Radiant energy – Ionic separation or analysis – Ion beam pulsing means with detector synchronizing means
Reexamination Certificate
2002-07-18
2003-09-16
Lee, John R. (Department: 2881)
Radiant energy
Ionic separation or analysis
Ion beam pulsing means with detector synchronizing means
C250S282000
Reexamination Certificate
active
06621074
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to mass spectrometers and to methods of performing mass spectroscopy. In particular, this invention relates to tandem time-of-flight mass spectrometers and to methods of performing mass spectroscopy using tandem time-of-flight mass spectrometers.
BACKGROUND OF THE INVENTION
Mass spectrometers vaporize and ionize a sample of interest and determine the mass-to-charge ratio of the resulting ions. Time-of-flight (TOF) mass spectrometers determine the mass-to-charge ratio of an ion by measuring the amount of time it takes a given ion to migrate from an ion source to a detector, under the influence of electric fields. The time it takes for an ion to reach the detector, for electric fields of given field strengths, is a direct function of the ion's mass and an inverse function of the ion's charge.
Recently, TOF mass spectrometers have become widely accepted, particularly for the analysis of relatively nonvolatile biomolecules, and for other applications requiring high speed, high sensitivity, and/or wide mass range. New ionization techniques such as matrix-assisted laser desorption/ionization (MALDI) and electrospray (ESI) have greatly extended the mass range of molecules that can be analyzed by mass spectrometers. These techniques can produce intact molecular ions in a gas phase suitable for analysis.
TOF mass spectrometers have unique advantages for these applications. The recent development of delayed ion extraction, for example, as described in U.S. Pat. Nos. 5,625,184, 5,627,369, and 6,057,543 has made high resolution and precise mass measurement routinely available with MALDI-TOF mass spectrometers. The entire disclosures of U.S. Pat. Nos. 5,625,184, 5,627,369, and 6,057,543 are incorporated herein by reference. Orthogonal injection with pulsed extraction has provided similar performance enhancements for ESI-TOF. These techniques provide accurate data on the molecular weight of samples. However, these techniques provide little information on molecular structure.
Some prior art MALDI-TOF mass spectrometers use a technique known as post-source decay (PSD) to fragment the ions. However, the fragmentation spectra produced by PSD are often relatively weak and difficult to interpret. Other prior art MALDI-TOF mass spectrometers include a collision cell that causes some of the ions to undergo high energy collisions with neutral gas molecules to enhance the production of low mass fragment ions and to produce some additional fragmentation. However, these prior art mass spectrometers are not useful for every application.
Other prior art techniques, such as ion traps and Fourier-transform ion-cyclotron-resonance mass spectrometry (FT-ICR-MS), allow multiple steps of fragmentation of primary ions to be observed. These techniques provide a more detailed picture of the fragmentation and in some cases may allow more structural information to be obtained. However, these devices are limited to low energy collisional processes that do not provide some of the specificity provided by high energy collisional dissociation.
Still other prior art mass spectrometers use ESI-TOF that produce fragmentation by causing energetic collisions to occur in the interface between the atmospheric pressure electrospray and the evacuated mass spectrometer. However, these prior art mass spectrometers have no means for selecting a particular primary ion.
There are several prior art tandem mass spectrometers that are generally referred to as MS-MS instruments. MS-MS instruments use mass spectrometer techniques for selecting a primary ion and/or detecting and analyzing fragment ions. The most common form of tandem mass spectrometry is the triple quadrupole mass spectrometer. The first quadrupole selects the primary ion. The second quadrupole is typically maintained at a sufficiently high pressure and voltage so that multiple low energy collisions occur causing some of the ions to fragment. The third quadrupole is scanned to analyze the fragment ion spectrum. The resulting spectra are typically easy to interpret and numerous analysis techniques have been developed. For example, techniques have been developed for determining the amino acid sequence of a peptide from such spectra.
Another prior art tandem mass spectrometer uses two quadrupole mass filters and a TOF mass spectrometer. The first quadrupole selects the primary ion. The second quadrupole is maintained at a sufficiently high pressure and voltage so that multiple low energy collisions occur causing some of the ions to fragment. The TOF mass spectrometer detects and analyzes the fragment ion spectrum.
U.S. Pat. No. 5,202,563 describes a tandem time-of-flight mass spectrometer that includes a grounded vacuum housing, two reflecting-type mass analyzers coupled via a fragmentation chamber, and flight channels electrically floated with respect to the grounded vacuum housing. These mass spectrometers are generally limited to analyzing relatively small molecules and do not provide the sensitivity and resolution required for biological applications, such as sequencing of peptides or oligonucleotides.
For peptide sequencing and structure determination by tandem mass spectrometry, both mass analyzers must have adequate mass resolution and good ion transmission over the mass range of interest. MS-MS systems are typically used for peptide sequencing above a molecular weight of 1000. These systems may include two double-focusing magnetic deflection mass spectrometers having high mass range. Although these instruments provide high mass range and mass accuracy, they are limited in sensitivity, compared to time-of-flight mass spectrometers, and are not readily adaptable for use with modern ionization techniques, such as MALDI and electrospray. These instruments are also very complex and expensive.
Another prior art tandem mass spectrometer that uses time-of-flight mass spectrometer techniques includes two linear time-of-flight mass analyzers that use surface-induced dissociation (SID). One such mass spectrometer includes an ion mirror.
U.S. Pat. No. 5,206,508 describes a tandem mass spectrometer that uses either linear or reflecting analyzers, which are capable of obtaining tandem mass spectra for each parent ion without requiring the separation of parent ions of differing mass from each other.
Tandem mass spectrometers (MS-MS) employing time-of-flight can provide structural information. Such a tandem MS-MS instrument is described in U.S. Pat. No. 6,348,688, the entire disclosure of which is incorporated herein by reference. In this MS-MS instrument, a first mass analyzer is used to select a primary ion of interest, for example, a molecular ion of a particular sample. The ion of interest is then fragmented by increasing the internal energy of the ion. For example, the ion of interest can be fragmented by causing a collision of the ion with a neutral gas molecule. The mass spectrum of the fragment ions is then analyzed by a second mass analyzer. The structure of the primary ion can be determined by interpreting its fragmentation pattern.
SUMMARY OF THE INVENTION
The present invention relates to improving the performance of mass spectrometers. In one embodiment, a mass spectrometer according to the present invention includes a plurality of TOF mass separators operating in series in a TOF mass spectrometer. A mass separator of the present invention can separate and fragment ionic species generated by a previous mass separator, thereby providing increasingly detailed analysis of a chemical sample with each successive stage. One aspect of the mass spectrometer of the present invention is that modes of operation of the stages of mass spectrometric measurement can be selected electrically.
Accordingly, a tandem time-of-flight mass spectrometer (TOF-MS) of the present invention includes a pulsed ion source that generates a plurality of ions. In one embodiment, the pulsed ion source includes an injector that injects ions into a first field-free region, and a pulsed ion accelerator that extracts the plurality ions from th
Johnston Phillip
Karnakis Andrew T.
Lee John R.
PerSeptive Biosystems Inc.
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