Internal Standard Quantification Using Tandem Mass Spectrometry of

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Rapid internal standard quantification using tandem mass spectrometry of a tryptic peptide in the presence of an isobaric interferent. Dany Jeanne Dit Fouque, Alicia Maroto, and Antony Memboeuf Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.8b05016 • Publication Date (Web): 21 Nov 2018 Downloaded from http://pubs.acs.org on November 22, 2018

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Analytical Chemistry

Rapid internal standard quantification using tandem mass spectrometry of a tryptic peptide in the presence of an isobaric interferent. Dany Jeanne Dit Fouque, Alicia Maroto, Antony Memboeuf* CEMCA, Université de Brest, CNRS, Université Bretagne Loire, CS 93837, 6 Av. Le Gorgeu, Brest 29238 Cedex 3, France. ABSTRACT: Model mixtures of isobaric peptides were studied to evaluate the possibility, using tandem mass spectrometry experiments, for internal standard quantification of a tryptic peptide in the presence of an isobaric interferent. To this end, direct injection ESI-MS/MS experiments were performed on an ion trap instrument: using a large mass-selection window (15 m/z) encompassing the isobaric mixture and the internal standard, MS/MS experiments were carried out to remove completely the interferent from the mixture by fragmenting it. This allowed for the correct intensity assignment for the protonated peptide peak and thus, for the analyte to be quantified through the relative intensity estimate of this peak with respect to the internal standard. This was done by monitoring the 15 m/z mass-selection window only and, without the necessity for careful inspection of any fragment ions peaks. The interferent removal was assessed by determining an excitation voltage large enough for the analyte/internal standard ratio to remain constant ensuring correct quantification despite isobaric contamination. A calibration curve was obtained to predict reference samples and compared to reference samples purposedly spiked with the interferent: using the proposed methodology, internal standard quantification of the analyte was made possible with ~1% deviation despite the isobaric contamination.

Internal standards are widely used in mass spectrometry not only to correct for sample preparation variations during extraction and chemical derivatization, but also to compensate for variability in signal intensity due to ion-suppression caused by matrix components that may influence the efficiency of ionization.1–3 In the field of proteomics, internal standards allow the absolute quantification of proteins with tandem mass spectrometry.3–6 In this case, stable-isotope labeled peptides are used as internal standards for the quantification of signature peptides obtained from the enzymatic digestion of the protein, usually the tryptic digestion.7,8 Even if internal standards allow for correcting matrix effects, the presence of signal interferents may drastically affect quantification possibly leading to erroneous results.9 If on-line coupling of orthogonal techniques may overcome the problem, this cannot be guaranteed in the case of complex background. In this sense, quantification using hyphenated mass spectrometry may be distorted due to iso-baric/meric interferent. In several recent studies, it has been shown that unequivocal structural and quantitative analysis of an isobaric/meric compound in model mixtures can be performed using energy-resolved tandem mass spectrometry and the Survival Yield (SY) technique.10,11 More recently, we have reported a method for selectively getting rid of such an interferent by fragmenting it and monitoring the Survival Yield as a function of excitation voltage in MS/MS

experiments (parent ions intensity peak divided by the sum of intensities of all peaks on the MS/MS spectrum).12 With this technique, possibly combined with MS3 measurements, analysis of the purity of synthetic samples may be done using the standard addition method.11,12,13 In the work presented herein, selective fragmentation of the isobaric contaminant is also performed however, with the aim of absolute quantification of the analyte of interest using an internal standard and without the need for SY monitoring. By performing the isolation and excitation stage on an unconventionally large 15 m/z range and by monitoring this m/z range only, both the compound of interest and internal standard can be measured simultaneously while the interferent is fragmented extensively up to complete disappearance. A criterium for assessing the removal of isobaric interferent is then proposed and, the potential for absolute quantification is evaluated using calibration curves and purposedly contaminated reference samples.

EXPERIMENTAL SECTION Chemicals. Methanol (HPLC-MS grade) and poly(ethylene glycols) (HO-(C2H4O)n-H, PEG) with 1000 Da average molecular weight (no grade specified) were purchased from Sigma-Aldrich (St. Louis, MO, USA. De-ionized ultra-pure water (18 MΩ cm resistivity) was obtained using Milli-Q Integral 3 Water System (Merck Millipore, Guyancourt,

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France). Formic acid was purchased from Amresco (Solon, Ohio, USA) with grade higher than 94.5%. Isobaric peptides. Two isobaric peptides were synthesized at the Nanobio Plateform (Université Grenoble-Alpes, Grenoble, France) with two different amino acid sequences. The first peptide corresponds to the arginine-containing peptide (ISTYTR, 738.402 Da, Arg-Pept), while the second one (FIFTNV, 738.406 Da, Int-Pept) corresponds to the interferent isobaric peptide and does not contain any basic amino-acid residue. The two isobaric peptides were assembled on a Syro II peptides synthesizer using the Fmoc strategy.13 Sample preparation. Three sets of samples were prepared separately: as a first set, samples of both arginine-containing peptide and isobaric interferent peptide were diluted separately and in a 1:1 mixture at 3 µM in MeOH/H2O (7:3) with formic acid 0.1% (v/v) to obtain tandem mass spectra of protonated peptides (Arg-Pept and Int-Pept) and the corresponding Survival Yield curves. As a second set of samples, PEG was added, to generate sodiated adducts (dummy internal standard, IS), to different mixtures of peptides in MeOH/H2O (7:3) with formic acid 0.1% (v/v) with the following molar ratios of IS/Arg-Pept/Int-Pept: 1:6:0, 1:6:1.5, 1:6:3, 1:6:4.5, 1:6:6 and 1:0:6. Concentration of IS was maintained constant at 0.5 µM and concentration for Arg-Pept, when used, was 3µM. Consequently, the concentration of Int-Pept ranged from 0 to 3µM. Separately, to ensure there is no additional isobaric contaminant from this sample, a blank MS spectrum was obtained from PEG sample in MeOH/H2O (7:3) with formic acid 0.1% (v/v) (cf. Figure S-2). Using a third set of samples, an internal standard calibration curve was obtained with four calibration standards of IS/Arg-Pept prepared in MeOH/H2O (7:3) with formic acid 0.1% (v/v). In this case, the concentration of IS was also maintained constant at 0.5 µM, while the concentrations of Arg-Pept used were 3, 3.25, 3.5 and 3.75 µM.

Figure 1. SY curves for pure protonated (full lines) Int-Pept (squares) and Arg-Pept (circles) and in mixture (dashed line) with a molar ratio of Int-Pept/Arg-Pept of 1:1 (triangles).

CID MS/MS spectra were obtained on 200-755 m/z range, after averaging 5 acquisitions and 2 rolling averages, and combined over 1 minute acquisition at each excitation voltage. DataAnalysis 3.3 (Bruker Daltonics, Bremen, Germany) was used for data acquisition and mass spectra processing using default software parameters for data processing (background reduction, smoothing and peak centering). Survival Yield curves were plotted using the freely available LibreOffice software package.14

RESULTS AND DISCUSSION MS/MS spectra of isobaric peptides and Survival Yield curves. The behavior of the two isobaric protonated peptide ions in CID-MS/MS experiments is first analyzed in light of the Survival Yield technique. Tandem mass spectrometry analysis (MS2) was performed for isobaric peptides Int-Pept and Arg-Pept, both separately and in a 1:1 mixture (cf. Figure S-1). Survival Yield curves were obtained for those three samples as a result of energy-resolved tandem mass spectrometry experiments (cf. Figure 1). The Survival Yield (SY) is a quantitative measure of the precursor ions surviving the CID excitation process10,11,15–18 and is calculated from a MS/MS spectrum as:

Mass spectrometry. Mass spectrometry experiments were performed in positive ion mode using an ion trap mass spectrometer (HCTplus, Bruker Daltonics) equipped with an electrospray ionization source (ESI, Agilent Technologies). The solutions were introduced by direct injection and electrosprayed via a syringe pump at a 2 µL/min flow rate. The nebulizing gas (N2) pressure was set at 10 psi and the N2 drying gas flow rate at 5 L/min heated at 300°C. Helium was used as the trapping and collision gas at 2.08 10-5 mbar pressure (uncorrected gauge reading). All data were acquired in the low resolution Ultra-scan mode using a 26 000 Th/s scan speed (leading to ~250 resolution). The settings of the instrument were the following: capillary voltage 3.8 kV, end plate -0.5 kV, skimmer 40 V, cap exit 146.4 V and a trap drive at 68.7. The Ion Charge Control option was unchecked, only the accumulation time was maintained constant at 40 ms to ensure a high number of ions inside the ion trap and stabilize the signal. CID experiments were performed using a 15 m/z isolation window, centered at m/z 742.5 that intentionally does not correspond to the masses of the peptides and IS dummy standard rather is intermediate to their corresponding masses. Isolation was followed by an excitation delay of 200 ms and, a CID stage with 100 ms excitation time and 15 m/z excitation width (with the same target mass as for the isolation stage).

SY =

IP IP +  IF

(1)

where IP corresponds to the intensity of the precursor ions peak and IF to the intensity of a fragment ions peak. By plotting SY values as a function of excitation voltage, a SY curve with a sigmoid shape can be obtained (cf. Figure 1). This type of curves starts at 1 for low excitation voltages (no fragmentation of precursor ions) to reach 0 at high excitation voltages (corresponding to the fragmentation of all precursor ions). Figure 1 shows the SY curves obtained for both protonated peptides separately. A large shift to higher excitation voltages is observed for Arg-Pept as compared with the isobaric


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Figure 2. A 15 m/z isolation window is applied at m/z 742.5 (blue diamond) prior to the 15 m/z CID excitation stage is performed. MS/MS spectrum shows the mixture of isobaric protonated peptides (Int-Pept=[FIFTNV+H]+ and Arg-Pept=[ISTYTR+H]+) and the internal standard [PEG16 + Na]+ (IS) at m/z 739.8 and m/z 745.6 respectively.

Figure 3. Ratio R (cf Eq. 2) of peaks intensities for various mixtures of sodium cationized PEG (IS) and isobaric protonated peptides (Arg-Pept and Int-Pept) as a function of excitation voltages.

peak can be monitored together with the analyte’s peak. At this stage, only the complete removal of Int-Pept interferent from the MS spectrum is discussed and assessed using this strategy. MS/MS spectra were obtained for several mixtures of ArgPept, IS and Int-Pept at excitation voltages ranging from 0.90 V to 1.20 V, however, by monitoring only the same 15 m/z range that was used in the isolation stage. Mixtures (second set of samples) were prepared as described in the experimental section: the concentration of Arg-Pept and IS was maintained constant for all samples, whereas different concentrations of Int-Pept interferent were used. MS/MS spectra for a mixture of Int-Pept and IS were also recorded on the same 0.90 up to 1.20 V range. The ratio of intensities of isobaric peptides precursor ions and IS was then calculated according to:

peptide Int-Pept. In the case of Arg-Pept, proton sequestration by the arginine residue leads to an increased stability and a higher excitation voltage is necessary to obtain fragmentation in CID-MS/MS experiments.19,20 On contrary, protonated peptides without basic amino-acids may fragment at lower excitation voltages due to charge-induced fragmentation processes. Such distinct features are clearly observed when plotting Survival Yield curves for both compounds separately.15 Similarly to earlier reports, the SY curve exhibits a plateau when the two isobaric peptides, Arg-Pept and IntPept, are prepared in a mixture (cf. blue curve with triangles in Figure 1). This plateau is observed, in our conditions, at excitation voltages ranging from 1.11 to 1.20 V. This range corresponds to the range of excitation voltages for which the complete population of Int-Pept adduct ions has been fragmented while Arg-Pept ions do not show a single fragment ion yet. Removal of isobaric interferent using “Gas-phase collisional purification”. Quantification can be done by using a reference peak to which the analyte’s signal can be normalized. In order to quantify our Arg-Pept analyte we have used a dummy internal standard (designated as IS), namely sodium cationized PEG, [PEG16 + Na]+ at m/z 745.5, that is very close in m/z to our analyte of interest Arg-Pept (m/z 739.8). Similarly to the recently reported “gas-phase collisional purification” strategy,12 the interfering signal, originating from isobaric Int-Pept contaminant, can be removed. This strategy consists in using a CID stage at a carefully selected excitation voltage to fully fragment the isobaric contaminant, while keeping the analyte of interest for an additional MS or multistage MS analysis. In our case, this strategy was however modified by using a 15 m/z large isolation window prior to the CID stage rather than the usual monoisotopic peak massselection (cf. Figure 2). In this way, the intensity of the IS

R

mixture I mPeptides / z  739.8 I mIS/ z 745.5

(2)

where mixture - Pept Int - Pept I mPeptides  I mArg / z  739.8 / z  739.8  I m / z  739.8

(3)

Figure 3 shows this ratio R as a function of excitation voltage for the different mixtures. In the case of a mixture of Arg-Pept and IS only, the ratio remains constant (red filled circles data). This can be explained by the fact that neither Arg-Pept nor IS compounds do fragment on this range of excitation voltages: this is indeed observed in Figure 1 (SY curves of Arg-Pept, red filled dots) and Figure S-3 (SY curve of IS, green filled diamonds). This observation confirms the appropriateness of [PEG16 + Na]+ adduct as a dummy IS to normalize the intensity of the precursor ions peak of Arg-Pept on this range of excitation voltages.



An internal standard calibration curve was first obtained (cf. Figure 4) using the calibration standards (third set of samples). Standards were prepared as described in the experimental section at 3, 3.25, 3.5 and 3.75 µM of Arg-Pept and 0.5 µM of IS. MS/MS spectra for each calibration standard were performed three times under repeatability conditions at each excitation voltages corresponding to the plateau (i.e. 1.11, 1.13, 1.15 and 1.17 V, cf. Figure 3). An average value of the ratio R (cf. Eq. 2) was calculated by accounting for the data obtained at those four excitation voltages, leading to 3 averaged data points per calibration standard (virtually 12 data points per sample). By plotting those average values against the concentration of Arg-Pept, a calibration curve was obtained. Linear regression analysis can be used on this small range of concentrations obtained: a good coefficient of determination was obtained (R2=0.993) and, experimental data points were randomly distributed around the calibration curve. Then, among the four calibration samples, two calibration standards, Arg-Pept at 3.0 µM and at 3.5 µM (each with 0.5 µM of IS), were spiked with 3 µM of Int-Pept interferent. MS/MS spectra for those two polluted samples were recorded five times under repeatability conditions. Average values of R were calculated for the same four excitation voltages corresponding to the plateau (i.e. 1.11, 1.13, 1.15 and 1.17 V) leading to 5 averaged data points per sample. The resulting values for R are shown in Figure 4: in red for the 3.0 µM sample and in blue for 3.5 µM sample. Both polluted standards showed very similar ratios compared to the calibration standards, which were free from isobaric interferent. Predicted values for the concentrations of Arg-Pept for both isobarically contaminated standards were then calculated with the internal standard calibration curve to obtain: 3.03±0.04 µM (for the sample at 3.0 µM) and 3.51±0.04 µM (for the sample at 3.5 µM). The uncertainty was calculated as the 95% confidence interval of the predicted concentration.21 Since the confidence interval contains the reference values for both polluted calibration standards, it demonstrates Arg-Pept can be correctly quantified in spite of the isobaric interferent using the proposed strategy with ~1% deviation.

Figure 4. Calibration curve (black line and filled squares) obtained from the ratio of peaks intensities for several mixtures of Arg-Pept and IS (constant at 0.5 µM). Triplicates for R were obtained for each sample. Averaged values for R were calculated using data corresponding to excitation voltages at the plateau (cf. Figure 1). Isobarically contaminated samples of Arg-Pept (at 3 and 3.5µM) were evaluated for quantification using “gas-phase collisional purification” strategy (red filled circles and blue filled triangles).

On contrary, in the case of the mixture Int-Pept/IS (black filled squares data), the ratio decreases with the excitation voltage to reach a 0 value at 1.11 V. This is in agreement with the SY curve of Int-Pept (cf. Figure 1) showing that Int-Pept has totally been fragmented at 1.11 V. In the case of ternary mixtures containing IS/Arg-Pept/IntPept (cf. Figure 3), the higher is the concentration of Int-Pept, the higher is the ratio R at low excitation voltages. However, when increasing the excitation voltage this ratio decreases to reach approximately the same plateau R at the same voltage 1.11 V, independently of the concentration of Int-Pept. This plateau corresponds to the ratio obtained for the 1:6:0 IS/ArgPept/Int-Pept sample (i.e. without the interferent). Indeed, according to Figure 1, at 1.11 V Int-Pept has been totally fragmented leaving only Arg-Pept as precursor ions. As a conclusion, at excitation voltages ranging from 1.11 to 1.20 V, the ratio R is constant and independent of the amount of interferent peptide Int-Pept. It is, indeed, expected to depend only on the relative concentrations of Arg-Pept and IS. Clearly, we have performed a “gas-phase collisional purification”, from the interferent Int-Pept, of Arg-Pept in the presence of an internal standard as a reference compound. Absolute and selective quantification of Arg-Pept is now made possible thanks to the reference compound by using a suitable excitation voltage and despite the interferent. Internal standard quantification of Argininecontaining peptide despite isobaric interference. In this part of the work, quantification of our Arg-Pept analyte in isobarically contaminated samples is compared with calibration curves to evaluate the performance for quantification of the proposed strategy.

CONCLUSIONS A synthetic tryptic-type peptide (Arg-Pept) sample has been analyzed to obtain quantitative information in the context of isobaric contamination with a synthetic non-tryptic type peptide (Int-Pept) with few mDa mass difference. To this end, internal standard quantification method was used with a dummy internal standard (IS), namely sodiated poly(ethylene glycols) adduct ions. The analysis has been performed on an ion trap mass spectrometer using tandem mass spectrometry and the Collision Induced Dissociation technique. Unconventionally 15 m/z wide isolation and excitation windows were used to select the isobaric mixture together with the dummy standard to monitor the ratio of the two peaks for quantification. Only this 15 m/z range was monitored to obtain a MS/MS spectrum. The whole population of ions has been subjected to a CID stage to perform a “gas-phase


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Analytical Chemistry collisional purification”, GPCP,12 of the tryptic peptide from the non-tryptic peptide. This strategy consists in fragmenting completely the non-tryptic protonated peptides to keep only the tryptic protonated peptides signal. In this report, the GPCP strategy has first been assessed in the context of internal standard quantification. The sodiated PEG adduct has been confirmed as an appropriate internal standard in our context. Then, the performance of the proposed strategy for quantification has been evaluated by comparing intentionally contaminated reference samples with the calibration curve. This way, correct quantification of isobarically contaminated tryptic peptide sample was shown to be possible using internal standard method and GPCP with approximately 1% deviation from the correct value. The results presented herein suggest a facile and rapid method for the identification of isobaric contamination without the need for scanning a wide m/z range in MS/MS experiment: monitoring only the ratio of the two peaks (contaminated analyte and internal standard) should lead to a constant value at sufficiently large excitation voltage. Consequently, a monotonous decrease of the ratio as a function of excitation voltage is a signature of iso-baric/meric contamination. Moreover, in the case of contamination, a constant value for this ratio is expected at larger excitation voltages and, should be used for quantification. In practical terms, MS/MS experiments using a mass and excitation window encompassing the contaminated analyte and the internal standard, can be performed in low resolution mode very quickly at several excitation voltages to monitor the quantification ratio that should remain constant on the whole range of voltages used for quantification. The work presented here is a proof-of-concept for a novel strategy for internal standard quantification in the context of isobaric contamination of a tryptic peptide. However, we believe it may also be applied to other classes of molecules as well as isomerisms according to previous reports.11,13,17,22 This may indeed be useful providing there is enough difference in the fragmentation energetics of the compound and the interferent allowing for the complete fragmentation of the contaminant while there is still signal for the analyte and the structurally similar internal standard (e.g. isotope-labelled). This strategy might also be used as an orthogonal separation technique to chromatography, e.g. in the case of co-elution contaminant18,22–25 and/or ion mobility for compounds with similar arrival time/collision cross-sections.26,27

*Phone: +33 (0)2 98 01 61 20 *E-mail: [email protected] ORCID: 0000-0001-8540-2188

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT Université de Brest and the Doctorate School ED 3M are gratefully acknowledged for financial support. The authors thank Dr. R. Lartia (Nanobio Plateform, Grenoble-Alpes, France) for the synthesis of isobaric peptides.

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ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website.

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MS/MS spectra for isobaric protonated Int-Pept and Arg-Pept separately and in mixture (Figure S-1) (PDF) (13)

AUTHOR INFORMATION Corresponding Author

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