Radiant energy – Ionic separation or analysis – Ion beam pulsing means with detector synchronizing means
Reexamination Certificate
2000-11-15
2002-08-27
Lee, John R. (Department: 2881)
Radiant energy
Ionic separation or analysis
Ion beam pulsing means with detector synchronizing means
C250S281000, C250S282000, C250S292000, C250S288000
Reexamination Certificate
active
06441369
ABSTRACT:
FIELD OF INVENTION
The invention relates generally to mass spectrometers and specifically to tandem time-of-flight mass spectrometers.
BACKGROUND OF INVENTION
Mass spectrometers vaporize and ionize a sample 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 the ion source to the detector, under the influence of electric fields. The time it takes for an ion to reach the detector, for electric fields of given strengths, is a direct function of its mass and an inverse function of its charge.
Recently TOF mass spectrometers have become widely accepted, particularly for the analysis of relatively nonvolatile biomolecules, and 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 the 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 disclosure 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 excellent data on the molecular weight of samples. However, these techniques provide little information on molecular structure. Traditionally tandem mass spectrometers (MS-MS) have been employed to provide structural information. Tandem MS-MS instruments are described in pending U.S. patent application Ser. No. 09/020,142, filed on Feb. 6, 1998, and assigned to the present assignee. The entire disclosure of U.S. patent application Ser. No. 09/020,142 is incorporated herein by reference. In MS-MS instruments, a first mass analyzer is used to select a primary ion of interest, for example, a molecular ion of a particular sample. The ion is then caused to fragment by increasing its internal energy, for example, by causing the ion to collide with a neutral molecule. The spectrum of fragment ions is then analyzed by a second mass analyzer. The structure of the primary ion can be determined by interpreting the fragmentation pattern.
A technique known as post-source decay (PSD) can be employed in MALDI-TOF mass spectrometers, but the fragmentation spectra are often relatively weak and difficult to interpret. Some prior art mass spectrometers include a collision cell that causes some of the ions to undergo high energy collisions with neutral molecules to enhance the production of low mass fragment ions and produce some additional fragmentation. However, the spectra produced by these prior art mass spectrometers are also difficult to interpret. Prior art orthogonal ESI-TOF mass spectrometers typically 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.
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. 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.
There are several prior art tandem mass spectrometers that use time-of-flight mass spectrometer techniques for selecting a primary ion and/or detecting and analyzing fragment ions. One prior art tandem mass spectrometer uses two quadrupole mass spectrometers 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. The TOF mass spectrometer detects and analyzes the fragment ion spectrum.
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.
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 at least unit mass resolution and good ion transmission over the mass range of interest. MS-MS systems are typically used for peptide sequencing above molecular weight 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 resolution, compared to time-of-flight mass spectrometers, and are not readily adaptable for use with modem ionization techniques such as MALDI and electrospray. These instruments are also very complex and expensive.
SUMMARY OF THE INVENTION
The present invention relates to improving the performance of tandem TOF mass spectrometers. A discovery of the present invention is that the resolution of tandem TOF mass spectrometers can be improved by applying a time varying bias voltage that increases the energy of the fragments relative to the selected ions. Another discovery of the present invention is that near optimum resolution can be achieved in both the first and second mass spectrometer unit of a tandem TOF mass spectrometer by providing an additional grid interposed between the timed ion selector and the fragmentation chamber. Increasing the energy of the fragments relative to the selected ions and establishing near optimum resolution in both the first and second mass spectrometer units in a tandem TOF mass spectrometer according to the present invention results in a high resolution fragment spectra that has a resolution that is nearly independent of mass.
Accordingly, the present invention features a tandem time-of-flight mass spectrometer that includes a pulsed source of ions that focuses a packet of ions substantially within a predetermined mass-to-charge ratio range onto a focal plane in a flight path of the ions. An ion selector receives the focused packet of ions and selects ions substantially within the predetermined mass-to-charge ratio range and rejects substantially all other ions. In one embodiment, the ion selector is positioned substantially at the focal plane. In another embodiment, the focal plane is located between the ion selector and the pulsed ion accelerator.
An ion fragmentor that fragments a fraction of the ions is positioned in the flight path of the ions. In one embodiment, the ion fragmentor is positioned after the ion selector in the fight path of the selected ions. In anot
Gabeler Stephen C.
Vestal Marvin L.
Fernandez Kalimah
Karnakis Andrew T.
Lee John R.
PerSeptive Biosystems Inc.
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