Mass spectrometer

Details Mass spectrometer Mass spectrometer

2003-05-28

2004-03-16

Lee, John R. (Department: 2881)

Radiant energy

Ionic separation or analysis

C250S282000, C250S287000, C250S288000

Reexamination Certificate

active

06707033

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a mass spectrometer having an ion accumulator and a time-of-flight mass spectrometer coupled thereto and more particularly, to the provision of a mass spectrometer having both the function of multi-stage tandem mass spectrometry (MS
n
) and a high mass accuracy of less than 5 ppm.
With advanced genome decryption for a background, a proteome analysis for comprehensively analyzing protein appearing in vivo has been noticed. An analyzing method using the mass spectrometer features high sensitivity and high throughput and serves as a leading technique for the proteome analysis. Of the analyzing methods, the tandem mass spectrometry (MS
n
) technique can improve the analytical efficiency of the proteome analysis drastically and therefore has been thought much of.
As a mass spectrometer capable of performing the MS
n
spectrometry, an ion trap mass spectrometer described in U.S. Pat. No. 2,939,952 is known. In the ion trap mass spectrometer, a quadrupole electric field is formed inside an ion trap by applying an RF voltage so as to capture and accumulate ions and subsequently, accumulated ions are ejected and detected in order of smaller mass-to-charge ratios of ions by scanning the amplitude of the RF voltage, thereby undergoing mass spectrometry. In the ion trap mass spectrometer, an MS
2
spectrometry is made as follows. Firstly, ions are accumulated in the ion trap. Next, ions in an arbitrarily selected mass range are kept to remain and ions in other mass ranges are ejected out of the ion trap (this operation is called “isolation”). Thereafter, the selected ions (parent ions) are dissociated to create fragment ions (daughter ions) which in turn are captured in the ion trap. Finally the RF voltage is scanned, with the result that accumulated daughter ions are ejected and detected in order of smaller mass-to-charge ratios (m/z) of the daughter ions so as to undergo mass spectrometry. Out of the daughter ions, ions in a specified mass range are selected and the selected ions now personate parent ions to be applied with an operation similar to the above to create daughter ions which in turn undergo mass spectrometry. This is an MS
3
spectrometry. By repeating a similar operation, an MS
n
spectrometry can proceed. The dissociation of parent ions is achieved through collision induced dissociation (CID). In the CID, a neutral gas (target gas) is introduced into the ion trap and is caused to collide with ions to dissociate them. The MS
n
spectrometry can give detailed information of the structure of an analyte and is therefore a technique effective for analysis of a structure of an unknown substance. The ion trap mass spectrometer, however, faces a problem that the mass accuracy is poor because of space charge effects. The space charge effects referred to herein signify that the quadrupole electric field for capturing ions is affected by perturbation due to charges of captured ions. The larger the amount of captured ions, the more the space charge effects become noticeable, so that ions are lost and the mass resolution of mass spectrum and mass accuracy are degraded.
Known reference 1 (U.S. Pat. No. 5,572,022) discloses a method and apparatus for operating an ion trap mass spectrometer in such a manner that space charge effects do not become noticeable. A dissolved sample delivered out of a liquid chromatograph, for instance, is ionized in an ion source and then admitted to an ion trap. By controlling a lens system arranged immediately before the ion trap, ions can be admitted to the ion trap for a constant period of time. In the case of an MS
n
spectrometry, selection and dissociation of parent ions are performed. Finally, by scanning an RF voltage, mass spectrometry of ions captured in the ion trap is carried out. This operation is repeated until delivery of the dissolved sample from the liquid chromatograph ends. At that time, the time for introducing ions into the ion trap is determined on the basis of total content of ions detected in a mass spectrometry carried out immediately precedently and a threshold value preset in advance. The threshold value referred to herein is set to an amount of ions with which the space charge effects will not become noticeable. In the ion trap mass spectrometer, however, a neutral gas prevails inside the ion trap and hence collisions of ions with the gas take place even during mass spectrometry. Since a cross-section of collision with the gas differs to a great extent depending on the kind of ions and even for ions of the same m/z (mass-to-charge ratio), the ions are detected at shifted times. This makes it difficult to attain a mass accuracy of less than 0.1 amu (atomic mass unit) with the ion trap mass spectrometer.
Known reference 2 (B. M. Chien, S. M. Michael and D. M. Lubman, Rapid Commun. Mass in Spectrometry, Vol. 7, 837. (1993)) discloses an apparatus having an ion trap and a time-of-flight mass spectrometer coupled thereto. In the apparatus, a process up to capture and isolation of ions and dissociation of ions is carried out inside the ion trap and mass spectrometry of daughter ions is performed by means of the time-of-flight mass spectrometer. The time-of-flight mass spectrometer features a high mass accuracy of less than 5 ppm. But in the apparatus, the ion trap also serves as a portion of the time-of-flight mass spectrometer (accelerator) and as a result, collisions of ions with a neutral gas take place during mass spectrometry. Consequently, measurement accuracy of time of flight, accordingly, mass resolution and mass accuracy are degraded.
Known reference 3 (JP-A-2001-297730) discloses another type of apparatus having an ion trap and a time-of-flight mass spectrometer in combination. In the apparatus, a process up to capture and isolation of ions and dissociation of ions are carried out inside the ion trap and mass spectrometry of daughter ions is performed by means of the time-of-flight mass spectrometer. In the apparatus, the ion trap and the mass spectrometer are separated from each other, so that ions accumulated in the ion trap are once ejected out of the ion trap and then introduced to the time-of-flight mass spectrometer so as to undergo mass spectrometry therein. Inside the time-of-flight mass spectrometer, an acceleration field is formed in a direction orthogonal to the traveling direction of ions and time of flight required for ions to reach a detector from an accelerator is measured. The interior of the time-of-flight mass spectrometer is maintained at high vacuum and collisions of ions with gas hardly take place therein. Therefore, an MS
n
spectrometry can be executed at a high mass accuracy the time-of-flight mass spectrometer has.
SUMMARY OF THE INVENTION
Disadvantageously, in the ion trap mass spectrometer, loss of ions occurs inside the ion trap owing to the space charge effects and the mass resolution of mass spectrum and mass accuracy are degraded. In the known reference 1, the amount of ions accumulated in the ion trap can be so adjusted as to prevent the space charge effects from becoming noticeable but mass spectrometry is performed by means of the ion trap and there results a mass accuracy of only less than 0.1 amu. This accuracy is insufficient for proteome analysis. In the known reference 2, the apparatus is disclosed in which mass spectrometry of ions accumulated in the ion trap is performed by means of the time-of-flight mass spectrometer having high mass accuracies. But, since the ion trap also serves as an accelerator of the time-of-flight mass spectrometer, collisions of ions with gas take place inside and near the ion trap, with the result that the high mass accuracy the time-flight-mass spectrometer originally has cannot be realized. In the known reference 3, mass spectrometry is carried out after ions accumulated in the ion trap have been transferred to the time-of-flight mass spectrometer representing a high vacuum chamber, so that MS
n
spectrometry can be performed at a high mass accuracy of less than 5 ppm the time-of-flight mass spect

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