Lihua Zhai , Hu Deng , Leixin Yan , Zhiming Li","doi":"10.1016/j.ijms.2025.117408","DOIUrl":"10.1016/j.ijms.2025.117408","url":null,"abstract":"<div><div>Unlike traditional Thermal Ionization Mass Spectrometers (TIMS) with single-focusing magnetic mass analyzers (such as Triton, Phoenix, Nu TIMS, etc.), a newly developed Double-Focusing Thermal Ionization Mass Spectrometer (DF-TIMS) enhances the system stability by mitigating accelerating high-voltage noise and drift. Featuring a Nier-Johnson type double-focusing mass analyzer, the instrument includes a laminated magnet with a 250 mm radius and a cylindrical Electrostatic Analyzer (ESA) with a 350 mm radius, achieving a mass dispersion of 560 mm. It is equipped with of 16 Faraday cups and 4 full-size discrete dynode secondary electron multipliers (SEM), combined with variable dispersion double quadrupole zoom optics, allowing for multi-collection of isotopes with up to 20 % mass dispersion, such as isotopes of Lithium, Boron and Calcium. Additionally, a compact and advanced Retarding Filter enhances abundance sensitivity from < 2 ppm to < 5 ppb. Automated tuning and measurement improve efficiency for both positive and negative ions. With a 0.2 mm source slit and a 1 mm receiving slit, DF-TIMS achieves a resolution over 470 and a peak shape factor below 0.3. System stability is less than 15 ppm/30 min credit to the double-focusing design. Each Faraday cup operates with a dynamic range of 0–50 V, featuring Root Mean Square (RMS) noise (4s integration, 10<sup>11</sup> Ω high resistance) under 20 μV and baseline drift below 1 × 10<sup>−16</sup> A/h. The instrument has been applied extensively, delivering internal precision and external precision for Strontium and Neodymium measurements under 5 ppm, meeting stringent isotopic ratio analysis requirements in nuclear science and geoscience.</div></div>","PeriodicalId":338,"journal":{"name":"International Journal of Mass Spectrometry","volume":"510 ","pages":"Article 117408"},"PeriodicalIF":1.6,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143349790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-20DOI: 10.1016/j.ijms.2025.117411
Mack Shih, Patrick J. Faustino, Thomas F. O'Connor, Jinhui Zhang
Ion mobility mass spectrometry is emerging as a useful tool to probe native protein structural information. Advance ion mobility methods like collision-induced unfolding (CIU) can be used to characterize proteins’ conformational dynamics. The impact of instrument source conditions on the native protein conformations is not well characterized or standardized. High values of drying gas temperature and gas flow parameters on the Agilent IM-QTOF instrument were shown to apply collision-induced unfolding (CIU) effects on protein ions ionized from physiological solution condition. Ion conformation heat maps of model proteins ubiquitin, myoglobin, and bovine serum albumin were obtained using a novel CIU method utilizing high drying gas temperature and varying drying gas flow. Protein charge states also increased as drying gas flow was increased at high temperature indicating a thermal heating element. Overall, drying gas temperature and gas flow on IM-QTOF and the associated impacts on ionic structure need to be considered when using ion mobility mass spectrometry technology to assess protein structure.
{"title":"Influence of mass spectrometry source settings on native protein ion mobility mass spectrometry measurements","authors":"Mack Shih, Patrick J. Faustino, Thomas F. O'Connor, Jinhui Zhang","doi":"10.1016/j.ijms.2025.117411","DOIUrl":"10.1016/j.ijms.2025.117411","url":null,"abstract":"<div><div>Ion mobility mass spectrometry is emerging as a useful tool to probe native protein structural information. Advance ion mobility methods like collision-induced unfolding (CIU) can be used to characterize proteins’ conformational dynamics. The impact of instrument source conditions on the native protein conformations is not well characterized or standardized. High values of drying gas temperature and gas flow parameters on the Agilent IM-QTOF instrument were shown to apply collision-induced unfolding (CIU) effects on protein ions ionized from physiological solution condition. Ion conformation heat maps of model proteins ubiquitin, myoglobin, and bovine serum albumin were obtained using a novel CIU method utilizing high drying gas temperature and varying drying gas flow. Protein charge states also increased as drying gas flow was increased at high temperature indicating a thermal heating element. Overall, drying gas temperature and gas flow on IM-QTOF and the associated impacts on ionic structure need to be considered when using ion mobility mass spectrometry technology to assess protein structure.</div></div>","PeriodicalId":338,"journal":{"name":"International Journal of Mass Spectrometry","volume":"509 ","pages":"Article 117411"},"PeriodicalIF":1.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143101209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-20DOI: 10.1016/j.ijms.2025.117409
Scott M. Simpson , Eric J. Commendatore , Hou U. Ung
The synthesis, characterization, and binding interactions of novel 4-(bis(4,5-dihydro-1H-imidazole-2-yl)amino)-1-methylpyrimidin-2(1H)-one (compound A) with two i-motif forming DNA oligomers (telomeric and hypoxia-inducible factor 1 (HIF-1α) DNA sequences) is reported. DFT-D3 calculations are used to explore binding energies and structural bonding characteristics of compound A with various nucleobases and 1-methylcytosine. Results show a significant increase in DNA melting temperatures with the addition of compound A to both telomeric and HIF-1α DNA sequences. Other ligands have shown the ability to bind and increase i-motif stability. Compound A differs in that it possesses a modified cytosine base core, while lacking the ribose sugar to achieve a significant increase in the melting temperatures of both telomeric and HIF-1α sequences.
{"title":"Synthesis of bis(guanidinylated-methylcytosine) and its effect toward nucleobase binding","authors":"Scott M. Simpson , Eric J. Commendatore , Hou U. Ung","doi":"10.1016/j.ijms.2025.117409","DOIUrl":"10.1016/j.ijms.2025.117409","url":null,"abstract":"<div><div>The synthesis, characterization, and binding interactions of novel 4-(bis(4,5-dihydro-1H-imidazole-2-yl)amino)-1-methylpyrimidin-2(1H)-one (compound A) with two <em>i</em>-motif forming DNA oligomers (telomeric and hypoxia-inducible factor 1 (HIF-1α) DNA sequences) is reported. DFT-D3 calculations are used to explore binding energies and structural bonding characteristics of compound A with various nucleobases and 1-methylcytosine. Results show a significant increase in DNA melting temperatures with the addition of compound A to both telomeric and HIF-1α DNA sequences. Other ligands have shown the ability to bind and increase <em>i</em>-motif stability. Compound A differs in that it possesses a modified cytosine base core, while lacking the ribose sugar to achieve a significant increase in the melting temperatures of both telomeric and HIF-1α sequences.</div></div>","PeriodicalId":338,"journal":{"name":"International Journal of Mass Spectrometry","volume":"509 ","pages":"Article 117409"},"PeriodicalIF":1.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143101184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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