Mass Analyzers

rpd Somogyi Chemistry and Biochemistry MassSpectrometry Facility

Universit Joseph Fourier, Grenoble, November 19, 2010

Want to do MS or MS/MS ? Need a Mass Spectrometer

Ionization source Mass analyzer

Detector

inlet

all ions

sorted ions

Data system

Ionization Mass Detector source analyzer

inlet all ions sorted ions

Data system

Ion movement
Charged metal plates (electrodes, lenses) used to move ions between ion source and analyzers Electrodes and physical slits used to shape and restrict ion beam Good sensitivity is dependent on good ion transmittance efficiency in this area
Ionization source Mass analyzer Detector

inlet

all ions

sorted ions

Data system

Ion detection
Ions can be detected efficiently w/ high amplification by accelerating them into surfaces that eject electrons

Ionization source

Mass analyzer

Detector

inlet

all ions

sorted ions

Data system

Ion energy
Kinetic energy of ions defined by E = zeV = qV = mv2 E = kinetic energy m = mass v = velocity e = electronic charge (1.60217e-19 C) z = nominal charge V = accelerating voltage

Learning Check

Consider two electrodes, one at 1000 V and one at ground (0 V) t d t d(0V)

1000 V

0V

+ ion will travel with kinetic energy of ___________

Mass Resolution
Mass spectrometers separate ions with a defined resolution/resolving power Resolving power- the ability of a mass spectrometer to separate ions with different mass to charge (m/z) ratios. diff t t h ( / ) ti

Resolution defined at 10% valley

M

R=M/M

Example of ultrahigh resolution in an FTICR

J. Throck Watson Introduction to Mass Spectrometry p. 103

General about mass spectrometers

Common features
Accelerated charge species (ions) interact with
Electrostatic field (ESA, OT) Magnetic field ( , ICR) g (B, ) Electromagnetic (rf) fields (Q, IT, LT)

Or ions just fly (TOF)

Desirable mass spectrometer characteristics

1) 2) 3) 4) 5) They should sort ions by m/z They should have good transmission (improves sensitivity) They should have appropriate resolution (helps selectivity) They should have appropriate upper m/z limit They should be compatible with source output (pulsed or continuous)

For each of the following applications, choose the most appropriate mass analyzer from the following list. Use each analyzer only once. orbitrap (OT) time-of-flight (TOF) Analyzer ______ _______ _______ _______ quadrupole (Q) FTICR

Purpose synthetic organic chemist wants exact mass of compound biochemist wants protein molecular weight of relatively large protein (MW 300,000) EPA (Environmental Protection Agency) wants confirmation of benzene in extracts from 3000 soil samples Petroleum chemist wants to confirm the presence of 55 unique compounds at one nominal mass/charge value in a mass spectrum

Mass spectrometers record m/z values

m/z values are determined by actually measuring different physical parameters h i l t

Type of analyzer

electric sector magnetic sector quadrupole, ion trap time-of-flight FT-ion cyclotron resonance

Physical parameter used as basis for separation

kinetic energy/z momentum/z m/z flight time m/z (resonance frequencies)

Types of Mass Analyzers

Magnetic (B) and/or Electrostatic (E) (HISTORIC/OLDEST) Time-of-flight (TOF) Quadrupole (Q) Quadrupole Ion Trap (IT) Linear Ion Trap (LT) Orbitrap Fourier Transform-Ion Cyclotron Resonance (ICR)

Performance Advantages / Disadvantages / $$$

TOF

Quadrupole

Quadrupole Ion trap FTICR

Orbitrap

Notice: accelerating voltages vary with analyzer (has consequences for MS/MS)

High voltage (keV energy range) magnet (B) t electrostatic (E) time-of-flight (TOF) Low voltage (eV energy range) quadrupole (Q) ion trap (IT, LT) ion cyclotron resonance (ICR)

MS and MS/MS revisited

Ionization Analysis

MS:
Collide with target to produce fragments

MS/MS:
Ionization Selection Activation Analysis

http://www.iupac.org/goldbook/T06250.pdf

Current popular MS/MS arrangements (2009)

Tandem in Space QqQ Q Q Q Trap Q TOF TOF TOF Tandem in Time Ion Trap (2 or 3 D) FT-ICR (FT)

10

Decision factors when choosing a mass spectrometer

Speeeeeeeeeeeeed R e s o l u t i o n
Sensitivity

D na ic ang D
y m
r

Co$t

11

TOF

Quadrupole

Quadrupole Ion trap FTICR

Orbitrap

Time of Flight
D Detec ctor

m/z V

KE = zeV = mv2 v = D/t m(D/t)2 = zeV

t= m 2zeV

1/ 2

m = mass V = velocity D = distance of flight t = time of flight KE = kinetic energy e = charge

12

How does the ion generation step in TOF influence m/z analysis?
Consider MALDI
h
Target

Matrix
+

Analyte

Analyte ion may have (1) Kinetic Energy distribution or (2) Spatial distribution

How will KE spread influence the spectrum?

Ions of same m/z Has slightly greater KE

Effect is broad peaks

c/o Cotter

13

How will KE spread influence the spectrum?

Solution to peak broadening caused by kinetic energy spread: Reflectron (ion mirror)

Series of ring electrodes, typically with linear voltage gradient

Time-of-Flight Reflectron
Increased resolution by compensating for KE spread from the source

http://www.jic.bbsrc.ac.uk/services/proteomics/tof.htm

14

Reflectron TOF
Mass Analyzer (TOF) Ion Source (MALDI) x x x Reflectron Detector

High resolution

KE = mv2

Reflectron TOF
Mass Analyzer (TOF) Ion Source (MALDI) Reflectron Detector

High resolution

KE = mv2

15

http://www.abrf.org/ABRFNews/1997/June1997/jun97lennon.html

We talked about how to deal with kinetic energy spread. How do we deal with ions formed at different locations in the source (spatial distribution)?

16

Delayed Extraction
10 KV 10 KV
+ + + + + + + + + +

7 KV

Low mass (below 40 k Da)

High resolution

Continuous vs. Delayed Extraction

Continuous TOF Resolution = 700 (FWHM)

Delayed Extraction Resolution = 6000 (FWHM)

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Recent TOF designs: improved resolution, better sensitivity and mass accuracy (Ultraflex III MALDI TOF-TOF)
In te n s. [a .u .]

6000

3145.708

* Pepmix\0_N6\1\1SRef

5000

Resolution: 25,000 S/N: 46

4000

3000

2000
3177.722

1000

3140

3145

3150

3155

3160

3165

3170

3175

3180

3185

m/z

Typical TOF Specs

m/z Range: unlimited u Resolution: ~20 000 ~20,000 (Reflectron) Mass Accuracy: ~ 3-10 ppm (300-4,000 u) Scan Speed: 106 u/s Vacuum: 10-7 Torr

Quantification: low medium Positive and Negative Ions Variations: Linear, Reflectron, Tandem w/ quads, TOFs quads and/or sectors

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Can an MS/MS instrument be constructed if the only analyzer type available is TOF?

TOF-TOF

http://docs.appliedbiosystems.com/pebiodocs/00106293.pdf

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TOF TOF
(high energy, keV, collisions)

More fragmentation f t ti than QqQ or trap (low energy, eV, collisions) V lli i )

Advantages and Disadvantages

Mass Spectrometer TOF-TOF Advantages high resolution, high m/z fragment ions / f ti keV CID easier de novo peptide sequencing dn and wn to distinguish Ile/Leu Disadvantages Large size Not ideal for continuous ionization source $$$

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Analyzers
TOF Quadrupole

Quadrupole Ion trap FTICR

Orbitrap

21

Quadrupole (Q)

Quadrupole (Q)
four parallel rods or poles fixed DC and alternating RF voltages rf voltage +dc voltage rf voltage 180 out of phase -dc voltage only particular m/z will b f l ti l / ill be focused on th d the detector, all the other ions will be deflected into the rods scan by varying the amplitude of the voltages
(AC/DC constant).

22

Quadrupole Field Animation

Positive rod Negative rod

Positive rod

Negative rod

http://www.kettering.edu/~drussell/Demos/MembraneCircle/Circle.html

negative DC offset

-DC
+ positive DC offset

+DC

23

Ion Motion in Quadrupoles

- a qualitative understanding
+ DC, ions focused to center - DC, ions defocused +DC w/ rf, light ions respond to rf, eliminated (high mass filter) -DC w/ rf, light ions respond to rf, focused to center (low mass filter)

TSQ 7000 1993 to 2000

TSQ Quantum 2001 to

c/o ThermoFinnigan Corp.

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Quadrupole animation

http://www.youtube.com/watch?v=8AQaFdI1Yow&feature=related

QuickTime and a TIFF (LZW) decompressor are needed to see this picture.

25

RF only mode

Initial kinetic energy affects ion motion in quad

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Quadrupole Typical Specs

m/z Range: 2-4000 u 2 4000 Resolution: Unit Mass Accuracy: ca +/0.1 u Scan Speed: 4000 u/s Vacuum: 10-4 10-5 Torr Low Voltages: RF ~6000 10000 V DC ~500V-840V Source near ground Quantification: good choice Positive and Negative Ions Variations: SingleQ, TripleQ, Hybrids

What MS/MS instruments can be produced from Q? What MS/MS instruments can be produced from Q and TOF?

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Triple Quadrupole
- since 1970s and still going strong!
Q1 S Q2 Q3 D

Attractive Features:
Source near ground and operates at relatively high pressure Couples well to source and to chromatography Multiple scan modes easy to implement

Triple Quadrupole (QQQ)

Detection System Q3 Source Q0 Q1 Q2 Heated Capillary
Q3

Dynode

Turbo

Q2 Q1 Q0 Q00

c/o Thermo Finnigan Corp.

c/o Agilent Corp.

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Quadrupole Time of Flight (Q-TOF)

http://www.waters.com/WatersDivision/waters_website/products/micromass/ms_top.asp (outdated)

Low-energy (eV) Collisions with Gas The third Q in QQQ is replaced by a TOF Advantages?

29

Q-TOF

80 fmol BSA digest

QQQ

Shevchenko, A., et al., Rapid. Commum. Mass Spectrom., 1997, 11: 1015-1024

Ion Mobility in a Q-TOF - Animation

http://mass-spec-blog.blogspot.com/2007/09/ion-mobility-separation-animation.html

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Another important use of a modified Q-TOF:

Ion Mobility

http://mass-spec-blog.blogspot.com/2007/09/ion-mobility-separation-animation.html

Selection of [M+2H]+2 at m/z 246.1

600 500 400 300 200 100

m/z z Relative Int tenisty

100 80 60 40 20 0 0 1 2 3 4 Drift Time (ms) 5 6 7

GRGDS

SDGRG

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Transfer CID of [M+2H]+2 at m/z 246.1

Drift Time (ms) T
3.0 2.5 25 2.0 100

y3 Si R b4 y1 R
100 200

y4 SDGRG
dt = 2.68-2.83 ms

Relative Abundance e

50 0 100 50 0

Si

b2

GRGDS b3
300 400
dt = 2.49-2.68 ms

500

m/z

UL_110510_GNR.raw : 1

32

33

Corrected Cross Sections (A2) as a Function of m/z for Singly Protonated GnR (n=1-7)
150

G7 R

Ca alibrated Cross Sections (A )

140

130

120

G4 R

110

100

90 200

GR
250 300 350 400 450 500 550 600

m/z

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Analyzers
TOF Quadrupole

Quadrupole Ion trap FTICR

Orbitrap

What is small, inexpensive and still gives great MSMS ?????

Quadrupole Ion Traps

Miniature IT: Cooks, R. G. and coworkers Anal. Chem. 2002, 74, 6145-6153; 2000, 72, 3291-3297.

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http://www.chem.wm.edu/dept/faculty/jcpout/faculty.html

Ion path in a trap

Quadrupole Ion Trap (QIT)

http://www-methods.ch.cam.ac.uk/meth/ms/theory/iontrap.html

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Quadrupole Ion Trap (QIT)

Quadrupole ion trap mass analyzer consists of three hyperbolic electrodes: the ring electrode, the entrance end cap electrode and the exit endcap electrode. electrode Ions enter trap through inlet focusing system and entrance endcap electrode. An AC potential of constant frequency and variable amplitude is applied to the ring electrode to produce a 3D quadrupolar potential field within the trapping cavity which traps ions in a stable oscillating trajectory confined within the trapping cell cell. The oscillating trajectory is dependent on the trapping potential and the mass-to-charge ratio of the ions. During ion detection, the electrode system potentials are altered to produce instabilities in the ion trajectories and thus eject the ions.

Quadrupole Ion Trap (QIT)

37

3D - Quadrupole Ion Trap (Demo)

Activation: Low-energy (eV) Collisions with G ith Gas IRMPD (Infrared Multiphoton Dissoc)

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Research: Micro CIT Array

Matt Blain, Sandia Cooks, Purdue
1.8 1 8 m 2.4 m

Top End Cap Array Ring Electrode Array Bottom End Cap Array Collector Array

QIT Typical Specs

m/z Range: 20-6000 u Resolution: Unit Mass Accuracy: ca +/0.1 u Scan Speed: 4000 u/s Vacuum: 10-3 Torr

Quantification: possible, possible not accurate Positive and Negative Ions

39

Advantages and Disadvantages

Mass Spectrometer QIT Advantages Compact Disadvantages Limited storage of ions limits the dynamic range of the ion trap (space charge effect) 1/3 of low mass range lost in MS/MS mode, typical operation

MSn

Data dependent scanning Relatively inexpensive Low E collisions

Advantages and Disadvantages

Mass Spectrometer QIT Sensitive Advantages Disadvantages Poor quantification Collision energy not well-defined in CID MS/MS Mass Accuracy

To increase mass accuracy in a Trap LT, orbitrap, FT-ICR

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RF ION TRAP ELECTRODE STRUCTURES

LCQ-Type 3D Quadrupole Trap LTQ-Type (2D) Linear Quadrupole Trap

ASMS Fall Workshop 2006 JEPS

41

2D vs. 3D Ion Traps

Ion Transfer Tube Skimmer

Tube Lens

Linear Trap Demo

Ion Transfer Tube Skimmer

Tube Lens

42

Overall Performance Gains

LTQ Trapping efficiency Detection efficiency Trapping capacity ~ 55-70% ~ 50-100%

~ 20,000 ions

3D Traps

Increase ~ 11-14x ~ 1-2x

~ 40x

~5% ~50%
~500 ions

Motivating Factors Realized

Increased Trapping Efficiency Increased Trapping Capacity

Which means....
Increased Sensitivity Increased Inherent Dynamic Range I Increased S/N f f ll Scan MS d for full S n Practical MS Faster Scan Times - no scans (only one)

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How are 3-D traps and linear ion traps used in MS/MS
Stand alone 3-D traps LTQ Front or back end of tandem-in-space LT-TOF LT-FT, LT-Orbitrap, QTrap

LIT and QTrap; Different ways of using Linear Traps

Linear Ion Trap ~ 100% of ions trapped are detected due to radial ejection

Skimmer

Axial ejection allows for hybridization without compromise (FT)! Hybrid Quadrupole Trap Majority of trapped ions cannot be scanned out

~ 15% detected*

Axial ejection depends on fringe fields generated by grid this grid compromises triple quadrupole performance
*Hager, J., RCM., 2003, 17, 1389

44

Activation: CID Low-energy Low energy (eV) Collisions with Gas IRMPD (Infrared Multiphoton Dissoc) ETD (electron transfer dissociation)

45

Analyzers
TOF Quadrupole

Quadrupole Ion trap FTICR

Orbitrap

Cyclotron motion of an ion in a magnetic field (B). Note: ion motion is much more complex due to the presence of electrostatic field (magnetron/cyclotron motion, see below)

46

RF-excitation

Ion Detection Plates

Ion Detection Plates

Note: for clarity, the front and back trapping plates are not shown

47

48

Fourier Transform-Ion Cyclotron Resonance (FTICR)

In the presence of a magnetic field, sample ions orbit according to cyclotron frequency, fc g y q y, Cyclotron frequency related to charge of ion (z), magnetic field strength (B) and mass of ion (m).

All ions of same m/z will have same cyclotron frequency at a fixed B and will move in a coherent ion packet.

49

FTICR
Image is Fourier transformed to obtain the component frequencies and amplitudes (intensity) of the various ions. Cyclotron frequency value is converted into a m/z value to produce mass spectrum w/ the appropriate intensities.

C9H16N5 194.1405

time (ms)

C11H20N3 C7H12N7 194.1154 194.1657

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If the frequency is slightly off, The excitation is called SORI (sustained off-resonance irradiation)

FTICR animation

http://www.youtube.com/watch?v=a5aLlm9q-Xc&NR=1

QuickTime and a TIFF (LZW) decompressor are needed to see this picture.

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FTICR Typical Specs

m/z Range: > 15000 u Resolution: High 106 High, Mass Accuracy: 100 ppb Scan Speed: fast Vacuum: 10-7- 10-9 Torr

Quantification: possible, possible not accurate Positive and Negative Ions

11+

12+ 10+

9+

52

Charge state/MW determination for proteins

m = z (m/z) Carbons isotopes so

m 1 m=1 Da Calc (m/z)

Finnigan LTQ FT
Linear Ion Trap MS MS, MS/MS and MSn Analysis AGC Control Secondary Electron Multiplier Detector FTICR MS Ion Image Current Detector Accurate Mass, High Resolution ECD, IRMPD
FTMS Data

Linear Ion Trap Data

7 T Actively Shielded Superconducting Magnet

ECD Assembly
60m3/hr 15L/s 300L/s 400L/s 210L/s 210L/s

IRMPD Laser Assembly

Triple Ported Turbo Pump

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Introducing the New apex-ultra Hybrid Qq-FTMS

Announced at PittCon 2007 in Chicago, IL

The new apex-ultra combines ease-of-use ease of use with power and versatility Improved electronics for substantial gains in analytical performance and capabilities Comprehensive software tools that are specifically designed for protein characterization

Versatility matched with Performance

The apex-ultra
h1 Q1 h2
to analyzer

ESI source region Masses can be filtered here in a results-driven, targeted approach g pp CASI provides the means to enrich or amplify low abundant species for subsequent fragmentation and analysis

ECD / IRMPD

Ions accumulated here to build significant populations an in-cell event (e.g. ECD)

Continuous Accumulation of Selected Ions CASI

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Bruker 9.4 T FT-ICR Apex-Qh Tandem Mass Spectrometer MALDI Dual source, MS only, no ion selection

ESI QCID (eV) MS/MS

Ion selection and activation in the ICR IRMPD, SORI, ECD

HDX in the ICR cell

55

Activation: SORI CID Low-energy (eV) Collisions with Gas (off resonance) RE (resonance excitation) IRMPD (Infrared Multiphoton Dissoc) ECD (electron transfer dissociation)

Intens. x107 3.0

YIGSR_QCID_22eV_000002.d: +MS2(595.0)

MS/MS spectra depend on i) Charge state ii) Ion activation method iii) Collision energy (more details in the Ion Activation Methods by Vicki Wysocki)

2.5

MH+ QCID 22 eV

249.1593

595.3171

2.0

1.5

302.1453

1.0 175.1186 560.2803 0.5 90.2256 0.0 x108 408.1864 465.2077 YIGSR_doubly_QCID_6eV_000001.d: +MS2(298.0) YIGSR doubly QCID 6eV 000001 d: +MS2(298 0)

1.5

[M+2H]2+ QCID 6 eV
249.1593

319.1718

1.0

0.5

y5
277.1541 432.2552 136.0756 YIGSR_doubly_IRMPD_40P_0_30s_000001.d: +MS2(298.0)

0.0 x107

2.0

[M+2H]2+ IRMPD 0.3s, 30%

298.2804 298 2804

1.5

1.0 249.1644 0.5

102.7325 0.0 100 200 300 400 500

595.3466 600 m/z

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Advantages and Disadvantages

Mass Spectrometer FTICR Advantages Highest recorded mass resolution of all mass spectrometers MSn Non-destructive ion detection Disadvantages Limited Dynamic Range Low E collisions High vacuum Low presure (difficult GC/LC coupling) Big i Bi size

Accurate mass A t measurement

Powerful capabilities Not a high for ion chemistry throughput technique experiments (ionmolecule rxns)

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TOF

Quadrupole

Quadrupole Ion trap FTICR Magnetic sector

Orbitrap

Orbitrap

58

Orbitrap

LTQ Orbitrap Hybrid MS

Finnigan LTQ Linear Ion Trap
API Ion source Linear Ion Trap C-Trap

Differential pumping

Orbitrap

Differential pumping

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LTQ Orbitrap Hybrid MS System Integration

Finnigan LTQ Linear Ion Trap

Gas <1 mtorr 1

V x

-2 k V

Central Electrode Voltage

-3.5 k V

Lord of the ion rings: Retainment of the rings

Image current detection on split outer electrodes

k m/ z

1. Frequencies are determined using a Fourier Transformation 2. For higher sensitivity AND resolution, transients should not decay too fast Ultra-high vacuum Ultra-high precision
Thermo slide

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Ion Motion in the Orbitrap

Simulation of ion trajectory with SIMION

Characteristic frequencies

Frequency of rotation Frequency of radial oscillations r Frequency of axial oscillations z

Rm 1 2 R

r = z

Rm 2 R

z =

k m/q

Orbitrap --Resolving Power

+5 Insulin: m/z = 5733 Charge state: +5, +4 and +3 +3
m/m = 70,000

+5 +4

1,200

1,400

m/z

1,600

1,800

2,000

+4
1,147 1,148

m/z

1,149

m/m = 45,000

+3
m/m = 40,000

1,434

m/z

1,435

1,436

R. Noll, H. Li, 2002

1,911

1,912

m/z

1,913

1,914

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Consider an ion source block and an extraction lens. How would you bias the block and lens if you want the ions to be accelerated by a) 8000 eV (appropriate for magnetic sector)

Question:

b) 5 eV (appropriate for entering a quadrupole)

c) 20,000 eV (appropriate for entering a TOF)

62

Learning Check
Draw the appearance of the mass spectrum in which both singly and doubly charged YGGFLR (molecular weight 711.3782) are produced and analyzed with a quadrupole, TOF and FT-ICR (Hint: peaks widths important)

712 in Quad, TOF, ICR

TOF Intensity

QUAD Intensity

m/z ICR m/z Intensity

m/z

63

Instrument Performance for Proteomic Applications

Han et al., Curr. Opin. Chem. Biol. 2008; 12(5):483-490.

64

Many instruments are complementary More Activation methods the better methods, Assess your needs Assess your budget @ Research level, may want to build your own

Suggested Reading List

GENERAL MS AND MS/MS Kinter, M. and Sherman, N. E., Protein Sequencing and Identification Using Tandem Mass Spectrometry, Wiley and Sons, New York, NY, 2000. De Hoffmann E., Mass Spectrometry Principles and Applications (Second Edition), Wiley and Sons, New York, NY, 2002. Busch, K.L., et al., Mass spectrometry/ mass spectrometry: techniques and applications of tandem mass spectrometry, VCH Publishing, New York, NY, 1988. McLafferty, F.W. (Ed) Tandem Mass Spectrometry, Wiley and Sons, New York, NY, 1983. McLafferty, F.W. and Turecek, F. Interpretation of Mass Spectra, University Science Books, New York, NY, 1993. Siuzdak, G. Mass Spectrometry for Biotechnology, Academic Press, San Diego, CA, 1996. Gygi, S P G i S.P. and A b d Aebersold, R C ld R., Curr. O i Ch Opin. Chem. Bi l 4 (5) 489 2000 Biol., (5): 489, 2000. Roepstorff, P., Curr. Opin. Biotech., 8: 6, 1997. De Hoffmann, JMS, 31: 129, 1996. Mann, M. et al., Annu. Rev. Biochem., 70: 437, 2001. McLuckey, S and Wells, J.M., Chem. Rev., 101: 571, 2001.

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Suggested Reading List

Q-TOF Morris, H.R. et al., J. Protein Chem., 16: 469, 1997. Shevchencko A., et al., Rapid Commun. Mass Spectrom., 11: 1015, 1997. Shevchencko A., et al., Anal. Chem., 72: 2132, 2000. Medzihradszky, K.F., et al., Anal. Chem., 72: 552, 2000. Glish, G.L. and Goeringer, D.E., Anal. Chem., 56: 2291, 1984 Morris, H.R. et al., Rapid Commun. Mass Spectrom., 10: 889, 1996. Wattenberg, A. et al., JASMS, 13 (7): 772, 2002. Lododa, A.V. et al., Rapid Commun. Mass Spectrom., 14(12): 1047, 2000.

TOF Bush, K., Spectroscopy, 12: 22, 1997. Cotter, R.J., Time-of-Flight: Instrumentation and Applications in Biological Research, ACS, Washington, DC, 1994.

Suggested Reading List

TOF-TOF Yergey, A.L. et al., JASMS, 13 (7): 784, 2002. Go, E.P. et al., Anal. Chem., 75: 2504, 2003. FTICR Buchanan, M.V. (Ed), Fourier Transform MS, ACS, Washington, DC, 1987. Comisarow, M.B. and Marshall, A. G., Chem. Phys. Lett., 25: 282, 1974. McIver, R.T. et al., Int. J. Mass Spectrom. Ion Processes, 64: 67, 1985. Kofel, P. et al., Int. J. Mass Spectrom. Ion Processes, 65: 97, 1985. Williams, E. R. Anal. Chem., 70: 179A, 1998. McLafferty, F. W. Acc. Chem. Res., 27: 379, 1994. Fridriksson, E. K. et al., Biochemistry, 39: 3369, 2000. Fridriksson, E. K. et al., Biochemistry, 38: 8056, 1999. Kelleher, N. L.et al., Protein Science, 7: 1796, 1998. McLafferty, F. W. et al., Int. J. Mass Spectrom., 165: 457, 1997. .

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Suggested Reading List

Green, M. K. and Lebrilla, C. B. Mass Spectrom. Rev., 16: 53, 1997. Guan, S. and Marshall, A. G. Chem. Rev., 94: 2161, 1994 QIT Marsh, R.E. et al., Quadrupole Storage Mass Spectrometry, vol.102, Wiley and Sons, New York, NY, 1989. Cooks, R.G. et al., Ion trap mass spectrometry. Chem. Eng. News, 69(12): 26, 1991. Jonscher, K.R. et al., Anal Biochem, 244(1): 1, 1997. Louris, J.N. et al., Anal. Chem., 59(13): 1677, 1987. Louris, J.N. et al., Int. J. Mass Spectrom. Ion Processes, 96(2): 117 1990. Cooks, R.G. et al., Int. J. Mass Spectrom. Ion Processes, 118-119: 1 1992. McLuckey, S. A. et al., Int. J. Mass Spectrom. Ion Processes, 106: 213, 1991. Ngoka, L. C. M. and Gross, M. L. Int. J. Mass Spectrom. 194: 247, 2000.

Suggested Reading List

QQQ Yost, R. A. and Enke, C. G. J. Am. Chem. Soc., 100: 2274, 1978. Arnott, D. in Proteome Research: Mass Spectrometry, james, P (Ed.), pp 11-31, Springer-Verlag, Germany, 2001. Steen H. et al., JMS, 36: 782, 2001 Miller, P.E. and Denton, M.B., J. Chem. Educ., 7: 617, 1986. Yang, l. et al., Rapid Commun. Mass Spectrom., 16(21): 2060, 2002. Mohammed, S. et al., JMS, 36: 1260, 2001. Dongre, A.R. et al., JMS, 31: 339, 1996. Orbitrap Hu, Q, Noll, RJ, Li, H., Makarov, A., Hardman, M., Cooks, R.G. JMS, 430-443, 2005. Makarov A. Anal. Chem. 2000; 72(6):1156-1162. Makarov A, Denisov E, Kholomeev A, Baischun W, Lange O, Strupat K, Anal. Chem. 2006; 78(7):2113-2120. Makarov A, Denisov E, Lange O, Horning S. JASMS. 2006; 17(7):977-982. Macek B, Waanders LF, Olsen JV, Mann M. Mol. Cell. Proteom. 2006; 5(5):949-958. Perry RH, Cooks RG, Noll RJ. Mass Spectrom. Rev. 2008; 27(6):661-699. Scigelova M, Makarov A. Orbitrap mass analyzer - Overview and applications in proteomics. Proteomics. 2006: 1621. Olsen JV, Macek B, Lange O, Makarov A, Horning S, Mann M. Nature Methods. 2007; 4(9):709-712.

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