title: Supramolecular modification of ion chemistry: modulation of peptide charge state and dissociation behavior through complexation with cucurbit[n]uril (n = 5, 6) or alpha-cyclodextrin.
abstract: Electrospray Fourier transform ion cyclotron resonance mass spectrometry, ion mobility spectrometry, and computational methods were utilized to characterize the complexes between lysine or pentalysine with three prototypical host molecules: alpha-cyclodextrin (alpha-CD), cucurbit[5]uril (CB[5]), and cucurbit[6]uril (CB[6]). Ion mobility measurements show lysine forms externally bound, singly charged complexes with either alpha-CD or CB[5], but a doubly charged complex with the lysine side chain threaded through the host cavity of CB[6]. These structural differences result in distinct dissociation behaviors in collision-induced dissociation (CID) experiments: the alpha-CD complex dissociates via the simple loss of intact lysine, whereas the CB[5] complex dissociates to yield [CB[5] + H(3)O](+), and the CB[6] complex loses neutral NH(3) and CO, the product ion remaining a doubly charged complex. These results are consistent with B3LYP/6-31G* binding energies (kJ mol(-1)) of D(Lys + H(+)-alpha-CD) = 281, D(Lys + H(+)-CB[5]) = 327, and D(Lys + 2H(2+)-CB[6]) = 600. B3LYP/6-31G* geometry optimizations show complexation with alpha-CD stabilizes the salt bridge form of protonated lysine, whereas complexation with CB[6] stabilizes doubly protonated lysine. Complexation of the larger polypeptide pentalysine with alpha-CD forms a nonspecific adduct: no modification of the pentalysine charge state distribution is observed, and dissociation occurs via the simple loss of alpha-CD. Complexation of pentalysine with the cucurbiturils is more specific: the observed charge state distribution shifts higher on complexation, and fragmentation patterns are significantly altered relative to uncomplexed pentalysine: C-terminal fragment ions appear that are consistent with charge stabilization by the cucurbiturils, and the cucurbiturils are retained on the fragment ions. Molecular mechanics calculations suggest CB[5] binds to two protonated sites on pentalysine without threading onto the peptide and that CB[6] binds two adjacent protonated sites via threading onto the peptide.
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602-5700, USA.
authors.forename: Haizhen
authors.initials: H
authors.lastname: Zhang
authors.forename: Megan
authors.initials: M
authors.lastname: Grabenauer
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bowers
authors.forename: David V
authors.initials: DV
authors.lastname: Dearden
mesh_terms: D001952:Bridged-Ring Compounds / Q000737:chemistry*; D005583:Fourier Analysis; D007093:Imidazoles / Q000737:chemistry*; D007477:Ions; D007700:Kinetics; D008239:Lysine / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000737:chemistry*; D010455:Peptides; D011522:Protons; D011789:Quantum Theory; D021241:Spectrometry, Mass, Electrospray Ionization; D055672:Static Electricity; D013816:Thermodynamics; D047391:alpha-Cyclodextrins / Q000737:chemistry*; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils
chemical_list: D001952:Bridged-Ring Compounds; D007093:Imidazoles; D007477:Ions; D008239:Lysine; D009842:Oligopeptides; D010455:Peptides; D011522:Protons; D047391:alpha-Cyclodextrins; C523802:cucurbit(5)uril; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils; C026591:pentalysine; C454805:cucurbit(6)uril; C032613:alpha-cyclodextrin