Preparation of ion pulse for time-of-flight and for tandem...

Details Preparation of ion pulse for time-of-flight and for tandem... Preparation of ion pulse for time-of-flight and for tandem...

2003-02-03

2003-12-30

Lee, John R. (Department: 2881)

Radiant energy

Ionic separation or analysis

Ion beam pulsing means with detector synchronizing means

C250S281000, C250S282000, C250S284000, C250S288000, C250S290000, C250S291000, C250S292000, C250S297000, C250S397000

Reexamination Certificate

active

06670606

ABSTRACT:

FIELD OF INVENTION
This invention relates generally to mass spectrometry, in particular to a novel apparatus and method to prepare an ion pulse for ideal analysis in a time-of-flight mass spectrometer and in tandem mass spectrometers in which fragments are analyzed via time-of-flight mass spectrometry.
BACKGROUND OF THE INVENTION
Mass spectrometers are devices which vaporize and ionize a sample and then determine the mass to charge ratios of the collection of ions formed. One well known mass analyzer is the time-of-flight mass spectrometer (TOFMS), in which the mass to charge ratio of an ion is determined by the amount of time required for that ion to be transmitted, under the influence of pulsed electric fields, from the ion source to a detector. TOFMS has become widely accepted in the field of mass spectrometry, having the desirable attributes of high scan speed, high sensitivity, theoretically unlimited mass range, and, if an ion mirror is used, achievable resolutions of greater than 10,000. The spectral quality in TOFMS reflects the initial conditions of the ion beam prior to acceleration into a field free drift region. Specifically, any factor which results in ions of the same mass having different kinetic energies, and/or being accelerated from different points in space, will result in a degradation of spectral resolution, and thereby, a loss of mass accuracy. High mass accuracy is a desirable property in spectrometers used in the analysis of biomolecules, as it is one of the important factors in the unambiguous determination of peptide, and thereby protein, identity using database searching.
Two instrumental developments which minimize the effects of spatial and energy spreads on the final spectra are prevalent in the field. The first is the two-stage, or Wiley-McLaren, acceleration source, which provides first order space focusing, and the second is the ion mirror, or reflectron, which provides first order energy focusing. Additionally, the two widely adopted methods to produce gas phase biomolecular ions for mass spectrometric analysis, namely matrix assisted laser desorption ionization (MALDI) and electrospray ionization (ESI), have integrated certain instrumental attributes which have enhanced spectral resolution. The development of delayed extraction (DE) for MALDI-TOF as described in U.S. Pat. Nos. 5,625,184, 5,627,369 and 5,760,393 has made high resolution routine for MALDI based instruments. For ESI-TOFMS, high resolutions have been achieved by transmitting the ion beam through an RF only quadrupole and into the acceleration region of a TOFMS. The accelerating pulse is applied perpendicular to the direction of transmission. For both these methods, however, the resolution enhancement is not achieved without sacrificing another element of instrumental performance.
In DE-MALDI, a short delay is added between the ionization event, triggered by the laser, and the application of the accelerating pulse to the TOF source region. The fast (i.e., high-energy) ions will travel farther than the slow ions, in effect transforming the energy distribution upon ionization to a spatial distribution upon acceleration. A Wiley-McLaren source is used for space focusing. The delay time in DE-MALDI, however, can only optimize performance across a narrow range of mass to charge ratios, hence, resolution varies across the spectrum and calibration is non-linear. Additionally, the performance of the spectrometer is strongly coupled to the energy distribution from the ionization source. The highest mass resolution is achieved using so-called “threshold” conditions, i.e., operating the laser at the minimal fluence that yields observable ionization. If laser fluence is increased beyond this threshold value, ions are formed with a broader energy distribution, thereby degrading spectral quality.
It is known in the art that raising the laser fluence substantially above the threshold value increases the number of ions formed per laser pulse by orders of magnitude. As a consequence, in DE-MALDI the resultant direct coupling of the ionization source with the spectrometer is manifested in a tradeoff between resolution and sensitivity, that is one cannot simultaneously optimize conditions for ionization and mass analysis. An independent problem in MALDI based spectrometers is the observation, in some instances, of spectral features resultant from decay of ions during their flight time from the acceleration source region to the detector. Briefly, if ions created in the MALDI process are formed with excess internal energy, ions may dissociate prior to detection. The resulting fragments appear in the spectrum as unassignable chemical noise, “metastable” peaks, and/or increased background in the spectrum.
In a spectrometer equipped with an ESI source, a method termed orthogonal acceleration (oa) TOFMS is typically used. In oa-TOFMS, the ionization source may be separated from the acceleration region of the TOFMS by an RF-only quadrupole operating in the millitorr pressure regime. This quadrupole acts as a beam guide transmitting ions formed at atmosphere into the vacuum regions of the spectrometer. As described in U.S. Pat. No. 4,963,736, the passage of an ion beam through an RF-only quadrupole operated in the millitorr pressure regime leads to the “collisional cooling” of the beam. Through sequential collisions between the ion and the background gas, the internal energy of the ions is lowered to approach that of the background gas (i.e., the ion beam becomes thermalized). Similarly, the translational kinetic energy of the beam is lowered, restricting the motion of the ions to the low field region of the quadrupolar potential, resulting in a narrow beam of ions and more efficient transmission through restrictive ion optics. Lastly, reduction of the translational kinetic energy of ions coaxial to the beam, results in a denser beam with a smaller translational energy spread. As collisional cooling lowers the internal energy of the ions formed, harsh ionization conditions can be used without degrading spectral resolution and thus in an oa-TOFMS the ionization source becomes effectively decoupled from the spectrometer. The oa-TOFMS has been coupled to a MALDI ionization source, operated with a high repetition rate, high fluence Nd:YAG laser OPO 5000, as described by Anatoli Verentchikov et al. “Collisional Cooling and Ion Formation at Intermediate Gas Pressure”, Proc. 47
th
ASMS Conference on Mass Spectrometry and Allied Topics, 1999, to create a quasi continuous beam which is pulsed into the TOFMS.
A key element of oa-TOFMS is that the beam enters the acceleration region of the TOFMS orthogonal to the direction the pulse is accelerated. (see U.S. Pat. No. 5,117,107 and Dodonov USSR Patent No. SU 168134A1 and published PCT application WO91/03071). Thus, the initial conditions of the accelerated TOF pulse are defined by the properties of collisional cooling in a quadrupolar potential, i.e., the ions have small spatial and energy distribution. One limitation in oa-TOFMS is that the duty cycle of the instrument, which is defined as the ratio of the time required to fill the acceleration region of the TOF spectrometer to the time for mass analysis, is typically a low 5-20%. A further disadvantage of oa-TOFMS is that the ions of the accelerated pulse maintain a small velocity component in the direction perpendicular to TOF acceleration. Therefore the ion pulse accelerated in the TOF has a natural “drift” angle which must be compensated for, either through the use of a large detector surface or an electrostatic steering deflector, a device which is known in the art to degrade resolution.
The problem of poor duty-cycle in oa-TOFMS has been addressed in a combination, or “hybrid” instrument in which the continuous ion beam is stored in a quadrupole ion trap and ejected as discrete pulses into the TOFMS by Mark Q. Qian et al. “Procedures for Tandem Mass Spectrometry on an Ion Trap/Reflection Time-of-Flight Mass Spectrometer”, Rapid Communications in Mass Spectrometry, 10, 1996. According to the authors, careful sy

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