title: Structural influences on preferential oxazolone versus diketopiperazine b(2+) ion formation for histidine analogue-containing peptides.
abstract: Studies of peptide fragment ion structures are important to aid in the accurate kinetic modeling and prediction of peptide fragmentation pathways for a given sequence. Peptide b(2)(+) ion structures have been of recent interest. While previously studied b(2)(+) ions that contain only aliphatic or simple aromatic residues are oxazolone structures, the HA b(2)(+) ion consists of both oxazolone and diketopiperazine structures. The structures of a series of histidine-analogue-containing Xxx-Ala b(2)(+) ions were studied by using action infrared multiphoton dissociation (IRMPD) spectroscopy, fragment ion hydrogen-deuterium exchange (HDX), and density functional theory (DFT) calculations to systematically probe the influence of different side chain structural elements on the resulting b(2)(+) ion structures formed. The b(2)(+) ions studied include His-Ala (HA), methylated histidine analogues, including π-methyl-HA and τ-methyl-HA, pyridylalanine (pa) analogues, including 2-(pa)A, 3-(pa)A, and 4-(pa)A, and linear analogues, including diaminobutanoic acid-Ala (DabA) and Lys-Ala (KA). The location and accessibility of the histidine π-nitrogen, or an amino nitrogen on an aliphatic side chain, were seen to be essential for diketopiperazine formation in addition to the more typical oxazolone structure formation, while blocking or removal of the τ-nitrogen did not change the b(2)(+) ion structures formed. Linear histidine analogues, DabA and KA, formed only diketopiperazine structures, suggesting that a steric interaction in the HisAla case may interfere with the complete trans-cis isomerization of the first amide bond that is necessary for diketopiperazine formation.
authors.affiliation: Department of Chemistry and Biochemistry, The University of Arizona, 1306 East University Boulevard, Tucson, Arizona 85721, USA. ashley.gucinski@fda.hhs.gov
authors.forename: Ashley C
authors.initials: AC
authors.lastname: Gucinski
authors.forename: Julia
authors.initials: J
authors.lastname: Chamot-Rooke
authors.forename: Edith
authors.initials: E
authors.lastname: Nicol
authors.forename: Árpád
authors.initials: Á
authors.lastname: Somogyi
authors.forename: Vicki H
authors.initials: VH
authors.lastname: Wysocki
mesh_terms: D054659:Diketopiperazines / Q000737:chemistry*; D006639:Histidine / Q000031:analogs & derivatives / Q000737:chemistry*; D007477:Ions / Q000737:chemistry; D015394:Molecular Structure; D010081:Oxazolone / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D011789:Quantum Theory
chemical_list: D054659:Diketopiperazines; D007477:Ions; D010455:Peptides; D010081:Oxazolone; D006639:Histidine