Introduction to Peptide Sequencing

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Introduction to Peptide equencing Quadrupole Ion Traps tructural Biophysics Course December 3, 2014 12/8/14 Introduction to Peptide equencing - athan Yates 1

Why are ion traps used to sequence peptides? ensitive tandem mass spectrometers Improved ion statistics in MM mode compared to M due to the storage and isolation of a single parent m/z igh CID efficiency due to the continuous and mass selective excitation of the parent Rapid scan rate allows several full scan M/M spectra to be acquired each second Data-dependent acquisition of tandem M spectra Integration with automated sequencing tools EQUET, Mascot, Pepsea, GPM, Peptide Prophet, etc 12/8/14 Introduction to Peptide equencing - athan Yates 2

Example CAD / CID spectrum - LCQ sq3027 #868-1060 RT: 23.16-28.24 AV: 3 L: 4.53E7 T: + c EI RM ms2 612.42@35.00 [155.00-1850.00] x2 x2 x2 x4 x2 100 767.3 95 90 85 80 75 70 995.4 65 581.3 Relative Abundance 60 55 50 45 40 35 228.9 344.0 429.1 457.1 643.2 996.4 30 880.4 25 20 494.2 15 201.0 990.2 1077.3 10 347.2 730.2 495.2 234.0 1124.3 769.3 5 411.1 712.1 972.2 327.9 796.5 928.1 1060.1 1164.0 1235.2 0 200 300 400 500 600 700 800 900 1000 1100 1200 12/8/14 Introduction to Peptide equencing m/z - athan Yates 3

Acknowledgment 12/8/14 Introduction to Peptide equencing - athan Yates 4

ample Peptide tructure and C Termini 2 C C C 3 -Terminus basic site of protonation blocked by acetyl group, cyclization, and pyroglutamic acid basicity in gas phase close to amide bond 2 C-Terminus carboxilic acid acetyl Pyroglutamic acid 12/8/14 Introduction to Peptide equencing - athan Yates 5

ample Peptide tructure Glycine Glycine GLY (G) 57 2 C C C 3 2 12/8/14 Introduction to Peptide equencing - athan Yates 6

ample Peptide tructure 2 C C C 3 Alanine ALA (A) 71 2 12/8/14 Introduction to Peptide equencing - athan Yates 7

ample Peptide tructure erine and Threonine erine ER () 87 2 C C C 3 Threonine TR (T) 101 2 erine and Threonine alcohol loses 2 common site for phosphorylation 12/8/14 Introduction to Peptide equencing - athan Yates 8

ample Peptide tructure - Proline 2 C C C 3 Proline PR (P) 97 2 Proline 3 bonds to make it the most basic AA in gas phase preferential cleavage on the -terminal side 12/8/14 Introduction to Peptide equencing - athan Yates 9

ample Peptide tructure - Valine Valine VAL (V) 99 2 C C C 3 2 12/8/14 Introduction to Peptide equencing - athan Yates 10

ample Peptide tructure - Cysteine Cystiene CY (C) 103 C 2 2 C C C 3 Cystiene group can be oxidized during chromatography carboxymethylation of with iodoacetic acid forms disulfide bonds with other Cys reduce to brake - bonds 2 Caboxymethylcystiene CMC (C) 161 12/8/14 Introduction to Peptide equencing - athan Yates 11

ample Peptide tructure Leucine and Isoleucine Leucine LEU (L) 113 2 2 Isoleucine ILE (I) 113 2 2 Leucine and Isoleucine Identical residue mass Differentiated by high energy collisions Lxx (X) takes place of ILE and LEU 12/8/14 Introduction to Peptide equencing - athan Yates 12

ample Peptide tructure Asparagine and Glutamine 2 2 2 2 Asparagine A () 114 Glutamine GL (Q) 128 Asparagine and Glutamine amide side chains lose ammonia -17 slightly basic 12/8/14 Introduction to Peptide equencing - athan Yates 13

ample Peptide tructure Lysine Lysine LY (K) 128 2 2 2 2 Lysine 2 nd most basic site side chain free amino group acetylated with acetic anhydride C-terminal cleavage with trypsin o ammonia loss distinguishes from Gln (128) 12/8/14 Introduction to Peptide equencing - athan Yates 14

ample Peptide tructure Aspartic and Glutamic Acid Aspartic Acid AP (D) 115 2 2 2 2 Aspartic and Glutamic Acid Carboxylic acids o ammonia loss distinguish Asp/Asn and Glu/Gln Glutamic Acid GLU (E) 129 12/8/14 Introduction to Peptide equencing - athan Yates 15

ample Peptide tructure Methionine and Met sulfoxide 2 Methionine Met (M) 131 2 2 2 Methionine Readily oxidized with sample handeling Met sulfoxide and Phenylalanine = 147 Met sulfoxide can be reduced (-16) Met ulfoxide CMC (C) 147 12/8/14 Introduction to Peptide equencing - athan Yates 16

ample Peptide tructure istidine istidine I () 137 2 2 istidine 3 rd most basic side chain characteristic low mass fragment = 110 12/8/14 Introduction to Peptide equencing - athan Yates 17

ample Peptide tructure Phenylalanine 2 2 Phenylalanine PE (F) 147 Phenylalanine Met sulfoxide and Phenylalanine = 147 Met sulfoxide can be reduced (-16) 12/8/14 Introduction to Peptide equencing - athan Yates 18

ample Peptide tructure Arginine Arginine ARG (R) 156 2 2 Arginine most basic side chain c-terminal cleavage by trypsin proton held tight, blocks fragmentation in middle of molecule 12/8/14 Introduction to Peptide equencing - athan Yates 19

ample Peptide tructure Tyrosine and Tryptophan 2 Tryptophan TRP (W) 186 2 Tyrosine less common site of phosphorylation Tyrosine TYR (Y) 163 12/8/14 Introduction to Peptide equencing - athan Yates 20

Table 1 - Amino Acid Gas Phase Proton Affinity Amino Acid R- PA (kcal/mol relative to 3 = 205 kcal/mol) Glycine Gly G - 211.6 Alanine Ala A C 3-214.8 Cysteine Cys C -C 2 - - erine er -C 2-216.5 Valine Val V (C 3 ) 2 -C- 218.3 Aspartic acid Asp D C-C 2-218.6 Leucine Leu L (C 3 ) 2 -C-C 2-218.9 Threonine Thr T C 3 -C()- 219.2 Isoleucine Ile I C 3 -C 2 -C(C 3 )- 219.2 Phenylalanine Phe F Ph-C 2-220.0 Tyrosine Tyr Y -p-ph-c 2-220.7 Methionine Met M C 3 --(C 2 ) 2-220.9 Asparagine Asn 2 -C-C 2-222.1 Glutamic acid Glu E C-(C 2 ) 2-222.3 Proline Pro P -C 2 -C 3 -C 2-222.4 Tryptophan Trp W Ph--C=C-C 2-224.3 Glutamine Gln Q 2 -C-(C 2 ) 2-227.1 Lysine Lys K 2 -(C 2 ) 4-228.7 istidine is -C=-C=C-C 2-230.5 Arginine Arg R =C( 2 )--(C 2 ) 3-245.0 12/8/14 Introduction to Peptide equencing - athan Yates 21

Table 2 - Amino Acid Residue Mass and Mass Increments Amino Acid R- Residue Mass Me Increment Glycine Gly G - 57.02 - Alanine Ala A C 3-71.04-14 erine er -C 2-87.03-16 Proline Pro P -C 2 -C 3 -C 2-97.05-10 Valine Val V (C 3 ) 2 -C- 99.07-2 Threonine Thr T C 3 -C()- 101.05-2 Cysteine Cys C -C 2-103.01-2 Isoleucine Ile I C 3 -C 2 -C(C 3 )- 113.08-10 Leucine Leu L (C 3 ) 2 -C-C 2-113.08 - - Asparagine Asn 2 -C-C 2-114.04-1 Aspartic acid Asp D C-C 2-115.03 129.04 1 Glutamine Gln Q 2 -C-(C 2 ) 2-128.06-13 Lysine Lys K 2-(C2)4-128.09 - - Glutamic acid Glu E C-(C 2 ) 2-129.04 143.06 1 Methionine Met M C 3 --(C 2 ) 2-131.04-2 istidine is -C=-C=C-C 2-137.06-6 Phenylalanine Phe F Ph-C 2-147.07-10 Arginine Arg R =C( 2 )--(C 2 ) 3-156.10-9 Carboxymethyl Cystiene Cmc C CC 2 --C 2-161.02 175.04 5 Tyrosine Tyr Y -p-ph-c 2-163.06-2 Tryptophan Trp W Ph--C=C-C 2-186.08-23 Residue masses have structure --C(-R)-C- 12/8/14 Introduction to Peptide equencing - athan Yates 22

Table 3 - Amino Acid eutral Loss and Low Mass Fragments Amino Acid R- eutral Loss Low Mass Fragment Glycine Gly G - - - Alanine Ala A C 3 - - - erine er -C 2-18 (2) - Proline Pro P -C 2 -C 3 -C 2 - - 70 Valine Val V (C 3 ) 2 -C- - 72 Threonine Thr T C 3 -C()- 18 (2) - Cysteine Cys C -C 2-34 (2) - Isoleucine Ile I C 3 -C 2 -C(C 3 )- - 86 Leucine Leu L (C 3 ) 2 -C-C 2 - - 86 Asparagine Asn 2 -C-C 2-17 (3) 70, 87 Aspartic acid Asp D C-C 2 - - - Glutamine Gln Q 2 -C-(C 2 ) 2-17 (3) 84, 101, 129 Lysine Lys K 2-(C2)4-84, 101, 129 Glutamic acid Glu E C-(C 2 ) 2-18 (2) 84, 102 Methionine Met M C 3 --(C 2 ) 2-48 (C2) 104 istidine is -C=-C=C-C 2 - - 110 Phenylalanine Phe F Ph-C 2 - - 120 Arginine Arg R =C( 2 )--(C 2 ) 3-17 (3) 70, 98, 129 Carboxymethyl Cystiene Cmc C CC 2 --C 2-92 (C2C) 134 Tyrosine Tyr Y -p-ph-c 2 - - 136 Tryptophan Trp W Ph--C=C-C 2 - - 159 Bold face indicates strong signals 12/8/14 Introduction to Peptide equencing - athan Yates 23

Table 4 - Combined Residue Mass for Two Amino Acids Gly Ala er Pro Val Thr Cys Lxx Asn Asp Gln Lys Glu Met is Phe Arg Cmc Tyr Trp AA 57 71 87 97 99 101 103 113 114 115 128 128 129 131 137 147 156 161 163 186 Gly 57 114 Ala 71 128 142 er 87 144 158 174 Pro 97 154 168 184 194 Val 99 156 170 186 196 198 Thr 101 158 172 188 198 200 202 Cys 103 160 174 190 200 202 204 206 Lxx 113 170 184 200 210 212 214 216 226 Asn 114 171 185 201 211 213 215 217 227 228 Asp 115 172 186 202 212 214 216 218 228 229 230 Gln 128 185 199 215 225 227 229 231 241 242 243 256 Lys 128 185 199 215 225 227 229 231 241 242 243 256 256 Glu 129 186 200 216 226 228 230 232 242 243 244 257 257 258 Met 131 188 202 218 228 230 232 234 244 245 246 259 259 260 262 is 137 194 208 224 234 236 238 240 250 251 252 265 265 266 268 274 Phe 147 204 218 234 244 246 248 250 260 261 262 275 275 276 278 284 294 Arg 156 213 227 243 253 255 257 259 269 270 271 284 284 285 287 293 303 312 Cmc 161 218 232 248 258 260 262 264 274 275 276 289 289 290 292 298 308 317 322 Tyr 163 220 234 250 260 262 264 266 276 277 278 291 291 292 294 300 310 319 324 326 Trp 186 243 257 273 283 285 287 289 299 300 301 314 314 315 317 323 333 342 347 349 372 12/8/14 Introduction to Peptide equencing - athan Yates 24

http://www.dkfz-heidelberg.de/z_spek/m/research.htm 12/8/14 Introduction to Peptide equencing - athan Yates 25

http://www.dkfz-heidelberg.de/z_spek/m/research.htm 12/8/14 Introduction to Peptide equencing - athan Yates 26

Fragment Ion omenclature Roepstorff, P and Fohlman, J, Proposal for a common nomenclature for sequence ions in mass spectra of peptides. Biomed Mass pectrom, 11(11) 601 (1984). 12/8/14 Introduction to Peptide equencing - athan Yates 27

Fragment Ion omenclature Immonium Ions An internal fragment with just a single side chain formed by a combination of a type and y type cleavage is called an immonium ion. These ions are labelled with the 1 letter code for the corresponding amino acid. Internal Cleavage Ions Double backbone cleavage gives rise to internal fragments. Usually, these are formed by a combination of b type and y type cleavage to produce the illustrated structure, an amino-acylium ion. ometimes, internal cleavage ions can be formed by a combination of a type and y type cleavage, an amino-immonium ion. Internal fragments are labeled with their 1 letter amino acid code. 12/8/14 Introduction to Peptide equencing - athan Yates 28

Fragmentation scheme for [M+2] 2+ ion of ATFYK 2 + + 2 2 + 2 b 2 -ion + 2 y 4 -ion 12/8/14 Introduction to Peptide equencing - athan Yates 29

Formation of b-ion eries Fragment Ions 72 173 260 407 570 717 b-ions Ala - Thr - er - Phe - Tyr - Lys 717 645 544 457 310 147 y-ions 2 + b 5 -ion + 2 [M+2] 2+ 2 + 2 2 + + b 3 -ion b 4 -ion The ion of type b 1, --C(R)-C +, is at m/z = residue mass of amino acid #1 + + b 1 = (AA 1 + + ). b 2 = (b 1 + AA 2 ) etc. [M+] + = b n-1 + AA n + 2 2 2 + + b 1 -ion b 2 -ion 12/8/14 Introduction to Peptide equencing - athan Yates 30

Formation of y-ion eries Fragment Ions 2 + 72 173 260 407 570 717 b-ions Ala - Thr - er - Phe - Tyr - Lys 717 645 544 457 310 147 y-ions y 5 -ion 2 2 + + 2 [M+2] 2+ 2 + y 4 -ion 2 y 3 -ion 2 2 + The ion of type y 1, 2 - + -C(R)-C-, is at m/z = AA n + + + 2 y 1 = (AAn + 2 + + ). y 2 = (y 1 + AA n-1 ) etc. [M+] + = y n-1 + AA 1 2 2 + y 2 -ion 2 2 + 12/8/14 Introduction to Peptide equencing y 1 -ion - athan Yates 31

Corresponding b and y ion pairs [M+2]=910 b-ions 164 221 278 379 480 579 650 763 909 Tyr Gly Gly Thr Thr Val Ala Lxx Lys 909 746 689 632 531 430 331 260 147 y-ions 278 +632 910 579 +331 910 763 +147 910 12/8/14 Introduction to Peptide equencing - athan Yates 32

trategy for Interpreting CAD pectra Inspect the low-mass region for immonium ions Inspect the low-mass region for the b 2 and a 2 ions check dipeptide table for possibilities look for corresponding y-ions Inspect the low-mass region for the y 1 ion, Lys = 147, Arg = 175 Inspect the high-mass region to identify y n-1 ion Extend the y-ion series toward lower m/z calculate corresponding b-ions Extend the b-ion series toward higher m/z calculate corresponding y-ions Calculate the mass of the peptide Reconcile the amino acid content with spectrum data immonium ions, charge state Attempt to identify all ions in the spectrum doubly charged, internal cleavage, - 2, - 3, -C 3

Collision Activated Dissociation pectrum - Example 1 sq3027 #868-1060 RT: 23.16-28.24 AV: 3 L: 4.53E7 T: + c EI RM ms2 612.42@35.00 [155.00-1850.00] x2 x2 x2 x4 x2 100 767.3 95 90 85 80 75 70 995.4 65 581.3 Relative Abundance 60 55 50 45 40 35 228.9 344.0 429.1 457.1 643.2 996.4 30 880.4 25 20 494.2 15 201.0 990.2 1077.3 10 347.2 730.2 495.2 234.0 1124.3 769.3 5 411.1 712.1 972.2 327.9 796.5 928.1 1060.1 1164.0 1235.2 0 200 300 400 500 600 700 800 900 1000 1100 1200 12/8/14 Introduction to Peptide equencing m/z - athan Yates 34

Calc [M+] + sq3027 #868-1060 RT: 23.16-28.24 AV: 3 L: 4.53E7 T: + c EI RM ms2 612.42@35.00 [155.00-1850.00] x2 x2 x2 x4 x2 100 767.3 95 90 85 80 75 70 [M+] + = ([M+2] 2+ * 2) = (612.4*2)-1 = 1223.8 = 1223 995.4 65 581.3 Relative Abundance 60 55 50 45 40 35 228.9 344.0 429.1 457.1 643.2 996.4 30 880.4 25 20 494.2 15 201.0 990.2 1077.3 10 347.2 730.2 495.2 234.0 1124.3 769.3 5 411.1 712.1 972.2 327.9 796.5 928.1 1060.1 1164.0 1235.2 0 200 300 400 500 600 700 800 900 1000 1100 1200 12/8/14 Introduction to Peptide equencing m/z - athan Yates 35

Find b 2 + & a 2 + candidate ions sq3027 #868-1060 RT: 23.16-28.24 AV: 3 L: 4.53E7 T: + c EI RM ms2 612.42@35.00 [155.00-1850.00] x2 x2 x2 x4 x2 100 767.3 95 90 85 80 75 70 [M+] + = ([M+2] 2+ * 2) = (612.4*2)-1 = 1223.8 = 1223 995.4 65 581.3 Relative Abundance 60 55 50 45 40 35 b 2 228.9 344.0 429.1 457.1 643.2 996.4 30 880.4 25 20 15 10 5 0 a 2 494.2 201.0 990.2 1077.3 347.2 730.2 495.2 234.0 1124.3 769.3 411.1 712.1 972.2 327.9 796.5 928.1 1060.1 1164.0 1235.2 200 300 400 500 600 700 800 900 1000 1100 1200 12/8/14 Introduction to Peptide equencing m/z - athan Yates 36

Look up possible amino acid combinations for b 2 + ion sq3027 #868-1060 RT: 23.16-28.24 AV: 3 L: 4.53E7 T: + c EI RM ms2 612.42@35.00 [155.00-1850.00] x2 x2 x2 x4 x2 100 767.3 Relative Abundance 95 90 85 80 75 70 65 60 55 50 45 40 35 EV? XD?? MP? b 2 228.9 344.0 429.1 457.1 581.3 643.2 [M+] + = ([M+2] 2+ * 2) = (612.4*2)-1 = 1223.8 = 1223 995.4 996.4 30 880.4 25 20 15 10 5 0 a 2 494.2 201.0 990.2 1077.3 347.2 730.2 495.2 234.0 1124.3 769.3 411.1 712.1 972.2 327.9 796.5 928.1 1060.1 1164.0 1235.2 200 300 400 500 600 700 800 900 1000 1100 1200 12/8/14 Introduction to Peptide equencing m/z - athan Yates 37

Look for corresponding y n-1 ion sq3027 #868-1060 RT: 23.16-28.24 AV: 3 L: 4.53E7 T: + c EI RM ms2 612.42@35.00 [155.00-1850.00] x2 x2 x2 x4 x2 100 767.3 95 90 85 80 75 70 [M+] + = ([M+2] 2+ * 2) = (612.4*2)-1 = 1223.8 = 1223 995.4 65 581.3 Relative Abundance 60 55 50 45 40 35 b 2 228.9 344.0 429.1 457.1 643.2 996.4 30 880.4 25 20 15 10 5 0 a 2 494.2 201.0 990.2 1077.3 347.2 730.2 495.2 234.0 1124.3 769.3 411.1 712.1 972.2 327.9 796.5 928.1 1060.1 1164.0 1235.2 200 300 400 500 600 700 800 900 1000 1100 1200 12/8/14 Introduction to Peptide equencing m/z - athan Yates 38 y n-1

Extend the y-ion series toward lower m/z sq3027 #868-1060 RT: 23.16-28.24 AV: 3 L: 4.53E7 T: + c EI RM ms2 612.42@35.00 [155.00-1850.00] x2 x2 x2 x4 x2 100 767.3 95 90 [M+]+ = 1223 85 80 75 70 y n-2 995.4 65 581.3 Relative Abundance 60 55 50 45 40 35 b 2 228.9 344.0 429.1 457.1 643.2 996.4 30 880.4 25 20 15 10 5 0 a 2 201.0 y n-7 494.2 990.2 1077.3 347.2 730.2 495.2 234.0 1124.3 769.3 411.1 712.1 972.2 327.9 796.5 928.1 1060.1 1164.0 1235.2 200 300 400 500 600 700 800 900 1000 1100 1200 12/8/14 Introduction to Peptide equencing m/z - athan Yates 39 y n-1

Extend the y-ion series toward lower m/z sq3027 #868-1060 RT: 23.16-28.24 AV: 3 L: 4.53E7 T: + c EI RM ms2 612.42@35.00 [155.00-1850.00] x2 x2 x2 x4 x2 100 767.3 95 90 85 [M+]+ = 1223 80 75 y n-2 70 995.4 65 581.3 Relative Abundance 60 55 50 45 40 35 VE b 2 228.9 b 3 344.0 429.1 457.1 643.2 y n-3 996.4 30 880.4 25 20 15 10 5 0 a 2 494.2 201.0 990.2 1077.3 347.2 730.2 495.2 234.0 1124.3 769.3 411.1 712.1 972.2 327.9 796.5 928.1 1060.1 1164.0 1235.2 200 300 400 500 600 700 800 900 1000 1100 1200 12/8/14 Introduction to Peptide equencing m/z - athan Yates 40 y n-1

Extend the y-ion series toward lower m/z sq3027 #868-1060 RT: 23.16-28.24 AV: 3 L: 4.53E7 T: + c EI RM ms2 612.42@35.00 [155.00-1850.00] x2 x2 x2 x4 x2 100 767.3 95 90 85 y n-4 [M+]+ = 1223 80 75 y n-2 70 y n-5 995.4 65 581.3 Relative Abundance 60 55 50 45 40 35 VE b 2 228.9 b 3 344.0 429.1 457.1 643.2 y n-3 996.4 30 25 20 15 10 5 0 a 2 201.0 880.4 y y n-6 n-8 494.2 y n-1 y n-7 990.2 1077.3 347.2 730.2 495.2 234.0 1124.3 769.3 411.1 712.1 972.2 327.9 796.5 928.1 1060.1 1164.0 1235.2 200 300 400 500 600 700 800 900 1000 1100 1200 12/8/14 Introduction to Peptide equencing m/z - athan Yates 41

Extend the b-ion series toward higher m/z sq3027 #868-1060 RT: 23.16-28.24 AV: 3 L: 4.53E7 T: + c EI RM ms2 612.42@35.00 [155.00-1850.00] x2 x2 x2 x4 x2 100 767.3 95 90 85 y n-4 [M+]+ = 1223 80 75 y n-2 70 y n-5 995.4 65 581.3 Relative Abundance 60 55 50 45 40 35 VE b 2 228.9 b 3 344.0 429.1 b 4 457.1 b 5 643.2 y n-3 996.4 30 25 20 15 10 5 0 a 2 201.0 y n-6 200 300 400 500 600 700 800 900 1000 1100 1200 12/8/14 Introduction to Peptide equencing m/z - athan Yates 42 880.4 y b n-8 8 494.2 b 9 y n-7 b 7 b 6 y n-1 990.2 1077.3 347.2 730.2 495.2 234.0 1124.3 769.3 411.1 712.1 972.2 327.9 796.5 928.1 1060.1 1164.0 1235.2

Reconcile amino acid content sq3027 #868-1060 RT: 23.16-28.24 AV: 3 L: 4.53E7 T: + c EI RM ms2 612.42@35.00 [155.00-1850.00] x2 x2 x2 x4 x2 100 767.3 95 90 85 y n-4 [M+]+ = 1223 80 75 y n-2 70 y n-5 995.4 65 581.3 Relative Abundance 60 55 50 45 40 35 VE b 2 228.9 b 3 344.0 429.1 b 4 457.1 b 5 643.2 y n-3 996.4 30 25 20 15 10 5 0 a 2 201.0 y n-6 200 300 400 500 600 700 800 900 1000 1100 1200 12/8/14 Introduction to Peptide equencing m/z - athan Yates 43 880.4 y b n-8 8 494.2 b 9 y b b n-7 o 6 7 o o y n-1 990.2 1077.3 347.2 730.2 495.2 234.0 1124.3 769.3 411.1 712.1 972.2 327.9 796.5 928.1 1060.1 1164.0 1235.2

olution to CAD 1 457->643 trp causes some difficulty 767->643 = 124 not an AA b2 combinations = MP, VE, 12/8/14 Introduction to Peptide equencing - athan Yates 44

Collision Activated Dissociation pectrum - Example 2 sq3027 #62-284 RT: 1.58-7.36 AV: 3 L: 1.85E8 T: + c EI RM ms2 434.81@35.00 [105.00-1315.00] 100 584.2 95 90 85 80 75 70 65 453.3 Relative Abundance 60 55 50 45 40 35 30 186.1 285.2 323.2 338.4 585.2 683.2 25 20 684.2 454.3 531.1 15 399.2 10 169.1 257.2 416.2 586.2 5 240.2 342.5 514.1 532.1 685.2 141.1 214.1 371.1 455.2 533.1 631.1 677.0 694.1 720.2 797.1 809.3 0 150 200 250 300 350 400 450 500 550 600 650 700 750 800 850 12/8/14 Introduction to Peptide equencing m/z - athan Yates 45

Collision Activated Dissociation pectrum - Example 3 sq3027 #888-890 RT: 23.69-23.74 AV: 2 L: 5.21E6 T: + c EI RM ms2 980.67@35.00 [255.00-2000.00] 100 1104.4 95 90 85 80 75 70 65 888.4 Relative Abundance 60 55 50 45 40 975.4 1072.3 1274.4 35 30 25 20 15 10 5 0 645.3 686.2 744.4 856.3 400 600 800 1000 1200 1400 1600 1800 2000 12/8/14 Introduction to Peptide equencing m/z - athan Yates 46 1743.4 1217.4 1404.6 1298.3 516.2 1445.5 1590.7 500.2 410.1 1813.5 1554.3 1643.5 1832.9 1926.5

CAD Example 3 - Expanded sq3027 #888-890 RT: 23.69-23.74 AV: 2 L: 5.21E6 T: + c EI RM ms2 980.67@35.00 [255.00-2000.00] x4 100 1104.4 80 60 40 20 0 298.1 645.3 856.3 500.2 838.3 410.1 597.1 686.2 744.4 976.5 484.2 388.3 967.4 725.2 1054.3 758.3 916.8 1036.1 516.2 557.1 300 400 500 600 700 800 900 1000 1100 m/z 888.4 975.4 1072.3 Relative Abundance 1274.4 50 1275.5 40 30 20 10 0 1743.4 1217.4 1404.6 1298.3 1445.5 1590.7 1216.2 1742.5 1238.9 1554.3 1643.5 1813.5 1181.0 1317.3 1453.0 1719.5 1871.9 1926.5 1990.4 1200 1300 1400 1500 1600 1700 1800 1900 2000 12/8/14 Introduction to Peptide equencing m/z - athan Yates 47

Collision Activated Dissociation pectrum - Example 4 sq3027 #454-618 RT: 12.05-16.57 AV: 4 L: 2.47E7 T: + c EI RM ms2 524.38@35.00 [130.00-1585.00] x4 x2 x4 x4 100 737.3 95 90 85 80 75 70 65 Relative Abundance 60 55 50 45 40 35 30 25 283.0 368.0 310.9 416.2 503.0 517.3 680.3 719.3 20 15 10 5 0 447.7 531.0 614.0 632.0 885.3 311.9 486.1 604.2 739.3 743.4 855.0 174.8 238.0 895.3 944.2 1031.1 200 300 400 500 600 700 800 900 1000 m/z 12/8/14 Introduction to Peptide equencing - athan Yates 48 884.4

CAD Example 4 - Expanded sq3027 #454-618 RT: 12.05-16.57 AV: 4 L: 2.47E7 T: + c EI RM ms2 524.38@35.00 [130.00-1585.00] 50 283.0 368.0 x4 x2 x4 517.3 40 310.9 416.2 30 503.0 20 369.0 447.7 531.0 10 284.0 311.9 604.2 359.2 442.8 486.1 561.3 477.4 174.8 406.4 216.3 238.0 282.2 288.1 552.7 0 150 200 250 300 350 400 450 500 550 600 m/z 100 x4 x20 x4 x50 x4 737.3 Relative Abundance 80 60 40 20 738.3 855.0 873.1 680.3 719.3 743.4 844.9 614.0 884.4 632.0 689.4 760.1 772.4 826.6 885.3 633.0 690.9 895.3 933.5 948.1 1031.1 0 650 700 750 800 850 900 950 1000 1050 12/8/14 Introduction to Peptide equencing m/z - athan Yates 49