The invention generally relates to chemical processing methods and apparatus, and, in particular, to peptide fragmentation methods and devices that support peptide-sample separations.
In mass spectrometry, peptide ions are often fragmented prior to mass analysis. A relatively new method of peptide fragmentation entails reaction of peptide cations and reagent anions in quadrupole ion traps, in particular, in linear ion traps (LIT) based on a quadruple set of rod electrodes, which utilize radio-frequency (RF) fields for ion confinement. The technical literature typically refers to an ion-ion fragmentation reaction as Electron-Transfer Dissociation (ETD), in which electron transfer is assumed to be central to the reaction process.
In principal, as described by Liang, Hager and McLuckey, Analytical Chemistry, Vol. 79, pages 3363-3370 (2007), four methods provide peptide ion ETD reactions in a LIT. Three of these methods entail allowing cations and/or anions to pass through the LIT, i.e., only cations or anions, or neither, are confined in the LIT. These three methods use a DC potential barrier for axial confinement of ions of a single polarity (where “axial” is a conventional reference to the lengthwise direction of a LIT.) The fourth method simultaneously confines ions of opposite polarities (i.e., cations and anions) along the axial direction, through use of RF pseudopotential barriers or application, to the quadrupole rod set, of unbalanced RF fields. An axial pseudopotential barrier is formed, for example, with application, to containment lenses at the axial ends of the LIT, of RF oscillating potentials.
Optimal ion flow control is difficult to achieve with single-polarity confinement because the DC potential barrier, used for axial confinement of ions of a single polarity, acts as an accelerating potential for the opposite-polarity ions flowing through the LIT. Thus, the kinetic energy difference between the flowing ions and the confined ions may be too high for some ion-ion reactions to favorably occur; ETD researchers believe that the ion-ion reaction rate is inversely proportional to the cube of the relative velocity between the ions. Thus, mutual storage of peptide cations and reagent anions is expected to provide the lowest relative ion velocities, for more efficient dissociation.
Mutual confinement, however, as indicated, above, typically requires more complex use of RF voltages. Moreover, the barrier height of an RF-generated pseudopotential barrier is a function of the mass-to-charge ratio of the ions being stored, thus restricting the mass range of analyte or reagent ions that can be mutually confined for ion-ion reactions.
As an alternative to reliance on RF fields for mutual confinement, two separate quadrupole rod sets, i.e., two adjacent LITs, are used to separately store cations and anions in the two adjacent LITs, prior to allowing ions from one LIT to flow through the other LIT. Such an approach to mutual confinement, however, increases the complexity and cost of a fragmentation device.
Some embodiments of the invention provide mutual confinement of opposite-polarity ions in a linear fragmentation device that does not rely on axial pseudopotential barriers, unbalanced RF fields, or two adjacent ion traps. In particular, some embodiments of the invention arise from the realization that mutual confinement of opposite-polarity ions, for peptide fragmentation, is advantageously accomplished in a linear stacked-electrode based fragmentation device, using DC potentials for axial confinement of both polarity types.
One such device includes, for example, a set of stacked-rings, such as those found in a stacked-ring ion guide (SRIG); the device has DC voltage control features that provide simultaneous storage, mixing, and/or release of positive ions and negative ions, or electrons, through use of discrete potential wells. In some alternative embodiments, a stacked-electrode-based fragmentation device can also be used for mass-related analysis of the ions and/or fragments, and/or can selectively eject ions and/or fragments for further analysis by down-stream modules. Moreover, with application of an axial magnetic field, mutual confinement of peptide ions and electrons optionally supports peptide fragmentation via reaction of peptide ions and free electrons.
Thus, some embodiments of the invention provide a means of mutually confining cations and anions to perform ETD without the disadvantages described above. Some embodiments of the present invention relate to apparatus for mass spectrometry that is designed to spatially manipulate and confine mixtures of ions with opposite-polarity charged particles, such as reagent ions and/or electrons, to fragment the ions. Some embodiments of the invention are suitable for ion-ion reactions such as ETD and proton-transfer reactions (PTR) and/or for electron-capture dissociation (ECD).
Accordingly, one embodiment of the invention is a method of protein analysis that includes confining positive peptide ions in a first DC potential well in an ion-manipulation region of a fragmentation device, confining negatively charged particles in a second DC potential well in the ion-manipulation region, reducing a DC barrier between the first and second DC potential wells to mix the positive peptide ions and the negatively charged particles, and mass analyzing peptide ion fragments derived from the mixture.
Another embodiment of the invention is a chemical processing apparatus that includes a fragmentation device. The fragmentation device includes stacked electrodes, which each define at least one aperture, disposed in series along an axial direction of the fragmentation device. The apertures define an ion-manipulation region. The apparatus also includes means for applying at least a first DC voltage to at least two contiguous electrodes to define a first DC potential well, and applying at least a second DC voltage to at least two different contiguous electrodes to define a second DC potential well, means for reducing a DC potential barrier between the first and second DC potential wells to permit positive peptide ions, confined in the first DC potential well, and negatively charged particles, confined in the second DC potential well, to mix, and a mass-spectrometry module for analyzing at least some fragments of the positive peptide ions extracted from the mixture.
In the drawings, like reference characters generally refer to the same parts throughout the different views. Also, the drawings are not necessarily to scale, emphasis instead generally being placed upon illustrating the principles of the invention.
a is a block diagram of a chemical processing apparatus, in accordance with one embodiment of the invention;
b is a cross-sectional three-dimensional diagram of a fragmentation device that includes stacked ring electrodes, in accordance with one embodiment of the invention;
a is a cross sectional schematic view of a stacked-electrode fragmentation device, under a particular operating condition, in accordance with one embodiment of the invention;
b is a qualitative graph of DC voltages applied to the electrodes shown in
a is a cross sectional schematic view of a stacked-electrode fragmentation device, and an associated qualitative graph of the DC voltage as a function of axial position along the fragmentation device, illustrating creating and filling a DC potential well, in accordance with one embodiment of the invention;
b is a cross sectional schematic view of a stacked-electrode fragmentation device, and an associated qualitative graph of the DC voltage as a function of axial position along the fragmentation device, illustrating creating and filling a DC potential well, in accordance with one embodiment of the invention;
a is a schematic view of a fragmentation device and an associated DC voltage graph, in association with
b is a schematic view of a fragmentation device and an associated DC voltage graph, similar to that of
a is a schematic view of a device and associated voltage graph, in association with
b is a schematic view of a device and associated voltage graph, illustrating fragments trapped in a single well of a fragmentation device, prior to release from the device, in accordance with one embodiment of the invention;
As used herein, the following terms generally refer to the indicated meanings:
DC—constant, or substantially constant, electrical potentials, voltages and/or currents. A DC electrical state can vary in time. For example, a DC voltage, in some cases, is transient or otherwise varies in time. A DC voltage is contrasted to an AC voltage, in particular, an RF voltage, which oscillates in time.
Protein—a specific primary sequence of amino acids assembled as a single polypeptide.
Peptide—a specific sequence of amino acids assembled as a single polypeptide contained within the primary sequence of a protein. As will be clear in context, “peptide” is used herein to refer to both peptides and polypeptides, including proteins.
Precursor peptides—peptide molecules that have yet to be fragmented in a fragmentation device. The precursors are optionally separated chromatographically prior to delivery to a fragmentation device. An ion source ionizes these precursor peptides to typically produce positively charged, protonated forms of the precursors.
Fragments—In context, fragments (or products) herein refer in particular to fragments of peptide ions, as formed in stacked-electrode based fragmentation devices of the invention. More generally, multiple types of fragments can occur in LC/MS analyses. In the case of tryptic peptide precursors, fragments can include polypeptide ions that are produced from collisional fragmentation of the intact peptide precursors and whose primary amino acid sequence is contained within the originating precursor peptide.
Some embodiments entail LC/MS analysis, in which precursor ions are fragmented in a fragmentation after LC separation and before MS analysis. Such analysis optionally provides an empirical description of a peptide in terms of its mass, charge, retention time, total intensity and other data. When a peptide elutes from the chromatographic column, it elutes over a specific retention time period and reaches its maximum signal at a single retention time. After ionization and (possible) fragmentation, the peptide appears as a related set of ions. The different ions in the set correspond to different isotopic compositions and charges of the common peptide. Each ion within the related set of ions produces a single peak retention time and peak shape. Since these ions originate from a common peptide, the peak retention time and peak shape of each ion is identical, within some measurement tolerance. Thus, typically, the MS acquisition associated with each peptide produces multiple ion detections for all isotopes and charge states, all sharing the same peak retention-time and peak shape within some measurement tolerance.
a is a block diagram of chemical processing apparatus 10, according to one embodiment of the invention. The apparatus includes a fragmentation device 11 and a control unit 14, and optionally includes an ion supply module 12 and a mass-spectrometry module 13. The fragmentation device 11 includes a linear arrangement of electrodes, herein referred to as “stacked electrodes”. The stacked electrodes optionally define a curved path through the device 11, but the device 11 would still be viewed herein as being “linear”. The control unit 14 manages the application of voltages to the electrodes of the fragmentation device 11.
b is a cross-section three-dimensional diagram of one optional embodiment of the fragmentation device 11. The device 11, in this example, includes a set 110 of stacked ring electrodes 110A, in a linear arrangement. Each ring electrode 110A has a central aperture; the co-linear arrangement of apertures defines an ion radial-confinement region and a longitudinal direction of the fragmentation device 11; a perpendicular direction, relative to the longitudinal direction, is herein referred to as a “radial” direction. The longitudinal direction is also referred to herein as the axial direction.
The apertures, in this example, are depicted as having a circular shape. Though preferred, the particular shape and/or size of the apertures are optionally varied, as desired. The apertures also define an ion-manipulation region and a reaction region, within the device 11.
As an illustrative example, the stacked electrodes 110A are optionally conductive circular stainless steel ring plates with a pitch of 1.5 mm, a thickness of 0.5 mm and a central aperture diameter of 5 mm. An argon buffer gas pressure of 0.076 Torr is optionally used. The length of the device is optionally 90 mm. The control unit 14 applies opposing phases of 100 V RF to adjacent electrodes 110A to provide radial confinement of positive and negative ions.
Next, use of fragmentation devices of the invention for mutual confinement of opposite polarity particles is described, for convenience, with reference to the fragmentation device 110 having stacked ring electrodes 110A. In view of the following description, however, it will be clear that principles of the invention are applicable to a variety of configurations of stacked electrodes.
a is a cross sectional schematic view of the set 110 of stacked ring electrodes 110A, under a particular operating condition, illustrating some general principles of one embodiment of the invention. The dashed line indicates the longitudinal axis AD, associated with the axial direction, of the device. The electrodes 110A contain positively charged peptide ions and negatively charged particles, such as reagent ions or electrons. The ions and particles are trapped in neighboring potential wells (see
b, in association with
In
More generally, positive and negative particles are optionally confined in one or more wells, each well associated with one or more electrodes 110A having an applied DC voltage that is, respectively, lower or higher than a neighboring electrode.
Next, referring to
Illustrating one option for filling a potential well,
As illustrated in
Some embodiments of the invention include a magnetic field generator, such as a permanent magnet or an electromagnet. A magnetic field (field direction indicated by arrow H) is then optionally disposed in the radial-confinement region of the electrodes 110A. The magnetic field supports radial confinement of electrons, assisting optional use of the device 11 for, for example, ECD.
b illustrates a variation of the DC voltage configuration depicted in
Negatively charged reagent ions are optionally provided by any suitable source, including known sources, such as a chemical-ionization (CI) source.
Suitable peptide ions include, for example, singly- or multiply-protonated peptide molecules (precursor ions), generated by a ionized-sample source. The source, such as the source 12, is any suitable source, including known sources. For example, the peptide ion source 12 is optionally any one of, or combination of: (i) an Electrospray ionization (ESI) ion source; (ii) an Atmospheric Pressure; (iii) an Atmospheric Pressure Chemical Ionization ((“APCI”) ion source; (iii) an Atmospheric Pressure Photo Ionization (“AAPPI”) ion source; (iv) a Matrix Assisted Laser Desorption Ionization (“MALDI”) ion source; (v) a Laser Desorption Ionization (“LDI”) ion source; (vi) an Inductively Coupled Plasma (“ICP) ion source; (vii) an Electron Impact (“EI”) ion source; (viii) a Chemical Ionization (“CI”) ion source; (ix) a Fast Atom Bombardment (“FAB”) ion source; and (x) a Liquid Secondary Ions Mass Spectrometry (“LSIMS”) ion source. Further examples of alternatives for a source 12 are described below, with reference to
Reagent ions are any suitable ions, including known ions. Some polyaromatic (polycyclic aromatic) hydrocarbon (PAH) compounds are particularly well suited as reagents. Alternatively, some azo compounds (which have a N═N bond, i.e., a nitrogen-nitrogen double bond) are suitable; azobenzene, in particular, is well suited as a reagent. More generally, some suitable reagents have aryl rings connected by conjugated double bonds, such as an azo N═N bond, or a hydrocarbon C═C bond.
Polyaromatic hydrocarbon anions are generated, for example, from a low electron affinity compound such as anthracene, 9,10-diphenyl-anthracene, naphthalene naphthalene, fluorene, phenanthrene, pyrene, fluoranthene, chrysene, triphenylene, perylene, acridine, 2,2′-dipyridyl, 2,2′-biquinoline, 9-anthracenecarbonitrile, dibenzothiophene, 1,10′-phenanthroline, 9′-anthracenecarbonitrile, and anthraquinone. Anions are alternatively generated from substituted derivatives of these low electron affinity compounds.
Alternatively, modified aromatic hydrocarbons, which include, for example, sulfur, oxygen and/or nitrogen (heterocyclics), are suitable reagent compounds.
Substituted azonitrile compounds include some suitable compounds, such as VAZO free-radical source compounds (available from DuPont) such as VAZO 68 4,4′-axobis (4-cyanovaleric acid).
Some additional specific reagent radical anions are formed from sulfur dioxide, fluoranthene, diphenylanthracene, 2,2′ biquinoyline, and azulene. Though the fragmentation process is not entirely understood, some suitable reagents are associated with anions having sufficiently low electron affinities to act as electron donors for an ECD-like reaction with peptide cations. Benzyl peroxide is another suitable compound.
Reagent anions are prepared by any suitable technique, including known techniques, such as atmospheric-pressure chemical ionization (APCI), glow discharge or electrospray ionization (ESI). Some preferred anions have a m/z range of 100-1000, low (or negative) electron affinity, potentially in an excited state, are radical (i.e., have odd electrons in an outer shell) are sufficiently stable for transfer into a fragmentation cell, and/or are double-charged anions.
Some suitable reagents are neutral rather than ionic. For example, some alkali metals, such as cesium, are suitable, likely because they tend to readily surrender an electron. Thus, in the case of some reagents, electrons are transferred from one or more neutral, non-ionic or uncharged gases, vapors or atoms selected, for example, from sodium, lithium, potassium, rubidium, francium, C60, and magnesium.
As an alternative to electron transfer, protons may be transferred from one or more multiply charged analyte cations or positively charged ions to one or more neutral, non-ionic or uncharged reagent gases or vapors whereupon at least some of the multiply charged analyte cations or positively charged ions are preferably reduced in charge state. It is also contemplated that some of the cations may also be induced to dissociate and form product or fragment ions. The multiply charged analyte cations or positively charged ions preferably include peptides, polypeptides, proteins or biomolecules.
Features of the invention are applicable to PTR as well as ETD. According to an embodiment, in order to cause PTR, either the reagent anions or negatively charged ions may be derived from a compound selected from a group including: (i) carboxylic acid; (ii) phenolic; and (iii) a compound containing alkoxide. The reagent anions or negatively charged ions may alternatively be derived from a compound selected from the group of: (i) benzoic acid; (ii) perfluoro-1, 3-dimethylcyclohexane or PDCH; (iii) sulphur hexafluoride or SF6; and (iv) perfluorotributylamine or PFTBA. According to an embodiment, the one or more reagent gases or vapors include a superbase gas. The one or more reagent gases or vapors may be selected from the group of: (i) 1,1,3,3-Tetramethylguanidine (“TMG”); (ii) 2,3,4,6,7,8,9,10-Octahydropyrimidol [1,2-a]azepine {Synonym: 1,8-Diazabicyclo[5.4.0]undec-7-ene (“DBU”)}; or (iii) 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (“MTBD”) {Synonym: 1,3,4,6,7,8-Hexahydro-l-methyl-2H-pyrimido[l,2-a]pyrimidine}. Further embodiments are contemplated wherein the same reagent ions or neutral reagent gas that is disclosed above in relation to causing ETD may also be used to cause PTR.
a illustrates three completed, and filled, DC potential wells: a positive potential well storing reagent ions and two neighboring negative potential wells storing positively charged peptide ions. In view of the above description, it will be apparent that one or more wells are optionally formed and filled for each polarity of particles, with particles admitted from one or both ends of a device.
b is a schematic view of a device and an associated DC voltage graph, similar to that of
Next, with reference to
a, in association with
The reduction in well depth is associated with a corresponding height reduction of the two DC potential barriers associated with the well. The barrier reduction permits peptide ions to begin to mingle, and react with, the negatively charged ions; by preserving some level of the negative well, at least some confinement of negative ions remains.
The reduction in well depth is particularly suitable if, for example, at least some of the peptide ions have greater kinetic energy than at least some of the regent particles. In this case, the reduced well can continue to confine negative particles while admitting peptide ions. For example, room temperature electrons can be confined in a reduced well, while hotter peptide ions can penetrate the remaining potential barrier associated with the reduced well, to mingle with the confined electrons.
Alternatively, the nested negative potential well is entirely removed (see
As the oppositely charged ions mix and react, at least some of the peptide ions fragment, as illustrated in
After formation of fragments, the fragments are manipulated and/or analyzed in the fragmentation device and/or ejected from the fragmentation device for analysis, for example, in the mass-spectrometry unit 13.
Where the negatively charged particles are electrons, some methods of the invention provide ECD of peptides. Capture of an electron by a protonated peptide is associated with an exothermic reaction, releasing, for example, 6 eV. The peptide's backbone fragments, leading, for example, to c and z fragments.
Next, referring to
Mobility separation is optionally used, for example, to remove ions having a mass outside a selected mass window around precursor ions and/or reagent ions. Ion separation can improve mass-analysis sensitivity and duty cycle.
As noted, the apparatus 10 optionally includes an analysis module 13. In one alternative embodiment, the fragments are fed to a mass spectrometer (MS). The MS is any suitable device, including known devices. For example, the MS is a quadrupole mass filter, a time-of-flight (TOF) mass analyzer, a Fourier Transform Ion Cyclotron Resonance (FTICR) mass analyzer, or a 2D (linear) quadrupole ion trap or a 3D (Paul) quadrupole ion trap.
Some embodiments of the invention advantageously include separate ion sources for analytes and regents, to generate cation analytes and reagent anions. In order to efficiently introduce both cations and anions from separate ion sources into a fragmentation device 11, one option is to use an ion guide that simultaneously and continuously receives and transfers ions of either polarity from multiple ion sources at different locations. One suitable ion guide for this purpose is described in U.S. Pat. No. 6,891,157 to Bateman. Next referring to
Returning now to the control unit 14, the unit 14 has any suitable configuration for individually and selectively applying DC voltages to the electrodes 110A of the fragmentation device 11. The control unit 14 is in data and/or electrical communication with other components of the apparatus 10 via wired and/or wireless means, such as those known in the data-communication arts. The control unit 14 receives process data, for example, from the mass-spectrometer module 13, and provides control signals to other components, for example, the fragmentation device 11. The control unit 14 is configured to support automation of operation of the apparatus 10. The control unit 14, in various illustrative embodiments, is implemented in software, firmware, and/or hardware (e.g., as an application-specific integrated circuit), and includes, if desired, a user interface. The control unit 14 includes and/or is in communication with storage component(s).
Suitable implementations of the control unit 14 include, for example, one or more integrated circuits, such as microprocessors. A single integrated circuit or microprocessor in some alternative embodiments includes the control unit 14 and other electronic portions of the apparatus 10. In some embodiments, one or more microprocessors implement software that enables the functions of the control unit 14. In some embodiments, the software is designed to run on general-purpose equipment and/or specialized processors dedicated to the functionality herein described.
In some implementations of the apparatus 10, the control unit 14 includes a user interface to support interaction with the control unit 14 and/or other portions of the apparatus 10. For example, the interface is configured to accept control information from a user and to provide information about the apparatus 10 to a user. The user interface is used, for example, to set system control parameters and/or to provide diagnostic and troubleshooting information to the user. In one embodiment, the user interface provides networked communication between the apparatus 10 and users located either local to the operating environment or remote from the operating environment. The user interface in some implementations is used to modify and update software.
Where a travelling pulse(s) and/or barrier(s) are used to manipulate ions in the fragmentation device 11, the control unit 14 is configured to control parameters such as pulse shape, wavelength and amplitude. These parameters can also be optimized to provide control over the relative ion velocity of cations and anions. Also, the velocity of ion-neutral collisions can be manipulated to exploit collision induced dissociation (CID) within the fragmentation device 13.
Variations, modifications, and other implementations of what is described herein will occur to those of ordinary skill in the art without departing from the scope of the invention as claimed. Accordingly, the invention is to be defined not by the preceding illustrative description but instead by the scope of the following claims.
This application claims benefit of and is a continuation of International Application No. PCT/US2009/049133, filed 30 Jun. 2009, filed and designating the United States, which claims benefit of a priority from U.S. Provisional Patent Application No. 61/077,270, filed 1 Jul. 2008.
Filing Document | Filing Date | Country | Kind | 371c Date |
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PCT/US2009/049133 | 6/30/2009 | WO | 00 | 2/22/2011 |
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WO2010/002819 | 1/7/2010 | WO | A |
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20110266434 A1 | Nov 2011 | US |
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61077270 | Jul 2008 | US |