of 67
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Mass Analyzersrpd Somogyi
Chemistry and Biochemistry MassSpectrometry Facility
Universit Joseph Fourier, Grenoble, November 19, 2010
Want to do MS or MS/MS ?Need a Mass Spectrometer
Ionizationsource
Massanalyzer
Detector
inlet all ions sortedions
Datasystem
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Ionizationsource
Massanalyzer
Detector
ions
a asystem
Ion movement Charged metal plates (electrodes, lenses) used
Electrodes and physical slits used to shape andrestrict ion beam
Good sensitivit is de endent on ood iontransmittance efficiency in this area
inlet all ions
Ionizationsource
Massanalyzer
sortedions
Detector
Datasystem
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Ion detection
Ions can be detected efficiently w/ high
that eject electrons
inlet all ions
Ionizationsource
Massanalyzer
sortedions
Detector
Datasystem
Kinetic energy of ions defined by
Ion energy
E = zeV = qV = mv2
E = kinetic energy
m = mass
v = velocitye = electronic charge (1.60217e-19 C)
z = nominal charge
V = accelerating voltage
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Learning Check
Consider two electrodes,
one at 1000 V and one at ground (0 V)
1000V 0 V
+ ion will travel with kinetic energy of___________
Mass spectrometers separate ions with a
Mass Resolution
defined resolution/resolving power
Resolving power- the ability of a massspectrometer to separate ions with
eren mass o c arge m z ra os.
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M
Resolution defined at 10% valley
R=M/M
M
Example of ultrahigh resolutionin an FTICR
J. Throck Watson Introduction to Mass Spectrometry p. 103
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General about mass
spectrometers
Common features
Accelerated charge species (ions) interactwith
Electrostatic field (ESA, OT)
Ma netic field B ICR
Electromagnetic (rf) fields (Q, IT, LT)
Or ions just fly (TOF)
1) They should sort ions by m/z
Desirable mass spectrometercharacteristics
2) They should have good transmission (improvessensitivity)
3) They should have appropriate resolution (helpsselectivity)
4) They should have appropriate upper m/z limit
5) They should be compatible with source output(pulsed or continuous)
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For each of the following applications, choose the mostappropriate mass analyzer from the following list. Use eachanalyzer only once.
orbitrap (OT) quadrupole (Q)time-of-flight (TOF) FTICR
Analyzer Purpose______ synthetic organic chemist wants exact mass of
compound_______ biochemist wants protein molecular weight of
relatively large protein (MW 300,000)_______
confirmation of benzene in extracts from 3000
soil samples_______ Petroleum chemist wants to confirm the
presence of 55 unique compounds at onenominal mass/charge value in a mass spectrum
m/z values are determined by actually measuring different
Mass spectrometers record m/zvalues
Type of analyzer electric sector
magnetic sector
Physical parameter used asbasis for separation kinetic energy/z
momentum/z
p ys ca parame ers
quadrupole, ion trap time-of-flight
FT-ion cyclotron resonance
m/z flight time
m/z (resonance frequencies)
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Magnetic (B) and/or Electrostatic (E) (HISTORIC/OLDEST)
Time-of-flight (TOF)
Types of Mass Analyzers
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
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Notice: accelerating voltages vary with analyzer(has consequences for MS/MS)
High voltage (keV energy range)
magne
electrostatic (E)
time-of-flight (TOF)
quadrupole (Q)
ion trap (IT, LT)
ion cyclotron resonance (ICR)
IonizationIonization AnalysisAnalysis
MS and MS/MS revisited
MS:
Collide withtarget to producefragments
Collide with
fragments
MS/MS:
Ionization
MS/MS:
Ionization AnalysisAnalysisSelectionSelection ActivationActivation
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http://www.iupac.org/goldbook/T06250.pdf
Tandem in Space
Current popular MS/MSarrangements (2009)
q
Q Trap
Q TOF
TOF TOF
Tandem in Time
Ion Trap (2 or 3 D)
FT-ICR (FT)
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Decision factors when choosing a
mass spectrometer
S p e e e e e e e e e e e e e d
R e s o l u t i o n Sensitivity
r Co$t
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TOFQuadrupole
Quadrupole Ion trap
FTICR
Orbitrap
D
tor
Time of Flight
KE = zeV = mv2 m = massV = velocity
v = D/t D = distance of flight
m/z
V
Dete
t = time of flightm(D/t)2 = zeV KE = kinetic energy
e = charge
D=t
21
2zeVm
/
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How does the ion generationstep in TOF influence m/z
analysis?
Matrix
h
et
Analyte+
Targ
Analyte ion may have (1) Kinetic Energydistribution or (2) Spatial distribution
How will KE spread influencethe spectrum?
Ions of same
Hasslightlygreater KE
Effect is broadpeaks
c/o Cotter
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Solution to peak broadening caused by
How will KE spread influencethe spectrum?
kinetic energy spread:
Reflectron (ion mirror)
Series of ring electrodes, typicallywith linear voltage gradient
Increased resolution by compensating for KE spread from thesource
Time-of-Flight Reflectron
http://www.jic.bbsrc.ac.uk/services/proteomics/tof.htm
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Ion Source
Detector
Mass Analyzer
(TOF)
Reflectron
Reflectron TOF
xx
x
x x
(MALDI)
KE = mv2
High resolution
Ion Source
Detector
Mass Analyzer(TOF)
ReflectronReflectron TOF
x
(MALDI)
KE = mv2
High resolution
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http://www.abrf.org/ABRFNews/1997/June1997/jun97lennon.html
We talked about howto deal with kineticenergy spread.
How do we deal withions formed atdifferent locations inthe source (spatialdistribution)?
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10 KV 10 KV
Delayed Extraction
+
+
+
+
7 KV
++
++
+
+
Low mass (below 40 k Da)High resolution
Continuous TOF
Resolution = 700 (FWHM)
Continuous vs. Delayed Extraction
Delayed Extraction
Resolution = 6000 (FWHM)
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3145.708 * Pepmix\0_N6\1\1SRef
5000
6000
In
te
n
s.
[a
.u.
]
Recent TOF designs: improved resolution, better sensitivity and mass accuracy(Ultraflex III MALDI TOF-TOF)
Resolution: 25 000
3177.722
1000
2000
3000
4000
S/N: 46
03140 3145 3150 3155 3160 3165 3170 3175 3180 3185
m/z
m/zRange: unlimited u
~
Quantification: low -
Typical TOF Specs
,(Reflectron)
Mass Accuracy: ~ 3-10ppm (300-4,000 u)
Scan Speed: 106 u/s
Vacuum: 10-7 Torr
Positive andNegative Ions
Variations: Linear,Reflectron, Tandem
,and/or sectors
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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
ragmen a on
than QqQ
or trap
(low energy,e , co s ons
Mass Spectrometer Advantages Disadvantages
TOF-TOF high resolution, high Large size
Advantages and Disadvantages
m/z fragment ions
keV CID
Not ideal forcontinuous
ionization source
easier de novopeptide sequencing
$$$
dn and wn todistinguish Ile/Leu
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TOFQuadrupole
Analyzers
Quadrupole Ion trap
FTICR
Orbitrap
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Quadrupole (Q)
four parallel rods or poles
fixed DC and alternating RF voltages
Quadrupole (Q)
rf voltage+dc voltage
rf voltage 180 out of phase-dc voltage
on y part cu ar m z w e ocuse on t edetector, all the other ions will be deflected intothe rods
scan by varying the amplitude of the voltages
(AC/DC constant).
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Positive rod
Quadrupole Field Animation
Negative rod
http://www.kettering.edu/~drussell/Demos/MembraneCircle/Circle.html
Positive rod Negative rod
negative DC offset
+
+
-- positive DC offset
-DC
+DC
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+ DC, ions focused to center
Ion Motion in Quadrupoles- a qualitative understanding
- DC, ions defocused
+DC w/ rf, light ions respond to rf, eliminated(high mass filter)
-DC w/ rf, light ions respond to rf, focused tocenter(low mass filter)
TSQ 70001993 to 2000
TSQ Quantum2001 to
c/o ThermoFinnigan Corp.
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Quadrupole animation
http://www.youtube.com/watch?v=8AQaFdI1Yow&feature=related
QuickTime and aTIFF (LZW) decompressor
are needed to see this picture.
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RF only mode
Initial kinetic energy affects ion motion in quad
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m/zRan e: 2-4000 u Quantification: good
Quadrupole Typical Specs
Resolution: Unit Mass Accuracy: ca +/-
0.1 u
Scan Speed: 4000 u/s Vacuum: 10-4 10-5
Torr
Positive and NegativeIons
Variations: SingleQ,TripleQ, Hybrids
Low Voltages:
RF ~6000 10000 VDC ~500V-840V
Source near ground
What MS/MS instruments can be
What MS/MS instruments can beproduced from Q and TOF?
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Triple Quadrupole- since 1970s and still going strong!
Q1 Q2 Q3
S D
Attractive Features:
Source near ground and operates at relatively high pressure
Couples well to source and to chromatographyMultiple scan modes easy to implement
DetectionSystem
Q3
Dynode Turbo
Triple Quadrupole (QQQ)
Source
HeatedCapillary
Q2
Q1Q0
c/o Thermo Finnigan Corp.
Q3
Q2
Q1 Q0 Q00
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) Collisionswith Gas
The third Q in QQQ is replacedby a TOF
Advantages?
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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 / z246.1
600
500
400
100
80enisty
300
200
100
m/z
SDGRGGRGDS
40
20
0RelativeIn
76543210Drift Time (ms)
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Transfer CID of [M+2H]+2 at m / z246.1
3.0
ime(ms)
100eAbundance
100
50
0
.
2.0Drift
dt = 2.68-2.83 ms
SDGRG
b4
RSi
y4y3
50
0
Relativ
500400300200100
m / z
dt = 2.49-2.68 ms
GRGDS
b3
b2
y1
R
Si
UL_110510_GNR.raw : 1
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140
150
)
Corrected Cross Sections (A2) as a Function of m/z for SinglProtonated GnR (n=1-7)
G7R
100
110
120
130
libratedCrossSections(A
G4R
200 250 300 350 400 450 500 550 600
90
C
m/z
GR
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TOFQuadrupole
Analyzers
Quadrupole Ion trap
FTICR
Orbitrap
What is small, inexpensiveand still gives great MSMS ?????
Quadrupole Ion TrapsMiniature 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 threehyperbolic electrodes: the ring electrode, theentrance end cap electrode and the exit endcape ec ro e.
Ions enter trap through inlet focusing system andentrance endcap electrode.
An AC potential of constant frequency and variableamplitude is applied to the ring electrode to producea 3D quadrupolar potential field within the trappingcavity which traps ions in a stable oscillating
. The oscillating trajectory is dependent on the trapping
potential and the mass-to-charge ratio of the ions. During ion detection, the electrode system potentialsare altered to produce instabilities in the iontrajectories and thus eject the ions.
Quadrupole Ion Trap (QIT)
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3D - Quadrupole Ion Trap (Demo)
Activation:Low-energy (eV) Collisions
w as
IRMPD(Infrared Multiphoton Dissoc)
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Research: Micro CIT ArrayResearch: Micro CIT Array
Matt Blain, SandiaCooks, Purdue
. m
2.4 m
Top End Cap Array
Ring Electrode Array
Bottom End Cap Array
Collector Array
QIT Typical Specs
m/zRange: 20-6000 u Quantification:
Mass Accuracy: ca +/-0.1 u
Scan Speed: 4000 u/s
Vacuum: 10-3 Torr
,
Positive andNegative Ions
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Mass Spectrometer Advantages Disadvantages
QIT Compact Limited storage of ions limits the
Advantages and Disadvantages
ion trap (spacecharge effect)
MSn 1/3 of low massrange lost in MS/MS
mode, typicaloperation
scanning
Relativelyinexpensive
Low E collisions
Mass Spectrometer Advantages Disadvantages
QIT Poor uantification
Advantages and Disadvantages
Sensitive Collision energy notwell-defined in CIDMS/MS
Mass Accuracy
To increase mass accuracy in aTrap LT, orbitrap, FT-ICR
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RF ION TRAP ELECTRODESTRUCTURES
LCQ-Type 3D LTQ-Type (2D)
ASMS Fall Workshop2006 JEPS
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2D vs. 3D Ion Traps
Skimmer
Ion Transfer
Tube
Tube Lens
Linear Trap Demo
Skimmer
Ion Transfer
Tube
Tube Lens
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Overall Performance GainsOverall Performance Gains
Trapping efficiency
Detection efficiency
Trapping capacity
~ 50-100% ~50% ~ 1-2x
~ 55-70% ~5% ~ 11-14x
~ 20,000 ions ~500 ions ~ 40x
Increased Trapping Efficiency
Increased Trapping Capacity
Motivating Factors Realized
Increased Sensitivity
Increased Inherent Dynamic Range
Which means....
ncrease or u can Practical MSn
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
Skimmer
~ 100% of ions trapped aredetected due to radial ejection
Linear Ion Trap
LIT and QTrap; Different ways of using Linear TrapsLIT and QTrap; Different ways of using Linear Traps
Axial ejection allows forhybridization without compromise (FT)!
Hybrid Quadrupole Trap
~ 15% detected*
Majority of trapped ionscannot be scanned out
Axial ejection depends on fringe fields generated by grid this grid compromises triple quadrupole performance
*Hager, J., RCM., 2003, 17, 1389
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Activation:
CID-
with Gas
IRMPD
ETD(electron transfer dissociation)
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TOFQuadrupole
Analyzers
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 ofelectrostatic field (magnetron/cyclotron motion, see below)
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Ion Detection Plates
RF-excitation
B
v
Ion Detection Plates
Note: for clarity, the front and back trapping plates are not shown
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In the presence of a magnetic field, sampleions orbit accordin to c clotron fre uenc f
Fourier Transform-Ion Cyclotron
Resonance (FTICR)
Cyclotron frequency related to charge of ion(z), magnetic field strength (B) and mass ofion (m).
All ions of same m/z will have same cyclotronfrequency at a fixed B and will move in acoherent ion packet.
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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.
a
b c194.1405
C9H16N5time (ms)
194.1657
194.1154
C11H20N3
C7H12N7
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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 aTIFF (LZW) decompressor
are needed to see this picture.
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FTICR Typical Specs
m/zRange: > 15000 u6
Quantification:,
Mass Accuracy: 100ppb
Scan Speed: fast
Vacuum: 10-7- 10-9 Torr
,
Positive andNegative Ions
11+
10+
12+
9+
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Charge state/MW determination
for proteins
m = z(m/z)
Carbonsisotopes som=1 Da
Calc(m/z)
FTMS Data
Finnigan LTQ FTLinear 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
7 T Actively Shielded
Superconducting Magnet
Linear Ion Trap Data
210L/s60m3/hr 300L/s 400L/s 210L/s15L/s
Triple Ported Turbo Pump
ECD Assembly
IRMPD Laser Assembly
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The new apex-ultra- -
Introducing the New apex-ultraHybrid Qq-FTMS
Announced at PittCon 2007 in Chicago, IL
with power and versatility
Improved electronics forsubstantial gains inanalytical performanceand capabilities
Comprehensive softwaretools that are specificallydesigned for proteincharacterization
Versatility matched with Performance
The apex-ultra
Q1 h2h1
Masses can be filteredhere in a results-driven,targeted approach
ESI source region ECD / IRMPD
Ions accumulated hereto build significantpopulations an in-cellevent (e.g. ECD)
Continuous Accumulation of Selected Ions CASI
CA SI p rov ides the means to en r i ch o r am p l i f y l ow abundan t spec ies fo r subsequen t f ragm en ta t ion and ana lys is
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Bruker 9.4 T FT-ICR Apex-Qh Tandem Mass Spectrometer
MALDIDual 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
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Activation:
SORI CIDLow-energy (eV) Collisionswith Gas (off resonance)
RE(resonance excitation)
IRMPD(Infrared Multiphoton Dissoc)
ECD(electron transfer dissociation)
90.2256
175.1186
249.1593
302.1453
408.1864465.2077
560.2803
595.3171
YIGSR_QCID_22eV_000002.d: +MS2(595.0)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
7x10
Intens.
1 : +81
MH+
QCID 22 eVMS/MS spectra depend
oni) Charge stateii) Ion activation methodiii) Collision energy
136.0756
249.1593
277.1541
319.1718
432.2552
_dou y_ _ e _ 1.d: + ( .
0.0
0.5
1.0
1.5
x1
YIGSR_doubly_IRMPD_40P_0_30s_000001.d: +MS2(298.0)7x10
[M+2H]2+
QCID 6 eV
y5
(more details in theIon ActivationMethodsby Vicki Wysocki)
100 200 300 400 500 600 m/z100 200 300 400 500 600 m/z
102.7325
249.1644
.
595.34660.0
0.5
1.0
1.5
2.0
100 200 300 400 500 600 m/z
IRMPD 0.3s, 30%
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Mass Spectrometer Advantages DisadvantagesFTICR Highest recorded
mass resolution of allLimited Dynamic
Range
Advantages and Disadvantages
mass spectrometers
MSn Low E collisions
Non-destructive iondetection
High vacuum
Low presure
(difficult GC/LCcoupling)
Accurate massmeasurement
Big size
Powerful capabilitiesfor ion chemistryexperiments (ion-
molecule rxns)
Not a highthroughput technique
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TOFQuadrupole
Quadrupole Ion trap
Magnetic sector
FTICR
Orbitrap
Orbitrap
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Orbitrap
LTQ Orbitrap Hybrid MSFinnigan LTQ Linear Ion Trap
API Ion source Linear Ion Trap C-Trap
Differential pumping
Differential pumping
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LTQ Orbitrap Hybrid MSSystem Integration
Gas
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Ion Motion in the Orbitrap
Simulation of ion trajectory with SIMIONSimulation of ion trajectory with SIMION
2
Rm2
RmCharacteristic frequenciesCharacteristic frequencies
Frequency of rotation
Frequency of radial oscillations r
Frequency of axial oscillations z
2
=R
2
=R
2
2
=R
Rmzr
2
2
=R
Rmzr
qm
kz
/=
qm
kz
/=
Insulin: m/z = 5733
Charge state: +5, +4 and +3
Insulin: m/z = 5733
Charge state: +5, +4 and +3
Orbitrap --Resolving Power
+
+5
+3
m/z1,1491,1481,147
+4
m/z2,0001,8001,6001,4001,200
+4m/m = 70,000
m/m = 45,000
m/z1,4361,4351,434
m/z1,9141,9131,9121,911
+3
m/m = 40,000
R. Noll, H. Li, 2002
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Question: Consider an ion source block and anextraction lens. How would you bias the block andlens if you want the ions to be accelerated by
b) 5 eV (appropriate for entering a quadrupole)
c) 20,000 eV (appropriate for entering a TOF)
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Learning Check
Draw the appearance of the mass spectrum in whichboth singly and doubly charged YGGFLR (molecular.
quadrupole, TOF and FT-ICR (Hint: peaks widthsimportant)
712 in Quad, TOF, ICR
sity
TOF
m/z
Intensity
Inten
QUAD
ICR
m/z
m/z
Intensity
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Instrument Performance for Proteomic Applications
Han et al., Curr. Opin. Chem. Biol. 2008; 12(5):483-490.
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Many instruments are complementary
,
Assess your needs
Assess your budget
@ Research level, may want to buildyour own
Suggested Reading ListGENERAL 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 tandemmass spectrometry, VCH Publishing, New York, NY, 1988.
McLafferty, F.W. (Ed) Tandem Mass Spectrometry, Wiley and Sons, New York, NY, 1983.
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