Radiant energy – Ionic separation or analysis – Ion beam pulsing means with detector synchronizing means
Reexamination Certificate
2001-09-12
2004-01-06
Nguyen, Kiet T. (Department: 2881)
Radiant energy
Ionic separation or analysis
Ion beam pulsing means with detector synchronizing means
Reexamination Certificate
active
06674069
ABSTRACT:
BACKGROUND OF THE INVENTION
Mass spectrometers are commonly used for the determination of the mass of analyte molecules. In these instruments, ionized molecules are typically either created or introduced into a high vacuum chamber and accelerated to a known kenetic energy. Magnetic fields and electric fields are then used in various methods and fashions for mass selection, mass filtering, and thereby mass determination of the ionized molecules. Among the various types of mass spectrometers commercially available today, there are included magnetic sector, time-of-flight (TOF), ion trap, quadrupole, and ion cyclotron resonance instruments. There are also available instruments that are combinations of the various techniques of mass analysis.
In a typical sector mass spectrometer, a magnetic field (magnetic sector) mass analyzer is scanned over a mass range of interest causing an ion beam output spectrum of mass versus magnetic field intensity. There is commonly also an electrostatic analyzer (ESA) either before or after the magnetic sector, so as to select only ions of a narrow energy distribution, thereby improving resolution, a measure of the selectivity of the mass analysis. Scanning of the magnetic fields and electric fields is a relatively slow process resulting in low efficiency as the ionization is typically, although not always, a continuous process.
By contrast, in a typical time-of-flight mass spectrometer, the entire mass range is analyzed in a single experiment, limited in time only by the mass dependant flight time of the ions in the vacuum chamber, a period measured in microseconds. Time-of-flight instruments have a significant duty cycle advantage over scanning instruments which require a much longer time period to scan the selected mass range.
In mass spectrometry, it is desirable not only to investigate the mass of the intact analyte molecules, but to also be able to dissociate selected analyte molecules (precursor ions) and investigate the mass of the dissociated product ions (fragment ions), and thereby investigate the structure of the precursor analyte molecules. In a typical mass spectrometer designed for MS/MS experiments, there is an MS1 mass analyzer wherein the analyte precursor molecule is mass analyzed and selected, a dissociation region wherein the mass selected precursor ion is collided with a gas, photons, or a surface, thereby causing dissociation of the precursor ions, and an MS2 mass analyzer wherein the resulting product ions are mass analyzed. This is commonly referred to as MS/MS spectrometry or tandem mass spectrometry. Tandem mass spectrometry plays an essential role in the structural analysis of a wide variety of compounds including biomolecules, such as peptides, proteins, and oligonucleotides.
In Collision Induced Dissociation (CID), the mass selected precursor ions from MS1 are passed through a region of relatively high pressure, causing the precursor ions to collide with a target gas molecule. The energy imparted to the precursor ion in such a collision will frequently lead to dissociation of the precursor ion. The efficiency of the CID process is determined in great part on the choice of target gas and the density of the target gas in the collision cell and is proportional to the kenetic energy (KE) of the precursor ion.
The most common MS/MS instruments have until recently been high performance tandem sector instruments. These instruments tend to be large and expensive, and, due to the scanning nature of sector instruments, the product ion collection efficiency has been very low.
An alternative solution is the use of a TOF analyzer as a second stage (MS2) for a sector instrument. Clayton and Bateman (Rapid Communications in Mass Spectrometry (RCM) 6 (1992) 719) proposed such an instrument that employed orthogonal extraction into a TOF analyzer. However, to perform high energy CID experiments, only an “in-line” arrangement can be considered. An in-line arrangement also provides higher CID ion collection efficiency.
An in-line tandem TOF system was proposed by Davis and Evans in U.S. Pat. No. 5,180,914. In their system, a quadrupole field, pulsed, ion storage device was used to decelerate and mass analyze ions in a TOF MS1. The ions then passed through a dissociation region of a few millimeters where a timed laser pulse was applied (Photo Dissociation Spectrometry), after which the fragment ions (as well as the remaining parent ions) entered a TOF MS2 where the product ions were mass analyzed using a quadrupole field reflectron.
A reflectron (or ion mirror) as disclosed, for example, in Mamyrin et al. U.S. Pat. No. 4,072,862, is an electric field device that reflects ions backwards so as to increase the ion flight times and thereby increase the temporal resolution of the spectral results. Ion mirrors have the ability to correct the kinetic energy (KE) differences of ions of the same mass, thereby improving the quality of the mass spectrum. A true parabolic field reflectron is known to be energy independent for ions of the same mass over a very large mass range (Davis et al. U.S. Pat. No. 5,077,472), and has a single spatial focus point for ions irregardless of mass. This type of reflectron can correct for very large KE differences in the temporal focusing of ions. A disadvantage in using a parabolic field reflectron is that the spatial focal point of such a reflectron is located exactly at the entrance to the reflectron. In this invention, an offset parabolic field reflectron is introduced. Use of an offset parabolic field moves the reflectron spatial focal point beyond the entrance of the reflectron, thereby providing for field free regions to exist between the reflectron and its focal point.
Two groups have proposed in-line sector and TOF combinations: Derrick et al. (Int. J. Mass Spec. Ion Proc.) constructed a system based on some of the principles of the tandem TOF design of the Davis and Evans patent. In their implementation, a linear field two-plate ion buncher and a quadratic field planar symmetry reflectron were indicated. A parabolic curve of the shape V=Kd
2
is independent of energy variations, however, there is no field free drift region allowed prior to the focus. In a parabolic field reflectron, the spatial focal point of the reflectron will be located exactly at the entrance to the reflectron.
Cotter, Cornish, and Musselman (RCM 8 (1994) 339) proposed the use of a curved field reflectron in a tandem sector/TOF instrument, however, a method of selection and focusing of the analyte precursor ions was not considered. In a curved field reflectron, field free regions may be defined in front of the reflectron. In TOF systems, these field free regions are commonly referred to as L
1
and L
2
. In a curved field reflectron, ion flight times for a given mass are not completely energy independent. In an offset parabolic field reflectron, above a low energy threshold determined by the offset value, ion flight times of a given mass are completely energy independent, an important feature of this invention. In this invention, an offset parabolic field reflectron is used to achieve very high mass accuracy and resolution over the entire MS2 product ion mass range, above a low energy threshold determined by the offset value.
It will be recognized by those skilled in the art that other types of mass spectrometers, e.g., MALDI-TOF (Matrix Assisted Laser Desorption), or ESI-TOF (Electro Spray Ionization) instruments could, and have been, substituted for the sector instrument as MS1. The invention described herein has application in these other types of mass spectrometers, as well as the traditional sector instruments.
SUMMARY OF THE INVENTION
Briefly, according to this invention, there is provided a tandem mass spectrometry method with collision induced dissociation (CID) comprising the steps for: a) using a first mass spectrometer to select precursor ions of a selected mass, b) forming a packet of precursor ions, c) assigning a focusing energy to each packet of precursor ions in the ion buncher so as to bring the ions into temporal f
Finch Jeffrey W.
Martin Charles D.
Owen Edward E.
Samuelson Gary L.
Jeol USA, Inc.
Nguyen Kiet T.
Webb Ziesenheim & Logsdon Orkin & Hanson, P.C.
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