WO1999001889A1 - Nouveau spectrometre de masse - Google Patents

Nouveau spectrometre de masse Download PDF

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Publication number
WO1999001889A1
WO1999001889A1 PCT/US1998/013545 US9813545W WO9901889A1 WO 1999001889 A1 WO1999001889 A1 WO 1999001889A1 US 9813545 W US9813545 W US 9813545W WO 9901889 A1 WO9901889 A1 WO 9901889A1
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WO
WIPO (PCT)
Prior art keywords
tof
ion
path
pusher
time
Prior art date
Application number
PCT/US1998/013545
Other languages
English (en)
Inventor
Cornelis E. C. A. Hop
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU82747/98A priority Critical patent/AU8274798A/en
Publication of WO1999001889A1 publication Critical patent/WO1999001889A1/fr

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Classifications

    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/26—Mass spectrometers or separator tubes
    • H01J49/34—Dynamic spectrometers
    • H01J49/40—Time-of-flight spectrometers
    • H01J49/401—Time-of-flight spectrometers characterised by orthogonal acceleration, e.g. focusing or selecting the ions, pusher electrode
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/004—Combinations of spectrometers, tandem spectrometers, e.g. MS/MS, MSn

Definitions

  • This invention relates to a tandem mass spectrometry system based on principles of analysis by time-of flight.
  • the object is to indentify which molecules are present in a sample.
  • the molecular weight of a molecule may be readily measured by ionizing the molecule and providing it with a fixed amount of kinetic energy and measuring the time it takes for molecules to travel a fixed distance (time-of-flight).
  • time-of-flight a number of different molecules may have the same molecular weight and these can be distinguished from one another by dissociation and analysis of the molecular weight of the fragments that are produced.
  • tandem mass spectrometry with the highest sensitivities, complex biological and other molecules and complex mixtures of molecules.
  • mass spectrometers have come a long way in accommodating scientists to get better quality data in a shorter period of time.
  • biochemistry in particular analysis of peptides, proteins and oligonucleotides.
  • the technical requirements for mass spectrometers in order to meet the biochemical demand include high sensitivity, high scan speed, good mass accuracy, ease of use, and the ability to obtain structural information.
  • MS/MS Tandem Mass Spectrometry
  • a mass-selected ion beam (referred to as the parent ion beam) produced by a first mass analyzer is dissociated into a plurality of fragment ions.
  • the fragment ions are then subjected to a second stage of mass analysis, allowing molecular weight quantification of the various fragment ions. This information can be used to determine the structure of the parent ions.
  • triple quadrupole (QQQ) mass spectrometers are the most common mass spectrometers in the biochemical community, they lack in scan speed and mass accuracy. Due to the relatively low scan speed it is difficult to interface a triple quadrupole mass spectrometer with capillary electrophoresis (CE) and capillary electrochromatography (CEC) equipment.
  • CE capillary electrophoresis
  • CEC capillary electrochromatography
  • Quadrupole Time-Of-Flight (Q-TOF) mass spectrometer is an improvement over the triple quadrupole mass spectrometer.
  • This instrument has an electrospray or atomospheric pressure chemical ionization (APCI) source interfaced to a quadrupole mass filter followed by a hexapole gas cell and an orthogonal time-of-flight (TOF) mass spectrometer.
  • APCI electrospray or atomospheric pressure chemical ionization
  • TOF orthogonal time-of-flight
  • MS mode the quadrupole mass filter operates in the RF (radio frequency) oniy mode and acts as a wide bandpass device. All ions are mass analyzed by .the time-of-flight mass spectrometer.
  • the quadrupole is used to mass-select the ions of interest.
  • these ions are collisionally dissociated in the gas cell and the fragment ions are mass-analyzed with the TOF section.
  • This instrument has shown exceptional sensitivity in the MS and MS/MS mode especially in combination with nanoflow electrospray.
  • the increase in sensitivity (about a factor of 30-50 compared to triple quadrupole mass spectrometers) can be ascribed to the fact that all the ions in the spectrum are detected simultaneously, whereas with magnetic sector and quadrupole mass spectrometers the ions are detected consecutively according to their molecular weight-to-charge ratio (only one m/z ratio is detected at a time and all others are discarded).
  • the scan speed of the Q-TOF allows optimum use of the separation generated by CE equipment.
  • TOF-MS 1 The first part (TOF-MS 1) is an ion source interfaced with an orthogonal TOF mass spectrometer- 1.
  • the ions are orthogonally accelerated to a relatively high voltage, e.g. from about 1 keV to about 7 keV, preferably from about 2 to about 4 keV.
  • the ions from the first part are then transferred to an orthogonal TOF mass spectrometer-2 wherein the ions are orthogonally accelerated to a high voltage, e.g. from about 25 keV to about 50 keV, preferably from about 29 to about 35 keV.
  • a high voltage e.g. from about 25 keV to about 50 keV, preferably from about 29 to about 35 keV.
  • the resolution obtained after passing through the reflector can reach more than 5,000 (full- width at half maximum definition) with an effective path-length of three or less meters.
  • This invention is also concerned with an orthogonal tandem TOF mass spectrometer that provides high energy CID which results in a broader range of fragmentation pathways than low energy CID, as well as high sensitivity, mass accuracy, and resolution.
  • This invention is further concerned with an orthogonal tandem TOF mass spectrometer that is easy to manufacture and provides a small size footprint.
  • FIG. 1 Describes a tandem TOF/TOF mass spectrometer which contains two TOF-MS's, TOF-MS 1 and TOF-MS 2.
  • the novel orthogonal tandem TOF/TOF mass spectrometer (20) comprises an ion source (11), a first and second detector (16) and (16a), two time- of-flight analyzers (12) and (12a) each containing reflectors (12b), a first and second pusher (10) and (10a), an ion excitation device (13), and an electronic means for measuring the time-of-flight from the source to the detector, the point between the ion source (11) and the first detector (16) is referred to as TOF-MS 1 and the point between the second pusher (10a) and the second detector is referred to as TOF-MS 2, said first analyzer (12) is positioned between the ion source and the first detector, said second analyzer (12a) is positioned between the second pusher (10a) and the second detector (16a) in such a way that the ion path is orthogonal relative to the path of TOF-MS 1, said orthogonal ion path is controlled by pusher (10a
  • novel orthogonal tandem TOF/TOF mass spectrometer (20) optionally comprises a pulse deflection unit (17) positioned after the first time of flight analyzer (12) and before the excitation device (13) and is used when the sample is a mixture to mass select a particular ion prior to excitation.
  • the mass spectrometer (20) comprises suitable transfer optics (18) to assist in directing the path of the ions, said transfer optics (18) being located in close proximity to the ion source and second pusher.
  • the design of the transfer optics will take account of the need to prevent excessive temporal pulse spreading, thereby maintaining high resolution in the TOF-MS's l and 2.
  • the invention can be said to comprise a method of orthogonal tandem TOFTOF mass spectrometry comprising forming an ion flow along a path from an ion source (11), directing the path orthogonally relative to the ion source and accelerating it via a first pusher device [high voltage electrode at about 1-7 keV, preferably 2-4 keV] (10) through a first time-of-flight analyzer (12) to an excitation device (13), the point between the ion source and the excitation device being referred to as TOF-MS 1 , then accelerating the ion path (parent & fragment ions) orthogonally, relative to TOF-MS 1, to an energy (from about 20 to about 50 keV, preferably 25-40 keV) much higher than the acceleration employed with the first pursher (10) using a second pusher (10a), sending the ion path through a second time-of-flight analyzer (12a) to a second detector (16a), and detecting ions at the detector including measurement
  • the invention can be said to comprise a method of orthogonal tandem TOFTOF mass spectrometry comprising forming an ion flow along a path from an ion source (11), directing the path orthogonally relative to the ion source and accelerating it via a first pusher device [high voltage electrode at about 1-7 keV, preferably 2-4 keV] (10) through a first time-of-flight analyzer (12) to a pulse deflection unit (17) then to an excitation device (13), the point between the ion source and the excitation device being referred to as TOF-MS 1, then accelerating the ion path (parent & fragment ions) orthogonally, relative to TOF-MS 1 , to an energy (from about 20 to about 50 keV, preferably 25-40 keV) much higher than the acceleration employed with the first pursher (10) using a second pusher (10a), sending the ion path through a second time-of-flight analyzer (12a) to a second detector (16a
  • the means of producing ions may be electron impact ionization, chemical ionization, field ionization, field desorption, atmosphere pressure ionization (such as electrospray, nebulizer-assisted electrospray, ionspray, atmospheric pressure chemical ionization and sonic spray), ion or atom bombardment (fast atom bombardment), laser desorption (including matrix assisted laser desorption) or resonance- enhanced multiphoton ionization.
  • the ions generated in the ion source (11) are pulsed into the tandem mass spectrometer by the first pusher so that ions are formed only within defined time intervals. Excitation of ions may be through collision with a gas (e.g. CID) or through laser- induced photodissociation. Either excitation process generates fragment ions, which can be mass-analyzed in the MS/MS mode.
  • a primary mass spectrum may be obtained by transferring the ions from the ion source (11) to the first detector (16) without excitation and measuring flight-times along the sections of the path such as from the ion source (11) to the first detector (16) for the different ions.
  • the mass spectrum is obtained by counting the number of ions striking the detector in each time interval.
  • pusher (10a) is off.
  • Tandem mass spectra may be obtained in a variety of ways.
  • pusher (10a) is on and the first detector (16) can be on or off, preferably off.
  • a pulse deflection unit (17) positioned after the first time-of-flight analyzer (12) and before the excitation device (13) can be used to select a particular ion prior to excitation. Fragmentation is induced by excitation, the ions are then accelerated orthogonally to an energy of from about 20 to about 50 keV using pusher (10a) and the tandem mass spectrum for that selected ion is measured using TOF-MS (2).
  • the first detector (16) is on it is used to detect the neutrals in the MS MS mode.
  • the second detector is used to get the MS/MS spectrum of the mass selected parent ion.
  • TOF-TOF's may be fully computer controlled and mass assignment may be performed automatically by the computer based on prior mass calibration.
  • the instant TOF-TOF comprises two reflectors or reflecting electrostatic mirrors.
  • An electrostatic mirror may be of a type described by Manyrin et al (Sov. Phys. JETP 37, 45-48 (1973) providing a degree of energy compensation and little spatial defoccussing or a type described by Hamilton et al (Rev, Sci Instrum., 61, 3104-3106 (1990) providing full energy compensation of an ion related to its mass-to- charge ratio even if ions of different masses have identical velocity.
  • the instant TOF-TOF does not contain reflectors or reflecting electrostatic mirrors.
  • TOF-TOF may be applied to either positive or negative ions and provides an infinite mass range.
  • TOF-TOF also provides capabilities which cannot be achieved using magnetic sector instruments or using quadrupoles and finds particular application in the analysis of large molecules, for example in biotechnology, biochemistry, and the like as well as in the analysis of mixtures. It will provide sensitivity greater than that achievable by other tandem mass spectrometry systems such as 4-sector or triple quadrupoles especially where a limited amount of sample is available.
  • Proteins can be enzymatically or chemically digested and the molecular weights of the generated peptides can be determined by the instant invention in the MS mode.
  • the amino acid sequence of peptides can be obtained by mass-selecting them, by the pulse deflection unit, followed by, for example, collision-induced fragmentation and mass analysis of the fragment ions. Since peptides fragment in a sequence specific manner, the sequence can be derived from the observed fragment ions.

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  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Other Investigation Or Analysis Of Materials By Electrical Means (AREA)

Abstract

Cette invention concerne un spectromètre (20) de masse à DDV/TTV en tandem qui combinent les avantages du spectromètre de masse quadripolaire-DDV avec une dissociation induite par collusion à haute énergie. La première partie (DDV-SM1) est une source (11) d'ion qui a pour interface un spectromètre - 1 (12) de masse à DDV orthogonale. Les ions sont accélérés de manière orthogonale à une tension relativement élevée, c'est à dire comprise entre environ 1 KeV et environ 7KeV, comprise de préférence entre environ 2 et environ 4 KeV. Dans la deuxième partie (DDV-SM2) les ions provenant de la première partie sont ensuite interface avec un spectromètre - 2 (12a) de masse DDV orthogonale dans lequel les ions sont accélérés de manière orthogonale à une tension élevée, c'est à dire à une tension comprise entre environ 25 KeV et environ 50 KeV, et comprise de préférence entre environ 29 et environ 35 KeV.
PCT/US1998/013545 1997-07-02 1998-06-29 Nouveau spectrometre de masse WO1999001889A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU82747/98A AU8274798A (en) 1997-07-02 1998-06-29 Novel mass spectrometer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US5156297P 1997-07-02 1997-07-02
US60/051,562 1997-07-02

Publications (1)

Publication Number Publication Date
WO1999001889A1 true WO1999001889A1 (fr) 1999-01-14

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PCT/US1998/013545 WO1999001889A1 (fr) 1997-07-02 1998-06-29 Nouveau spectrometre de masse

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AU (1) AU8274798A (fr)
WO (1) WO1999001889A1 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10116536A1 (de) * 2001-04-03 2002-10-17 Wollnik Hermann Flugzeit-Massenspektrometer mit gepulsten Ionen-Spiegeln
EP1297554A1 (fr) * 2000-06-14 2003-04-02 Syagen Technology Photo-ioniseur a pression atmospherique pour spectrometrie de masse
WO2004008481A1 (fr) 2002-07-16 2004-01-22 Leco Corporation Spectrometre de masse a temps de vol en tandem et procede d'utilisation associe
WO2004010459A1 (fr) * 2002-07-18 2004-01-29 Perseptive Biosystems, Inc. Spectrometre de masse a temps de vol en tandem pour determiner une structure moleculaire
WO2004059693A2 (fr) * 2002-12-20 2004-07-15 Perseptive Biosystems, Inc. Analyseur de masse de type temps de vol avec trajets de vol multiples
GB2406436A (en) * 2000-03-13 2005-03-30 Univ Warwick A tandem time-of-flight mass spectrometer
GB2408144A (en) * 2003-11-17 2005-05-18 Micromass Ltd A mass filter for a mass spectrometer
US7196324B2 (en) 2002-07-16 2007-03-27 Leco Corporation Tandem time of flight mass spectrometer and method of use
US7223966B2 (en) 2001-12-18 2007-05-29 Bruker Daltonik, Gmbh Time-of-flight mass spectrometers with orthogonal ion injection
WO2007064902A2 (fr) 2005-12-02 2007-06-07 Sirtris Pharmaceuticals, Inc. Dosages biologiques par spectrometrie de masse destines a determiner une activite d'acetyltransferase/desacetylase
US7297960B2 (en) 2003-11-17 2007-11-20 Micromass Uk Limited Mass spectrometer
WO2014096917A1 (fr) * 2012-12-20 2014-06-26 Dh Technologies Development Pte. Ltd. Analyse d'événements au cours d'expériences ms3
US8909481B2 (en) 2000-12-26 2014-12-09 The Institute Of Systems Biology Method of mass spectrometry for identifying polypeptides
US9196466B2 (en) 2002-07-24 2015-11-24 Micromass Uk Limited Mass spectrometer with bypass of a fragmentation device

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5202563A (en) * 1991-05-16 1993-04-13 The Johns Hopkins University Tandem time-of-flight mass spectrometer
US5206508A (en) * 1990-10-18 1993-04-27 Unisearch Limited Tandem mass spectrometry systems based on time-of-flight analyzer
US5763878A (en) * 1995-03-28 1998-06-09 Bruker-Franzen Analytik Gmbh Method and device for orthogonal ion injection into a time-of-flight mass spectrometer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5206508A (en) * 1990-10-18 1993-04-27 Unisearch Limited Tandem mass spectrometry systems based on time-of-flight analyzer
US5202563A (en) * 1991-05-16 1993-04-13 The Johns Hopkins University Tandem time-of-flight mass spectrometer
US5763878A (en) * 1995-03-28 1998-06-09 Bruker-Franzen Analytik Gmbh Method and device for orthogonal ion injection into a time-of-flight mass spectrometer

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2406436A (en) * 2000-03-13 2005-03-30 Univ Warwick A tandem time-of-flight mass spectrometer
GB2406436B (en) * 2000-03-13 2005-06-08 Univ Warwick Time of flight mass spectrometry apparatus
EP1297554A1 (fr) * 2000-06-14 2003-04-02 Syagen Technology Photo-ioniseur a pression atmospherique pour spectrometrie de masse
EP1297554A4 (fr) * 2000-06-14 2007-03-28 Syagen Technology Photo-ioniseur a pression atmospherique pour spectrometrie de masse
US8909481B2 (en) 2000-12-26 2014-12-09 The Institute Of Systems Biology Method of mass spectrometry for identifying polypeptides
DE10116536A1 (de) * 2001-04-03 2002-10-17 Wollnik Hermann Flugzeit-Massenspektrometer mit gepulsten Ionen-Spiegeln
DE10162267B4 (de) * 2001-12-18 2007-05-31 Bruker Daltonik Gmbh Reflektor für Flugzeitmassenspektrometer mit orthogonalem Ioneneinschuss
US7223966B2 (en) 2001-12-18 2007-05-29 Bruker Daltonik, Gmbh Time-of-flight mass spectrometers with orthogonal ion injection
US7196324B2 (en) 2002-07-16 2007-03-27 Leco Corporation Tandem time of flight mass spectrometer and method of use
WO2004008481A1 (fr) 2002-07-16 2004-01-22 Leco Corporation Spectrometre de masse a temps de vol en tandem et procede d'utilisation associe
WO2004010459A1 (fr) * 2002-07-18 2004-01-29 Perseptive Biosystems, Inc. Spectrometre de masse a temps de vol en tandem pour determiner une structure moleculaire
US10083825B2 (en) 2002-07-24 2018-09-25 Micromass Uk Limited Mass spectrometer with bypass of a fragmentation device
US9384951B2 (en) 2002-07-24 2016-07-05 Micromass Uk Limited Mass analysis using alternating fragmentation modes
US9196466B2 (en) 2002-07-24 2015-11-24 Micromass Uk Limited Mass spectrometer with bypass of a fragmentation device
US9697995B2 (en) 2002-07-24 2017-07-04 Micromass Uk Limited Mass spectrometer with bypass of a fragmentation device
JP2006511912A (ja) * 2002-12-20 2006-04-06 パーセプティブ バイオシステムズ，インコーポレイテッド 複数の飛行経路を有する飛行時間型質量分析器
WO2004059693A3 (fr) * 2002-12-20 2005-11-17 Perseptive Biosystems Inc Analyseur de masse de type temps de vol avec trajets de vol multiples
WO2004059693A2 (fr) * 2002-12-20 2004-07-15 Perseptive Biosystems, Inc. Analyseur de masse de type temps de vol avec trajets de vol multiples
GB2408144B (en) * 2003-11-17 2006-04-26 Micromass Ltd Mass spectrometer
US7297960B2 (en) 2003-11-17 2007-11-20 Micromass Uk Limited Mass spectrometer
GB2408144A (en) * 2003-11-17 2005-05-18 Micromass Ltd A mass filter for a mass spectrometer
WO2007064902A2 (fr) 2005-12-02 2007-06-07 Sirtris Pharmaceuticals, Inc. Dosages biologiques par spectrometrie de masse destines a determiner une activite d'acetyltransferase/desacetylase
US9343277B2 (en) 2012-12-20 2016-05-17 Dh Technologies Development Pte. Ltd. Parsing events during MS3 experiments
US9768002B2 (en) 2012-12-20 2017-09-19 Dh Technologies Development Pte. Ltd. Parsing events during MS3 experiments
WO2014096917A1 (fr) * 2012-12-20 2014-06-26 Dh Technologies Development Pte. Ltd. Analyse d'événements au cours d'expériences ms3

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