CA2227806C - Spectrometer provided with pulsed ion source and transmission device to damp ion motion and method of use - Google Patents

Spectrometer provided with pulsed ion source and transmission device to damp ion motion and method of use Download PDF

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CA2227806C
CA2227806C CA002227806A CA2227806A CA2227806C CA 2227806 C CA2227806 C CA 2227806C CA 002227806 A CA002227806 A CA 002227806A CA 2227806 A CA2227806 A CA 2227806A CA 2227806 C CA2227806 C CA 2227806C
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ions
ion
ion source
source
spectrometer
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CA2227806A1 (en
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Andrew N. Krutchinsky
Alexandre Loboda
Victor L. Spicer
Erich W. Ens
Kenneth G. Standing
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University of Manitoba
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University of Manitoba
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Priority claimed from US09/989,882 external-priority patent/US6680475B2/en
Priority claimed from US10/236,514 external-priority patent/USRE39099E1/en
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    • HELECTRICITY
    • H01BASIC ELECTRIC ELEMENTS
    • H01JELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00Particle spectrometers or separator tubes
    • H01J49/02Details
    • H01J49/06Electron- or ion-optical arrangements
    • H01J49/062Ion guides
    • H01J49/063Multipole ion guides, e.g. quadrupoles, hexapoles
    • HELECTRICITY
    • H01BASIC ELECTRIC ELEMENTS
    • H01JELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00Particle spectrometers or separator tubes
    • H01J49/02Details
    • H01J49/10Ion sources; Ion guns
    • H01J49/16Ion sources; Ion guns using surface ionisation, e.g. field-, thermionic- or photo-emission
    • H01J49/161Ion sources; Ion guns using surface ionisation, e.g. field-, thermionic- or photo-emission using photoionisation, e.g. by laser
    • H01J49/164Laser desorption/ionisation, e.g. matrix-assisted laser desorption/ionisation [MALDI]
    • HELECTRICITY
    • H01BASIC ELECTRIC ELEMENTS
    • H01JELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00Particle spectrometers or separator tubes
    • H01J49/26Mass spectrometers or separator tubes
    • H01J49/34Dynamic spectrometers
    • H01J49/40Time-of-flight spectrometers

Abstract

A method and apparatus are provided for providing an ion transmission device or interface between an ion source and a spectrometer. The ion transmission device can include a multipole rod set and includes a damping gas, to damp spatial and energy spreads of ions generated by an ion source. The multipole rod set has the effect of guiding the ions along an ion path, so that they can be directed into the inlet of a mass spectrometer. The invention has particular application to MALDI (matrix-assisted laser desorption/ionization) ion sources, which produce a small supersonic jet or matrix molecules and ions, which is non-directional, and can have ions travelling in all available directions from the source and having a wide range of energy spreads. The ion transmission device can substantially spread out the generated ions along an ion axis. Consequently, a number of pulses of ions can be delivered to the time-of-flight or other spectrometer, for each cycle of the spectrometer.

Description

B&P File No. 571-453 BERESKIN & PARK CANADA
Title: SPECTROMETER PROVIDED WITH PULSED ION SOURCE AND
TRANSMISSION DEVICE TO DAMP ION MOTION AND METHOD OF
USE
Inventors: Andrew N. Krutchinsky, Alexandre V. Loboda, Victor L. Spicer, Erich W. Ens, Kenneth G. Standing Title: SPECTROMETER PROVIDED WITH PULSED ION SOURCE AND
TRANSMISSION DEVICE TO DAMP ION MOTION AND METHOD OF USE
FIELD OF THE INVENTION
This invention relates to mass spectrometers and ion sources therefor.
More particularly, this invention is concerned with pulsed ion sources and the provision of a transmission device which gives a pulse ion source many of the characteristics of a continuous source, such that it extends and improves the application of Time of Flight Mass Spectrometry (TOFMS) and that it additionally can be used with a wide variety of other spectrometers, in addition to an orthogonal injection time-of-flight mass spectrometer.
BACKGROUND OF THE INVENTION
Ion sources for mass spectrometry may be either continuous, such as ESI (electrospray ionization) sources or SIMS (secondary ion mass spectrometry) sources, or pulsed, such as MALDI (matrix-assisted laser desorption/ionization sources). Continuous sources have normally been used to inject ions into most types of mass spe~ctrameter, such as sector instruments, quadrupoles, ion traps and ion cyclotron resonance spectrometers. Recently it has also become possible to inject ions from continuous sources into time-of flight (TOF) mass spectrometers through the use of "orthogonal injection", whereby the continuous beam is injected orthogonally to the main TOF axis and is converted to the pulsed beam required in the TOF technique. This is most efficiently carried out with the addition of a collisional damping interface between the source and the spectrometer.
On the other hand, pulsed sources, MALDI sources for example, have usually been coupled directly to TOF mass spectrometers, to take advantage of the discrete or pulse nature of the source. TOF mass spectrometers have several advantages over conventional quadrupole or ion tarp mass spectrometers. One advantage is that TOF mass spectrometers can analyze a wider mass-to-charge range than do quadrupole and ion trap mass spectrometers. Another advantage is that TOF mass spectrometers can record all ions simultaneously without scanning, with higher sensitivity than quadrupole and ion trap mass spectrometers. In a quadrupole or other scanning mass spectrometer, only one mass can be transmitted at a time, leading to a duty cycle which may typically be 0.1%, which is low (leading to low sensitivity). A TOF mass spectrometer therefore has a large inherent advantage in sensitivity.
However, TOF mass spectrometers encounter problems with many widely used sources which produce ions with a range of energies and directions. The problems are particularly acute when ions produced by the popular MALDI (matrix-assisted laser desorption/ionization) technique are u~~ed. In this method, photon pulses from a laser strike a target and desorb ions whose masses are measured in the mass spectrometer. The target material is composed of a low concentration of analyte molecules, which, usually exhibit only moderate photon absorption per molecule, embedded in a solid or liquid matrix consisting of small, highly-absorbing species. The sudden influx of energy is absorbed by the matrix molecules, causing them to vaporize and to produce a small supersonic jet of matrix molecules and ions in which the analyte molecules are entrained. During this Ejection process, some of the energy absorbed by the matrix is transferred to the analyte molecules. The analyte molecules are thereby ionized, but without excessive fragmentation, at least in the ideal case.
Because a pulsed laser is normally used, the ions also appear as pulses, facilitating their convenient measurement in a time-of-flight spectrometer. However, the ions acquire a considerable amount of energy in the supersonic jet, with velocities of the order of 700 m/s, and they also may lose energy through collisions with the matrix molecules during acceleration, particularly in high accelerating fields. These and similar effects lead to considerable peak broadening and consequent loss of resolution in a simple linear time-of-flight instrument, where the ions are extracted from the target nearly parallel to the spectrometer axis. A
partial solution to the problem is provided by a reflecting spectrometer, which. partially corrects for the velocity dispersion, but a more effective technique is the use of delayed extraction, either by itself or in combination with ~~ reflector. In delayed extraction, the ions are allowed to drift for a short period before the accelerating voltage is applied. This technique partially decouples the ion production process from the measurement, making the measurement less sensitive to the detailed pattern of ion desorption and acceleration in any particular case. Even so, successful operation requires careful control of the laser fluence (i.e. the amount of power supplied per unit area) and usually some hunting on the target for a favorable spot. Moreover, the extraction conditions required for optimum performance have some mass dependence; this complicates the calibration procedure and means that the complete range of masses cannot be observed with optimum resolution at any given setting. Also, the technique has had limited success in improving the resolution for ions of masses greater than about 20,000 Da and due to the pulsed nature of MALDI ion sources it is difficult to obtain high performance in MS/MS instruments.
Although coupling to a TOF instrument is used as an example above, similar problems arise in coupling MALDI and other pulsed sources to other types of mass spectrometer, such as quadrupole (or other multipole), ion trap, magnetic sector and FTICRMS (Fourier Transform Ion Cyclotron Resonance Mass Spectrometer). Further, it is also desirable to be able to couple MALDI or other pulsed sources to tandem mass spectrometers, e.g. a triple quadrupole or a QqTOF, which allows MS/MS of MALI~I ions to be formed. Standard MALDI instruments cannot be configured to carry out high performance MS/MS. The dispersion in energ~~ and angle of ions produced by a MALDI source, or similar source, acceni:uate the difficulty of ion injection. Also, because the residence times of ions in most other types of mass spectrometer are considerably longer than i:n TOF instruments, the large space charge in the pulse can introduce additional problems. These instruments are all designed to operate with continuous sources, so conversion of the pulsed source to a quasi-continuous one solves most of the problems.
BRIEF SUMMARY OF THE PRESENT INVENTION
Accordingly, it is desirable to provide an apparatus and method enabling a pulse source, such as a MALDI source, to be coupled to a variety of spectrometer instruments, in a manner which more completely decouples the spectrometer from the source and provides a more continuous ion beam with smaller angular and velocity spreads.
More particularly, it is desirable to provide an improved TOF mass spectrometer with a pulsed ion source, in which the energy spread in the ion beam is reduced, in which the source is more completely decoupled from the spectrometer than in existing instruments, in which problems resulting from ion fragmentation are reduced, enabling new types of measurement, and in which the results obtained from the mass spectrometer and its ease of operation are consequently improved.
It is also desirable to provide a TOF mass spectrometer with both continuous and pulsed sources, for example both ESI and MALDI
sourcE~s, so either source can be selected.
In accordance with the present invention, there is provided a mass spectrometer system comprising:
a pulsed ion source, for providing pulses of analyte ions;
a mass spectrometer;
an ion path extending between the ion source and the mass ;>pectrometer; and an ion transmission device located in said ion path and having a damping gas therein for reducing the spatial and energy spread of ions travelling from said ion source to said mass spectrometer.
The invention has particular applicability to time of flight mass spectrometers. As these require a pulsed beam, conventional teaching is that a pulsed source should be coupled maintaining the pulsed chara<aeristics. However, the present inventors have now realised that there are advantages to, in effect converting a pulsed beam into a continuous, or at least quasi-continuous, beam, and than back into a pulsed beam.The advantages are: improvement in beam quality through collisional damping; decoupling of the ion production from the mass measurement; ability to measure the beam current by dingle-ion counting because it is converted from a few large pulses to many small pulses, for examf>le from about 1 Hz. to about 4 kHz., or a factor of 4,000; compatibility with a continuous source , such as ESI, offering the possibility of running both sources on one instrument.
The invention also has applicability to mass spectrometers that work with or require a continuous beam. Then, the advantage is that a pulsed source can indeed be used with such spectrometers.
Preferably, the ion source provides the analyte for ionization by radiation, and wherein there is provided a source of electromagnetic radiation, more preferably a pulsed laser, directed at the ion sourcE~, for generating radiation pulses to cause desorption and ionization of analyte molecules.
Advantageously, the ion source comprises a target material composed of a matrix and analyte molecules in the matrix, the matrix comprising a species adapted to absorb radiation from the radiation source, to promote desorption and ionization of the analyte molecules.
Preferably, the transmission device comprises a multipole rod set.
there can be two or more multipole rod sets and means for supplying different RF and DC voltages to the rod sets.
The mass spectrometer system can include a continuous ion source, and means for selecting one of the pulsed ion source and the continuous ion source, and this then provides the characteristics of two separate instruments in one instrument. The two ion sources can comprise a MA1~DI source and an ESI source.

Another aspect of the present invention provides a method of generating ions and delivering ions to spectrometer, the method comprising:
(1) providing an ion source;
(2) causing the ion source to produce pulses of ions;
(3) providing an ion transmission device along an ion path extending from the ion source, and providing the ion transmission device with a~ damping gas to reduce the spatial and energy spread of ions from the ion source; and (4) passing the ions from the ion transmission device into a spectrometer, for mass analysis.
Preferably, step (3) comprises providing an RF rod set within the transmission device. Further, a DC field can be provided between the ion source and the spectrometer to promote movement of ions towards the spectrometer.
The method can include providing two or more rod sets in the ion transmission device, and operating at least one rod set with a DC
offset to enable selection of ions with a desired mass-to-charge ratio. A
potential difference can be provided between two adjacent rod sets significant to accelerate ions into the downstream rod set, to cause collisionally induced dissociation in to the downstream rod set.
When a pulsed laser is used, for each laser pulse, a plurality of pulses of ions are delivered into the time-of-flight mass spectrometer.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
For a better understanding of the present invention and to show more clearly how it may be carried into effect, reference will now be made, by way of example, to the accompanying drawings, which show preferred embodiments of the present invention and in which:
Figure 1 shows a block diagram of a mass spectrometer system;

Figure 2 is a schematic diagram showing a MALDI-TOF
mass spectrometer with orthogonal injection of the MALDI ions into the spectrometer through a collisional damping interface (quadrupole ion guide) according to the present invention;
Figure 3 shows a mass spectrum of a mixture of several peptides and proteins leucine-enkephalin-Arg (Le-R), substance P (Sub P), melittin (ME), CD4 fragment 25-58 (CD4), and insulin (INS) ) produced in the spectrometer of Figure 2;
Figure 4 shows plots of transit times through the interface for different ions;
Figure 5 shows a mass spectrum of substance P;
Figure 6 shows a mass spectrum of a tryptic digestion of citrate synthase;
Figure 7A shows a schematic of part of spectrometer of Figure 2, showing the collisional interface and indicating applied voltages;
Figures 7B, 7C and 7D show different operating regimes of the m;~ss spectrometer of Figure 2;
Figures 8A, 8B, 8C, and 8D are mass spectra obtained from substance P recorded in the different operation regimes, according to Figures 7B, 7C, and 7D;
Figure 9 shows the behaviour of the ion current from a single target spot as a function of time; and Figure 10 shows schematically combined ESI and MALDI
sources for a mass spectrometer.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The first embodiment shown in Figure 1 is a block diagrarn of a general mass spectrometer system. Here 1 represents any sort of puh,ed ion source (for instance MALDI), 2 is a collisional focusing chambE~r or region filled with a buffer gas and with a multipole 3 driven at some RF voltage. This is followed by an optional manipulation stage 4 and then a :mass analyzer 5. The collisional ion guide 3, in accordance with the -g_ present invention, spreads the pulsed ion beam in time, and improves its beam quality (i.e. space and velocity distributions) by damping the initial velocity and focusing the ions toward the central axis. The beam is then quasi-c~~ntinuous and may enter an optional manipulation stage 4, where ions ca.n be subjected to any sort of further manipulation. Finally the resultalit ions are analyzed in the mass analyzer 5.
A simple example of further manipulation in stage 4 is dissoci<~tion of the ions by collisions in a gas cell, so that the resulting daughter ions can be examined in the mass analyzer. This may be adequate to determine the molecular structure of a pure analyte. If the analyte is a complex mixture, stage 4 needs to be more complicated. In a triple quadrupole or a QqTOF instrument (as disclosed in A. Shevchenko et al, Rapid (~ommun. Mass Spectrom. 11, 1015, (1997)), stage 4 would include a quadrupole mass filter for selection of a parent ion of interest and a quadrupole collision cell for decomposition of that ion by collision-induced dissociation (CID). Both parent and daughter ions are then analyzed in section 5, which is a quadrupole mass filter in the triple quadrupole, or a TOF spectrometer with orthogonal injection in the QqTOF instrument. In both cases stages 1 and 2 would consist of a pulsed source and a collisional damping ion guide.
It will be appreciated that the collisional focusing chamber 2 is shown with a multipole rod set 3, which could be any suitable rod set, e.g. a quadrupole, hexapole or octopole. The particular rod set selected will depend upon the function to be provided.
Figure 2 shows a preferred embodiment of a MALDI-TOF
mass spectrometer 10 according to the present invention. The spectrometer 10 includes a conventional MALDI target probe 11, a shaft seal chamber 12, pumped in known manner, and a target installed in the target-holding electrode 13. A mixture of the sample to be investigated and a suitable matrix are applied to the sample probe following the usual procedure for preparing MALDI targets. A pulsed laser 14 is focused on the target surface 15 by lens 16, and is run at a repetition rate of some tens of pulses per second,, more specifically at a rate of 13 Hz. An inlet 18 is provided for nitrogen or other neutral gas. Each laser shot produces a plume of neutral and charged molecules. Ions of the sample analyte are produced and entrained in the plume which expands into vacuum chamber 30, which contains two quadrupole rod sets 31 and 32. Chamber 30 is pumped by a pump (not shown) connected to port 34 to about 70 mTorr but the pressure can be varied over a substantial range by adjusting the flow of gas through a controllLed leak valve 18. Lower pressures could be used, and an important characteristic is the product of pressure and rod length. Thus, a total length x pressure value of 22.5 mTorr-cm could be used, as in U.S. patent 4,963,736.
The ga;s in chamber 30 (typically nitrogen or argon or other suitable gas, preferable an inert gas) will be referred to as a damping gas or cooling gas or buffer g;as.
In the embodiment tested, the quadrupole rod sets 31 and 32 were made of rods 4.45 cm in length and 11 mm in diameter, and were separated by 3 mm, i.e. the spacing between rods on adjacent corners of the rod set. The quadrupoles 31 and 32 are driven by a power supply which providE~s operating sine wave frequencies from 50 to 2 MHz, and output voltages from 0 to 1000 volts peak-to-peak. Typical frequencies are 200 kHz to 1 Mlaz, and typical voltage amplitudes are 100 to 1000 V peak-to-peak.
Both guadrupoles are driven by the same power supply through a transformer with two secondary coils. Different amplitudes may be applied to the quadrupoles by using a different number of turns in the two secondary coils. D.C. Bias or offset potentials are applied to the rods of quadrupoles 31 and 32 and to the various other components by a multiple-output power supply. The RF quadrupoles 31 and 32, with the damping gas between their rods can be run in an RF-only mode, in which case they serve to reduce the axial energy, the radial energy, and the energy spreads., of the ions which pass through it, as will be described. This process substantially spreads the plume of ions out along the ion path, changing the initial beam, pulsed at about 13 Hz, into a quasi-continuous beam as described in more detail below. The first quadrupole 31, can also be run in a mass-filtering mode by the application of a suitable DC voltage. The second quadrupole 32 can then be used as a collision cell (and an RF-guide) in collision-induced dissociation experiments (see below).
From chamber 30, the ions pass along an ion path 27 and through a focusing electrode 19 and then pass through orifice 38, into a vacuum chamber 40 pumped by a pump (not shown) connected to a port 42.
There, ithe ions are focused by grids 44 through a slot 46 into an ion storage region ~I8 of a TOF spectrometer generally indicated at 50.
In known manner, ions are extracted from the storage region 48 and are accelerated through a conventional accelerating column 51 whir_h accelerates the ions to an energy of approximately 4000 electron volts per charge (4 keV). The ions travel in a direction generally orthogonal to the ion path 27 between the ion storage region, through a pair of deflection plates 52. The deflection plates 52 can serve to adjust the ion trajectories, so that the ions are then directed toward a conventional electrostatic ion mirror 54, which reflects the ions to a detector 56 at which the ions are detected. The ions are detected using single-ion counting and recorded with a time-to-digital converter (TDC). The accelerating column 51, plates 52, mirror 54 and detector 56 are contained in a main TOF
chamber 58 pumped to about 2 x 10-~ Torr by a pump (not shown) connected to a port 60.
The use of orthogonal-injection of MALDI ions from source 13 into the TOF spectrometer 50 has some potential advantages over the usual axial injection geometry. It serves to decouple the ion production process from the mass measurement to a greater extent than is possible in the usual delayed-extraction MALDI. This means that there is greater freedom to vary the target conditions without affecting the mass spectrum, and they plume of ions has more time to expand and cool before the electric field is applied to inject them into the spectrometer. Some improvement in performance might also be expected because the largest spread in velocities is along the ejection axis, i.e. the ion path 27, normal to the target, which in this cage is orthogonal to the TOF axis. However, orthogonal injection of MALD1 ions into the TOF 50 without collisional cooling has several problems which appear to make the geometry impractical, namely:
(1) The radial energy distribution, while much smaller than th.e axial energy is still sufficient to cause substantial spreading and expansion of the beam as it leaves the quadrupole rod set 32 and travels toward the TOF axis. The spatial spread of the beam along the TOF axis limits the resolution. The effect can be reduced with collimation but only at a significant sacrifice in sensitivity; a collimating slit must be placed sufficiently far from the TOF axis to avoid distorting the extraction field, and so the target must be placed far enough from the collimation slit to produce a reasonably parallel beam;
(2) The axial velocity of the ions, i.e. velocity along the ion path 27, in the plume is largely independent of mass which means the energy is mass dependent. Since the axial energy determines the direction of the trajjectory after acceleration into the TOF spectrometer, instrumental acceptance (or acceptance by the TOF spectrometer) is mass dependent; i.e.
there is mass discrimination. The same effect is observed when ESI ions are injected without collisional cooling as explained in detail in the prior application mentioned above; and (3) The width of the axial energy distribution is comparable in magnitude with the axial energy itself, so the beam spreads out along its axis by an amount comparable to the separation between the target and the TOF axis. The size of the aperture which admits ions from the storage region into the spectrometer must clearly be much smaller than this to maintain a uniform extraction field, particularly if a slit is placed between the target and the TOF axis. This further reduces the sensitivity.
In delayed extraction MALDI in the usual axial geometry, i.e. not the orthogonal configuration shown, acceptance is nearly complete, and while the largest velocity spread is along the TOF axis, the well-defined target-ylane perpendicular to the TOF axis allows a combination of time-lag focusing (delayed extraction with optimized values of delay and applied voltage) and electrostatic focusing (optimized value of the reflector voltage) in an ion mirror to produce resolution well above 10,000 in some cases.
Experiments carried out by the present inventors suggest that competitive resolution could not be obtained with an acceptable signal using orthogonal injection, unless collisional cooling according to the present invention is employed. Moreover, some disadvantages of delayed-extraction MALDI -- the dependence of optimum extraction conditions on mass, and the more complex calibration required -- are still present in orthogonal injection MALDI without cooling although to a lesser extent i:han with axial injection.
The introduction of an RF quadrupole or other multipole with collisional cooling of the ions between the MALDI target and the orthogonal injection geometry avoids the problems described above while offering additional advantages. These are detailed below with reference to the remaining figures.
By reducing the radial energies of the ions, an approximately parallel beam can be produced, greatly reducing the losses that re~~ult from collimation before the ions enter the storage region. This allows the use of a larger entrance aperture to the TOF spectrometer 50, further reducing losses. By reducing the axial energies of the ions, and then reaccel,erating them to a uniform energy, the mass discrimination mentioned above is not present.
The uniform energy distributions of the ions after cooling remove any mass dependence on the optimum extraction conditions and allow tlhe simple quadratic relation between TOF and mass to be used for calibration with two calibrant peaks. Figure 3 shows a spectrum of an equimolar mixture of several peptides and proteins from mass 726 to 5734 Da in an a-cyano-4-hydroxy cinnamic acid matrix. The spectrum was acquired in a single run and shows uniform mass resolution (M/~M~HM) of about 5000 throughout the mass range. Using a simple external calibration with substance P and melittin, the mass determination for each of the molecular ions is accurate within about 30 ppm. Here, the peaks for the various substances are identified as: peak 60 for Leucine-enkephalin;

peak 61 for substance P; peak 62 for Melittin; peak 63 for CD fragment 25-28;
and peak 64 for insulin. All peaks are identified both on the overall spectrum and as an enlarged partial spectrum. The resolution demon;~trated in Figure 3 is rather close to the resolution obtainable with the same instrument using an ESI source. In the present embodiment, the entrance orifice was made slightly larger than normally used in ESI, approximately 1 mm diameter as compared to a normal diameter of around 1 /3 mrn, to make adjustments easier in the preliminary experiments. This does not appear to have been necessary so it is reasonable to expect improved resolution is expected if a smaller orifice is used. Resolution up to 10,000 has been obtained with ESI ions in the same instrument.
The decreasing relative intensity of the molecular ions with mass is to some extent a reflection of the decreasing detection efficiency with increasing mass. Detection efficiency depends strongly on velocity, which decreases with mass for singly-charged ions at a given energy. In this embodiment the energy of singly-charged ions is only about 5 keV (compared to 30 keV in typical MALDI experiments), so the detection efficiency limits the practical range of application to less than about 6000 Da.
The relative intensities of the molecular ion peaks in Fig. 3 is consistent with that observed from the same sample when analyzed in a conventional MALDI experiment using 5 kV acceleration. The detection efficiency in the present embodiment can be increased by increasing the voltage which accelerates the ions into the spectrometer, or by increasing the voltage on the detE~ctor.
As mentioned above, the collisional cooling spreads the ions out along the ion beam axis changing the initial beam pulsed at 13 Hz into a duasi-continuous beam. This is illustrated in Figure 4 which shows the count rate as a function of time after the laser pulse; i.e. the distribution of transit times through the spectrometer. The width of the time distribution is on the order of 20 ms which represents an increase in the time spread by a factor of at least 10~ as each laser pulse is about 2 ns long.
Dispersion along the axis is a disadvantage in orthogonal-injection MALDI

without cooling, but with the present invention, since optimum extraction conditions do not depend on the time delay after the laser shot, multiple injection pulses into the TOF storage region 48 can be used for each laser shot. In the present embodiment, 256 injection pulses into the TOF storage region ~I8 were used for every laser shot. The losses are then determined by the duty cycle of the instrument which in this case is about 20%. The duty cycle is the percentage of the time that ions can be injected from the storage region into the TOF spectrometer; here, it effectively means the fraction of the tirrte, the TOF storage region 48 is available to accept ions. A
quasi-continuous beam is in fact an advantage in this mode of operation.
Approximately 104 to 106 ions are ejected from the target probe with every laser shot at a repetition rate of 13 Hz, but as a result of spreading along the beam axis or ion path 27 (and some losses) approximately 2 to 5 ions are injected into the instrument with every injection pulse less than one ion on average of a particular species. This allows single-ion counting to be used with a TDC (Time to Digital Converter), which makes the combination of high timing resolution (0.5 ns) and high repetition rate (essential for maximum duty cycle) technically much simpler than using a transient recorder which is necessary in conventional MALDI experiments. In addition, the use of single-ion counting eliminates problems with detector shadowing from intense matrix peaks, and problems with peak saturation which require attention in conventional MALDI because of the strong dependence of the signal on laser fluence and the shot-to-shot variation.
Finally, single-ion counting places much more modest demands on the detector and amplifier time resolution because the electronic reduction and digitization of the pulse is quite insensitive to the detector pulse shape.
In Figure 4, four graphs are shown of the count rate against time, for leucine-enkephalin shown at 70, substance P shown at 72, Melittin shown at 74 and insulin shown at 76. Additionally, for each of these substances, graphs or spectra 71, 73, 75 and 77, are inserted showing normal TOF spectra, similar to Figure 3.
Assuming 104 ions of a single molecular ion species are produced with each laser shot, the transmission efficiency of the RF-quadrupole is in the range of 10 %. Taking account of the duty cycle, about ;? % of the ions produced at the target are detected in the mass spectrometer. This represents significant losses compared to the conventional axial MALDI experiment in which transmission is probably 50% or more. However, from the point of view of data rate, the losses can be compensated to a large extent by the higher repetition rate and higher fluence of the laser. In these experiments, the repetition rate was 13 Hz, but can easily be increased to 20 Hz with the current laser, or in principle up to at least 100 Hz before the counting system becomes saturated. In contrast, the usual MALDI experiment is run at about 1 or 2 Hz. The laser fluence in a conventional MALDI experiment must be kept close to threshold to achieve the best performance, the threshold being the energy necessary to cause vaporization of the sample. In the present invention, the laser fluence can be increased to the fluence at which the ion production process saturates. As the quadrupole serves to smooth out the ion burst produced by the laser, a short intense burst of ions can be accepted. From the point of view of absolute sensitivity, it seems that the independence of the spectrum on laser conditions (see below) allows more efficient usage of the sample deposited on the target. Using fluence several times higher than threshold produces ions until the matrix is completely removed from the target probe.
Figure 5 shows that the practical sensitivity achieved with substance P is in the sane range as that obtainable with conventional MALDI. Five femtom.oles of substance P were applied to the target using 4HCCA as the matrix. The left hand side of the spectrum is indicated at 80, and the right hand side is shown enlarged by a factor of 44 as indicated at 81. A portion of this spectrum is shown enlarged at 82 showing the molecular ion (MH+) .
Figure 6 shows the spectrum 85 obtained from a tryptic digest of citrate synthase again showing the uniform mass resolution over the mass range; the inset 8b shows the spectrum obtained from 20 (moles applied to the target.
These results indicate that the performance of the inventi~~n for peptides is comparable to conventional MALDI experiments but wii:h the advantage of a mass-independent calibration, and a simple calibration procedure. However, the most important advantages result from the nearly complete decoupling of the ion production from the mass measurement. In a conventional MALDI experiment, the location of the laser s~~ot on the target and the laser fluence and location must be carefully selected for optimum performance, and these conditions are typically different for different matrices and even for different target preparation methodLs. The situation was improved with the introduction of delayed extraction but even so, many commercial instruments have implemented software to adjust laser fluence, detector gain, and laser position, and to reject shots in which saturation occurs. None of these techniques are necessary with the present invention.The performance obtained shows no dependence on target or laser conditions. The laser is simply set to maximum fluence (several times the usual threshold) and left while the target i;> moved to a fresh position occasionally. This means that alternative targets can easily be tried (including insulating targets), and alternative lasers with different wavelengths or pulse widths can be used.
The decoupling of the ion production from the mass measurement also provides an opportunity to perform various manipulations of the ions after ejection but before mass measurement. One example is parent ion selection and subsequent fragmentation (MS/MS).
This is most suitably done with an additional quadrupole mass filter as described below, but even in the present embodiment of Figure 2, some selectivity and fragmentation is possible.
Figures 7A, 7B and 7C show three different modes of operation of the instrument shown in Figure 2. The reference numerals of Figure 2 are provided along the z axis to indicate correspondence between potential level and the different elements of the apparatus. Voltages for the quadru~pole sections 31, 32 are indicated respectively at Ul (t) and U2 (t).
Figure 7A shows the simple collisional ion guide mode that was used in obtaining the results shown in Figures 4-6. Here the same amplitudes of RF voltage and no DC offset voltages are applied to different sections of the quadrupole. Potential differences in the longitudinal direction are kept small to minimize fragmentation due to CID.
Figure 7B shows a mass filtering mode, which is analogous to the same filtering mode implemented in conventional quadrupole mass filters. Here a DC offset voltage V is added to the first section of the quadrupole to select an ion of interest, while the second section again acts as an ordinary ion guide since there is no CID because of the smell potential difference between the sections. The amplitude of the voltage applied in the second quadrupole section 32 is only one third of the voltage applied in the first section 31.
Figure 7C is an MS-MS mode which differs from the mode of Figure 7B by a higher potential difference between the quadrupole sections> 31, 32, so ions are accelerated in that region and enter the second section with high kinetic energy, the additional energy being indicated as 0 collision energy. In that case the second section acts as an collision cell and parent ions are decomposed there by collisions with the buffer gas (CID).
Again, the amplitude of the RF voltage in the second section is only one third oi= the amplitude of the RF voltage in the first section, which allows daughter ions much lighter than the parent ions to have stable trajectories and to he transmitted through the second quadrupole.
Figure 8 shows examples of the spectra obtained in the different modes illustrated in Figure 7, and in particular gives an example of possible beam manipulation. All the spectra were acquired using the same initial sample.
Figure 8A is a mass spectrum where ions were cooled in a collisional focusing ion guide (the mode of Figure 7A).
Figure 8B is an example where ions of interest were selectedL in the first quadrupole 31 and cooled in the second quadrupole 32 section (the mode of Figure 7B). Once ions of interest have been selected, they can be used for fragmentation in CID to obtain detailed information on composition and structure.

Figure 8C presents an MS/MS spectrum of substance P
obtained in this way. Molecular ions if substance P are selected in the first quadrupole section and fragmented by collisions in the second quadrupole section (according to the mode of Figure 7C). The potential difference, 0 collision energy, between the first and second quadrupoles was 100V. The intensities of the fragment ions were small in comparison with intensity of the primary ion so the region inside dotted lines is expanded by a factor of 56. Figure 8B shows the spectrum obtained in the same mode but where the potenti~~l difference between the quadrupoles 31, 32 was 150 V. In this case, more fragment ions are observed and the parent ion peak is substantially reduced.
Figure 9 shows how long a signal from the same spot on a MALDI: target can last. In this experiment, a given spot was irradiated by a series of shots from the laser, running at 13 Hz. The laser intensity was two or three times the "threshold" intensity. On average the sample lasted for about one minute. The shape of the curve suggests that the laser shots dig deeper and deeper into the sample until it is exhausted. At that point the laser irradiates the metallic substate, so no signal is observed.
In the past it has not been possible to use both continuous sources, such as electrospray ionization (ESI), and pulsed sources, such as MALDI, in the same instrument, which would have significant advantages.
To the inventor's knowledge, the only successful ESI-TOF instruments to date have been the orthogonal injection spectrometers (by the present inventors, Dodonov, and now the commercial PerSeptive machines), so it appear; that orthogonal injection is necessary for ESI-TOF, with or without collisional damping, although the former improves the situation, as detailed in the earlier application. Up to now, the only attempts to put MALDI_ on an orthogonal injection instrument have been made by the present inventors (first) and Guilhaus, both without collisional damping and neither giving very promising results. The present invention enables two such sources to be available in one instrument. Here, the MALDI probe 11 in Figure 2 can be replaced by an ESI source to enable measurement of ESI

spectra in the instrument. The instrument would then be essentially the same as the one illustrated in the earlier patent application noted above.
This change could of course be carried out by actually taking off one source and replacing it by the other, but a number of more convenient arrangements can be provided.
For instance Figure 10 shows a further embodiment where i:he electrospray ion source 94 is attached to the input of a collisional damping interface 92, including a quadrupole, or other multipole, rod set 93. A MALDI ion source 94 is introduced on a probe 95 that enters from the side, arid can be displaced in and out; for this purpose, a shaft end 96 is slidingly and sealingly fitted into the housing of the collisional interface 92.
The M~~LDI ion source 94 is similar to the one shown in Figure 2 except in this case the sample is deposited onto a flat surface machined on the side of the probe shaft 95, instead of onto the end of a cylindrical probe. The sample is irradiated by a laser with corresponding optics, generally indicatE~d at 97, and ions are transmitted to a spectrometer indicated at 98.
When the ESI source is operating, shaft 96 is pulled out far enough to clear the path of the ESI ions. When the MALDI ion source 94 is operating the shaft 96 is inserted back so the MALDI target 94 is in the central position.
Presently, MALDI and ESI techniques are often considered to be complementary methods for biochemical analysis, so many biochennical or pharmaceutical laboratories have two instruments in use.
Obviously there are significant benefits of combining both ion sources in one instrument, as in the embodiments above. In particular, the cost of a combined instrument is expected to be little more than half the cost of two separai:e instruments. In addition. similar procedures for ion manipulation, detection and mass calibration could be used, since the ion production is largely decoupled from the ion measurement. This would simplify the analysis and processing of the separate spectra and their comparison.
The ability the use both MALDI and ESI sources on a single instrument is not restricted to the spectrometer shown in Figure 1, but is applicable to any mass spectrometer with a collisional damping interface. In particular it is applicable to the QqTOF instrument discussed above.
While specific embodiments of the invention have been described, it will be appreciated that a number of variations are possible within the scope of the present invention. Thus, the apparatus could include a single multipole rod set as shown in Figure 1, or two rod sets as shown in Figure 2. While quadrupole rod sets are preferred, other rod sets, such as hexapole and octopole are possible, and the rod set can be selected based on the known characteristics of the different rod sets. Additionally, it is possible that three or more rod sets could be provided. Further, while Figure :? shows the two rod sets, 31 and 32 provided in a common chamber, the rod sets could, in known manner, be provided in separate chambers operating at different pressures, to enable different operations to be preformed. Thus, to perform conventional mass selection, there could be one chamber operating at a very low pressure so that there is little or no collisional activity between the ions and the damping gas. Further, the pressure of the gas could be varied, between different chambers, to meet the requirements for collisional damping, where a relatively large number of collisions are desired as opposed to collision induced fragmentation, where excessi~Te collisions are not desirable.

Claims (22)

1. A mass spectrometer system comprising:
a pulsed ion source, for providing pulses of analyte ions;
a mass spectrometer;
an ion path extending between the ion source and the mass spectrometer; and an ion transmission device located in said ion path and having a damping gas, whereby there is effected at least one of: a reduction in the energy spread of ions emitted from said ion source; conversion of pulses of ions from the ion source into a quasi-continuous beam of ions; at least partial suppression of unwanted fragmentation of analyte ions; and spreading ions spatially and temporally along the ion path, whereby peak current and space charge effects are reduced.
2. A mass spectrometer system as claimed in claim 1, wherein the ion source provides the analyte for ionization by radiation, and wherein there is provided a source of electromagnetic radiation directed at the ion source, for generating radiation pulses to cause desorption and ionization of analyte molecules.
3. A mass spectrometer system as claimed in claim 2, wherein the radiation source comprises a laser.
4. A mass spectrometer system as claimed in claim 3, wherein the laser comprises a pulsed laser, for producing laser pulses at a fixed frequency.
5. A mass spectrometer system as claimed in claim 4, wherein the ion source comprises a target material composed of a matrix and analyte molecules in the matrix, the matrix comprising a species adapted to absorb radiation from the radiation source, to promote desorption and ionization of the analyte molecules.
6. A mass spectrometer system as claimed in claim 1, wherein the transmission device comprises a multiple rod set.
7. A mass spectrometer system as claimed in claim 6, which includes two or more mulitpole rod sets and means for supplying different RF and DC
voltages to the rod sets.
8. A mass spectrometer as claimed in any one of claims 1 to 7, wherein the spectrometer comprises one of a time-of flight spectrometer, a quadrupole spectrometer, an ion trap spectrometer, a magnetic sector spectrometer and a Fourier transform mass spectrometer.
9. A mass spectrometer as claimed in claim 1, which additionally includes a continuous ion source, and means for selecting one of the pulsed ion source and the continuous ion source.
10. A method of generating ions and delivering ions to a mass spectrometer, the method comprising:
(1) providing an ion source;
(2) causing the ion source to produce pulses of ions;
(3) providing an ion transmission device along an ion path extending from the ion source and providing the ion transmission device with a damping gas, to effect at least one of: a reduction in the energy spread of ions emitted from said ion source; conversion of pulse of ions from the ion source into a quasi-continuous beam of ions; and at least partial suppression of unwanted fragmentation of analyte ions; and (4) passing the ions from the ion transmission device into the mass spectrometer for mass analysis.
11. A method as claimed in claim 10, wherein step (2) comprises radiating the ion source with pulses of radiation.
12. A method as claimed in claim 11, wherein step (2) comprises radiating the ion source with pulses of radiation from a laser source.
13. A method as claimed in claim 12, which comprises providing the ion source comprising a matrix of a material consisting of small molecules strongly absorbent of the radiation and an analyte, whereby radiation of the ion source causes desorption and vaporization of the matrix, thereby promoting vaporization and ionization of the analyte molecules.
14. A method as claimed in claim 10, wherein step (3) comprises providing an RF rod set within the transmission device.
15. A method as claimed in claim 14, which comprises providing a DC field between the ion source and the spectrometer to promote movement of ions towards the spectrometer.
16. A method as claimed in claim 15, which comprises providing two or more rod sets in the ion transmission device.
17. A method as claimed in claim 16, which comprises operating at least one rod set with a DC offset to enable selection of ions with a desired mass-to-charge ratio.
18. A method as claimed in claim 17, which includes providing a potential difference between two adjacent rod sets significant to accelerate ions into the downstream rod set, to cause collisionally induced dissocation into a downstream rod set.
19. A method as claimed in claim 18, wherein step (4) comprises analyzing the ions in a time-of flight mass spectrometer.
20. A method as claimed in claim 19, wherein, for each laser pulse, a plurality of pulses of ions are delivered into the time-of-flight mass spectrometer.
21. A method as claimed in claim 20, which comprises providing two or more ions sources, and selecting one ion source to provide ions.
22. A method as claimed in claim 21, which comprises providing a matrix-assisted laser desorption/ionization source and an electrospray ionization source.
CA002227806A 1998-01-23 1998-01-23 Spectrometer provided with pulsed ion source and transmission device to damp ion motion and method of use Expired - Lifetime CA2227806C (en)

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CA002227806A CA2227806C (en) 1998-01-23 1998-01-23 Spectrometer provided with pulsed ion source and transmission device to damp ion motion and method of use
DK99900849.3T DK1050061T4 (en) 1998-01-23 1999-01-25 Spectrometer equipped with a pulsed ion source and the transmission device for the damping of ion motion and method of use thereof
AU20428/99A AU745866B2 (en) 1998-01-23 1999-01-25 Spectrometer provided with pulsed ion source and transmission device to damp ion motion and method of use
AT99900849T AT273561T (en) 1998-01-23 1999-01-25 Spectrometer with a pulsed ion source, coupling device for damping of ion motion, and method for use thereof
EP99900849.3A EP1050061B2 (en) 1998-01-23 1999-01-25 Spectrometer provided with pulsed ion source and transmission device to damp ion motion and method of use
PCT/CA1999/000034 WO1999038185A2 (en) 1998-01-23 1999-01-25 Spectrometer provided with pulsed ion source and transmission device to damp ion motion and method of use
DE69919325.7T DE69919325T3 (en) 1998-01-23 1999-01-25 Spectrometer with a pulsed ion source, coupling device for damping of ion motion and method of using same
DE1050061T DE1050061T1 (en) 1998-01-23 1999-01-25 Spectrometer with a pulsed ion source, kopplungsvorrichting for damping of ion motion, and method for use thereof
JP2000528992A JP4331398B2 (en) 1998-01-23 1999-01-25 Spectrometer and methods of use thereof with a transport device for braking the pulsed ion source and the ion motion
US09/989,882 US6680475B2 (en) 1998-01-23 2001-11-21 Spectrometer provided with pulsed ion source and transmission device to damp ion motion and method of use
US10/236,514 USRE39099E1 (en) 1998-01-23 2002-09-06 Spectrometer provided with pulsed ion source and transmission device to damp ion motion and method of use
US10/758,511 US6833543B2 (en) 1998-01-23 2004-01-15 Spectrometer provided with pulsed ion source and transmission device to damp ion motion and method of use
US10/919,859 US7189963B2 (en) 1998-01-23 2004-08-17 Spectrometer provided with pulsed ion source and transmission device to damp ion motion and method of use

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