We report a computational study of Ala–Lys (AK) and Lys–Ala (KA) dipeptide ions furnished with fixed-charged pyridinium groups that were attached by amide linkers to the N-terminal amino groups. Cation–radicals from one-electron reduction of the doubly charged AK and KA peptide conjugates showed various extents of unpaired electron density being delocalized between the pyridine and peptide moieties. The delocalization depended on the local recombination energies (REloc) of the charged groups. The REloc of the pyridine moieties were modified by introducing electron-donating substituents (CH3, OCH3, and N(CH3)2). The REloc of the peptide moieties were found to depend on the peptide conformation and internal solvation of the Lys ammonium groups. Substantial electron delocalization was found for combinations of pyridine substituents and peptide conformers with closely matched REloc, such as 4-dimethylaminopyridine and internally solvated Lys ammonium or unsubstituted pyridine and free (unsolvated) Lys ammonium. The dissociation (ΔHdiss) and transition state energies (ETS) for the loss of the pyridine ring from the conjugates were found to be ΔHdiss = 34–36 kJ mol−1 and ETS = 67–69 kJ mol−1 for the unsubstituted pyridine moieties, but did not depend much on the peptide sequence.
AebersoldR.BuresE.J.NamchukM.GoghariM.H.ShushanB.CoveyT.C., “Design, synthesis, and characterization of a protein sequencing reagent yielding amino acid derivatives with enhanced detectability by mass spectrometry”, Protein Sci.1, 494–503 (1992).
2.
GatlinC.L.TurečekF., “Quantitative electrospray ionization mass spectrometric studies of ternary complexes of amino acids with Cu2+ and phenanthroline”, J. Mass Spectrom.35, 172–177 (2000). doi: 10.1002/(SICI)1096-9888(200002)35:2<172::AID-JMS926>3.0.CO;2-C
3.
VathJ.E.BiemannK., “Microderivatization of peptides by placing a fixed positive charge at the N-terminus to modify high energy collision fragmentation”, Int. J. Mass Spectrom. Ion Proc.100, 287–299 (1990). doi: 10.1016/0168-1176(90)85079-H
4.
RenD.JulkaS.InerowiczH.D.RegnierF.E., “Enrichment of cysteine-containing peptides from tryptic digests using a quaternary amine tag”, Anal. Chem.76, 4522–4530 (2004). doi: 10.1021/ac0354645
5.
YangW.-C.MirzaeiH.LiuX.RegnierF.E., “Enhancement of amino acid detection and quantification by electrospray ionization mass spectrometry”, Anal. Chem.78, 4702–4708 (2006). doi: 10.1021/ac0600510
6.
LiJ.MaH.WangX.XiongS.DongS.WangS., “Enhanced detection of thiol peptides by matrix-assisted laser desorption/ionization mass spectrometry after selective derivatization with a tailor-made quaternary ammonium tag containing maleimidyl group”, Rapid Commun. Mass Spectrom.21, 2608–2612 (2007). doi: 10.1002/rcm.3133
7.
ShenT.L.AllisonJ., “Interpretation of matrix-assisted laser desorption/ionization postsource decay spectra of charge-derivatized peptides: Some examples of tris[(2,4,6-trimethoxyphenyl) phosphonium]-tagged proteolytic digestion products of phosphoenol-pyruvate carboxykinase”, J. Am. Soc. Mass Spectrom.11, 145–152 (2000). doi: 10.1016/S1044-0305(99)00131-2
8.
HuangZ.-H.WuJ.RothK.D.W.YangY.GageD.A.WatsonJ.T., “A picomole-scale method for charge derivatization of peptides for sequence analysis by mass spectrometry”, Anal. Chem.69, 137–144 (1997). doi: 10.1021/ac9608578
9.
RothK.D.W.HuangZ.-H.SadagopanN.WatsonJ.T., “Charge derivatization of peptides for analysis by mass spectrometry”, Mass Spectrom. Rev.17, 255–274 (1999). doi: 10.1002/(SICI)1098-2787(1998)17:4<255::AID-MAS1>3.0.CO;2-4
10.
Chamot-RookeJ.van der RestG.DalleuA.BayS.LemoineJ., “The combination of electron capture dissociation and fixed charge derivatization increases sequence coverage for O-glycosylated and O-phosphorylated peptides.”J. Am. Soc. Mass Spectrom.18, 1405–1413 (2007). doi: 10.1016/j.jasms.2007.04.008
11.
Chamot-RookeJ.MalosseC.FrisonG.TurečekF., “Electron capture in charge-tagged peptides. Evidence for the role of excited electronic states.”J. Am. Soc. Mass Spectrom.18, 2146–2161 (2007). doi: 10.1016/j.jasms.2007.09.009
12.
XiaY.GunawardenaH.P.EricksonD.E.McLuckeyS.A., “Effects of cation charge-site identity and position on electron-transfer dissociation of polypeptide cations”, J. Am. Chem. Soc.129, 12232–12243 (2007). doi: 10.1021/ja0736764
13.
GunawardenaH.P.GorensteinL.EricksonD.E.XiaY.McLuckeyS.A., “Electron transfer dissociation of multiply protonated and fixed charge disulfide linked polypeptides”, Int. J. Mass Spectrom.265, 130–138 (2007). doi: 10.1016/j.ijms.2007.01.017
14.
ZubarevR.A.HornD.M.FridrikssonE.K.KelleherN.L.KrugerN.A.LewisM.A.CarpenterB.K.McLaffertyF.W., “Electron capture dissociation for structural characterization of multiply charged protein cations”, Anal. Chem.72, 563–573 (2000). doi: 10.1021/ac990811p
15.
SykaJ.E.P.CoonJ.J.SchroederM.J.ShabanowitzJ.HuntD.F., “Peptide and protein sequence analysis by electron transfer dissociation mass spectrometry”, Proc. Natl. Acad. Sci. USA101, 9528–9533 (2004). doi: 10.1073/pnas.0402700101
16.
WolkenJ.K.TurečekF., “Modeling nucleobase radicals in the gas phase. experimental and computational study of 2-hydroxypyridinium and 2-(1h)pyridone radicals”, J. Phys. Chem. A103, 6268–6281 (1999). doi: 10.1021/jp991077g
17.
SyrstadE.A.TurečekF., “Toward a general mechanism of electron-capture dissociation”, J. Am. Soc. Mass Spectrom.16, 208–224 (2005). doi: 10.1016/j.jasms.2004.11.001
18.
NeffD.SobczykM.SimonsJ., “Through-space and through-bond electron transfer within positively charged peptides in the gas phase”, Int. J. Mass Spectrom.276(2/3), 91–101 (2008). doi: 10.1016/j.ijms.2008.04.012
19.
ShafferS.A.TurečekF., Hydrogentrimethylammonium. A marginally stable hypervalent radical”, J. Am. Chem. Soc.116, 8647–8653 (1994). doi: 10.1021/ja00098a026
20.
BeranovaS.WesdemiotisC., “The unimolecular chemistry of quaternary ammonium ions and their neutral counterparts”, Int. J. Mass Spectrom. Ion Proc.134, 83–102 (1994). doi: 10.1016/0168-1176(94)03972-0
21.
FrøsigL.TurečekF., “Hypervalent pyrrolidinium radicals by neutralization-reionization mass spectrometry. metastability and radical leaving group abilities”, J. Am. Soc. Mass Spectrom.9, 242–254 (1998). doi: 10.1016/S1044-0305(97)00249-3
22.
YaoC.TurečekF., “Hypervalent ammonium radicals. competitive N-C and N-H bond dissociations in methylammonium and ethylammonium”, Phys. Chem. Chem. Phys.7, 912–920 (2005). doi: 10.1039/b414764b
23.
ChungT.W.TurečekF., “Selecting fixed-charge groups for electron-based peptide dissociations. a computational study of pyridinium tags”, Int. J. Mass Spectrom.276(2/3), 127–135 (2008) doi: 10.1016/j.ijms.2008.04.014
24.
TurečekF., “N–Cα bond dissociation energies and kinetcs in amide and peptide radicals. Is the dissociation a non-ergodic process?”, J. Am. Chem. Soc.125, 5954–5963 (2003). doi: 10.1021/ja021323t
25.
TurečekF.SyrstadE.A.SeymourJ.L.ChenX.YaoC., “Peptide cation-radicals. a computational study of the competition between peptide N-Cα bond cleavage and loss of the side chain in the [glyphe-NH2 + 2H]+• cation-radical”, J. Mass Spectrom.38, 1093–1104 (2003). doi: 10.1002/jms.527
26.
ChenX.TurečekF., “The arginine anomaly: Arginine radicals are poor hydrogen atom donors in electron transfer induced dissociations”, J. Am. Chem. Soc.128, 12520–12530 (2006). doi: 10.1021/ja063676o
27.
YaoC.SyrstadE.A.TurečekF., “Electron transfer to protonated β-alanine N-methylamide in the gas phase: An experimental and computational study of dissociation energetics and mechanisms”, J. Phys. Chem. A111, 4167–4180 (2007). doi: 10.1021/jp0705020
28.
HayakawaS.HashimotoM.MatsubaraH.TurečekF., “Dissecting the proline effect: Dissociations of proline radicals formed by electron transfer to protonated Pro–Gly and Gly–Pro dipeptides in the gas phase”, J. Am. Chem. Soc.129, 7936–7949 (2007). doi: 10.1021/ja0712571
29.
TurečekF.ChenX.HaoC., “Where does the electron go? Electron distribution and reactivity of peptide cation radicals formed by electron transfer in the gas phase”, J. Am. Chem. Soc.130, 8818–8833 (2008). doi: 10.1021/ja8019005
30.
FrischM.J.TrucksG.W.SchlegelH.B.ScuseriaG.E.RobbM.A.CheesemanJ.R.MontgomeryJ.A.JrVrevenT.KudinK.N.BurantJ.C.MillamJ.M.IyengarS.S.TomasiJ.BaroneV.MennucciB.CossiM.ScalmaniG.RegaN.PeterssonG.A.NakatsujiH.HadaM.EharaM.ToyotaK.FukudaR.HasegawaJ.IshidaM.NakajimaT.HondaY.KitaoO.NakaiH.KleneM.LiX.KnoxJ.E.HratchianH.P.CrossJ.B.AdamoC.JaramilloJ.GompertsR.StratmannR.E.YazyevO.AustnA.J.CammiR.PomelliC.OchterskiJ.W.AyalaP.Y.MorokumaK.VothG.A.SalvadorP.DannenbergJ.J.ZakrzewskiV.G.DapprichS.DanielsA.D.StrainM.C.FarkasO.MalickD.K.RabuckA.D.RaghavachariK.ForesmanJ.B.OrtizJ.V.CuiQ.BaboulA.G.CliffordS.CioslowskiJ.StefanovB.B.LiuG.LiashenkoA.PiskorzP.KomaromiI.MartinR.L.FoxD.J.KeithT.Al-LahamM.A.PengC.Y.NanayakkaraA.ChallacombeM.GillP.M.W.JohnsonB.ChenW.WongM.W.GonzalezC.PopleJ.A., Gaussian 03, Revision B.05.Gaussian, Inc., Pittsburgh, PA, USA (2003).
31.
(a) BeckeA.D., “A new mixing of hartree-fock and local density-functional theories”, J. Chem. Phys.98, 1372–1377 (1993); doi: 10.1063/1.464304; (b) BeckeA.D., “Density functional thermochemistry. III. The role of exact exchange”, J. Chem. Phys.98, 5648–5652 (1993). doi: 10.1063/1.464913
32.
RauhutG.PulayP., “Transferable scaling factors for density functional derived vibrational force fields”, J. Phys. Chem.99, 3093–3100 (1995). doi: 10.1021/j100010a019
33.
MøllerC.PlessetM.S., “A note on an approximation treatment for many-electron systems.”Phys. Rev.46, 618–622 (1934). doi: 10.1103/PhysRev.46.618
34.
(a) SchlegelH.B., “Potential energy curves using un restricted Moller–Plesset perturbation theory with spin annihilation”, J. Chem. Phys.84, 4530–4534 (1986); doi: 10.1063/1.450026; (b) MayerI., “Spin-projected UHF method. IV. Comparison of potential curves given by different one-electron methods”, Adv. Quantum Chem.12, 189–262 (1980). doi: 10.1016/S0065-3276(08)60317-2
35.
TurečekF., “Proton affinity of dimethyl sulfoxide and relative stabilities of C2H6OSs molecules and C2H7OS+ ions. A comparative G2(MP2) ab initio and density functional theory study”, J. Phys. Chem. A102, 4703–4713 (1998). doi: 10.1021/jp980940u
36.
(a) TurečekF.WolkenJ.K., “Dissociation energies and kinetics of aminopyrimidinium radicals by ab initio and density functional theory”, J. Phys. Chem. A103, 1905–1912 (1999). doi: 10.1021/jp984826n; (b) TurečekF.PolášekM.FrankA.J.SadílekM., “Transient hydrogen atom adducts to disulfides. formation and energetics”, J. Am. Chem. Soc.122, 2361–2370 (2000). doi: 10.1021/ja993789q; (c) PolášekM.TurečekF., “Hydrogen atom adducts to nitrobenzene. formation of the phenylnitronic radical in the gas phase and energetics of Wheland intermediates.”J. Am. Chem. Soc.122, 9511–9524 (2000). doi: 10.1021/ja001229h; (d) RablenP.R., “Is the acetate anion stabilized by resonance or electrostatics? A systematic structural comparison”, J. Am. Chem. Soc.122, 357–368 (2000). doi: 10.1021/ja9928475; (e) RablenP.R., “Computational analysis of the solvent effect on the barrier to rotation about the conjugated C–N bond in methyl N,N-dimethylcarbamate”, J. Org. Chem.65, 7930–7937 (2000). doi: 10.1021/jo000945z; (f) RablenP.R.BentrupK.H., “Are the enolates of amides and esters stabilized by electrostatics?”, J. Am. Chem. Soc.125, 2142–2147 (2003). doi: 10.1021/ja029102a; (g) HiramaM.TokosumiT.IshidaT.AiharaJ., “Possible molecular hydrogen formation mediated by the inner and outer carbon atoms of typical PAH cations”, Chem. Phys.305, 307–316 (2004). doi: 10.1016/j.chemphys.2004.07.010; (h) RassolovV.A.RatnerM.A.PopleJ.A., “Electron correlation in chemical bonds”, J. Chem. Phys.112, 4014–4019 (2000). doi: 10.1063/1.480950
37.
StratmannR.E.ScuseriaG.E.FrischM.J., “An efficient implementation of time-dependent density functional theory for the calculation of excitation energies of large molecules”, J. Chem. Phys.109, 8218–8224 (1998). doi: 10.1063/1.477483
38.
ReedA.E.WeinstockR.B.WeinholdF., “Natural population analysis”, J. Chem. Phys.83, 735–746 (1985). doi: 10.1063/1.449486
39.
TurečekF.SyrstadE.A., “Mechanism and energetics of intramolecular hydrogen transfer atom transfer in amide and peptide radicals and cation–radicals”, J. Am. Chem. Soc.125, 3353–3369 (2003). doi: 10.1021/ja021162t
