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Protonated DP and LP diastereomers of the pentapeptide YAPGA were examined with IR–UV spectroscopy for their ability to form β-turns.

D-Proline (

A strategy to sequence lysine containing cyclic peptides by MS(n) is presented. Doubly protonated cyclic peptides ions are transformed into gold (I) cationized peptide ions via cation switching ion/ion reaction. Gold (I) cationization facilitates the oxidation of neutral lysine residues in the gas-phase, weakening the adjacent amide bond. Upon activation, facile cleavage N-terminal to the oxidized lysine residue provides a site-specific ring opening pathway that converts cyclic peptides into acyclic analogs. The ensuing ion contains a cyclic imine as the new N-terminus and an oxazolone, or structural equivalent, as the new C-terminus. Product ions are formed from subsequent fragmentation events of the linearized peptide ion. Such an approach simplifies MS/MS data interpretation as a series of fragment ions with common N- and C-termini are generated. Results are presented for two cyclic peptides, sunflower trypsin inhibitor and the model cyclic peptide, β-Loop. The power of this strategy lies in the ability to generate the oxidized peptide, which is easily identified via the loss of HAuNH(3) from [M + Au](+). While some competitive processes are observed, the site of ring opening can be pinpointed to the lysine residue upon MS(4) enabling the unambiguous sequencing of cyclic peptides.

Isomerization of the glutathione thiyl radical via hydrogen atom transfer (HAT) in its complexes with various singly and doubly charged metal ions was studied both experimentally and computationally. The glutathione thiyl radical/metal ion complexes were generated in a quadrupole ion trap mass spectrometer via collision-induced dissociation of S-nitrosoglutathione cationized by the metal ion of interest. The degree of HAT was monitored by gas-phase ion-molecule reactions of these complexes with nitric oxide – the initially formed thiyl radical species were shown previously to be reactive toward NO while the α-carbon (C α ) radicals were not. It was found that group IA metal ions facilitate HAT in the order K + > Na + > Li + > H + . This correlates well with the order of relative stability of the resulting C α species determined by density functional theory (DFT) calculations. Conversely, the glutathione thiyl radicals complexed by three different doubly-charged metal ions (Mg 2+ , Zn 2+ or Ni 2+ ) did not undergo HAT, thereby remaining the S-based radical species. This was rationalized in terms of the substantially smaller thermodynamic benefit of HAT in the case of Mg 2+ and Zn 2+ and even the endothermicity of this process for Ni 2+ , as predicted by the DFT calculations. Additionally, for the glutathione radical/Ni 2+ complex a possibility of iminol-type binding (as opposed to the “classical” keto form) to the metal ion was investigated computationally. It was found that the iminol structures are lower in energy than the keto ones, similar to the situation in the even-electron peptide/Ni 2+ complexes.

Correction for ‘Single-conformation spectroscopy of cold, protonated DPG-containing peptides: switching β-turn types and formation of a sequential type II/II′ double β-turn’ by John T. Lawler et al., Phys. Chem. Chem. Phys., 2022, 24, 2095–2109, https://doi.org/10.1039/D1CP04852J.

(2,2′-Bipyridine)M═O+ ions (M = Cu, Ni, Co) were generated by collision-induced dissociation and near-UV photodissociation of readily available [(2,2′-bipyridine)MII(NO3)]+ ions in the gas phase, and their structure was confirmed by ion–molecule reactions combined with isotope labeling. Upon storage in a quadrupole ion trap, the (2,2′-bipyridine)M═O+ ions spontaneously added water, and the formed [(2,2′-bipyridine)M═O + H2O]+ complexes eliminated OH upon further near-UV photodissociation. This reaction sequence can be accomplished at a single laser wavelength in the range of 260–340 nm to achieve stoichiometric homolytic cleavage of gaseous water. Structures, spin states, and electronic excitations of the metal complexes were characterized by ion–molecule reactions using 2H and 18O labeling, photodissociation action spectroscopy, and density functional theory calculations.

Incorporation of the unnatural d-proline (DP) stereoisomer into a polypeptide sequence is a typical strategy to encourage formation of β-hairpin loops because natural sequences are often unstructured in solution. Using conformation-specific IR and UV spectroscopy of cold (≈10 K) gas-phase ions, we probe the inherent conformational preferences of the DP and LP diastereomers in the protonated peptide [YAPAA+H]+, where only intramolecular interactions are possible. Consistent with the solution-phase studies, one of the conformers of [YADPAA+H]+ is folded into a charge-stabilized β-hairpin turn. However, a second predominant conformer family containing two sequential γ-turns is also identified, with similar energetic stability. A single conformational isomer of the LP diastereomer, [YALPAA+H]+, is found and assigned to a structure that is not the anticipated “mirror image” β-turn. Instead, the LP stereocenter promotes a cis-alanine–proline amide bond. The assigned structures contain clues that the preference ...

The formation and investigation of sulfur-based cysteine radicals cationized by a group 1A metal ion or Ag+ in the gas phase are reported. Gas-phase ion-molecule reactions (IMR) and infrared multiple-photon dissociation (IRMPD) spectroscopy revealed that the Li+ , Na+ , and K+ adducts of the cysteine radical remain S-based radicals as initially formed. Theoretical calculations for the three alkali metal ions found that the lowest-energy isomers are Cα -based radicals, but they are not observed experimentally owing to the barriers associated with the hydrogen-atom transfer. A mechanism for the S-to-Cα radical rearrangement in the metal ion complexes was proposed, and the relative energies of the associated energy barriers were found to be Li+ >Na+ >K+ at all levels of theory. Relative to the B3LYP functional, other levels of calculation gave significantly higher barriers (by 35-40 kJ mol-1 at MP2 and 44-47 kJ mol-1 at the CCSD level) using the same basis set. Unlike the alkali metal adducts, the cysteine radical/Ag+ complex rearranged from the S-based radical to an unreactive species as indicated by IMRs and IRMPD spectroscopy. This is consistent with the Ag+ /cysteine radical complex having a lower S-to-Cα radical conversion barrier, as predicted by the MP2 and CCSD levels of theory.

The effects of hydrogen bonding and spin density at the oxygen atom on the gas-phase reactivity of phenoxyl radicals were investigated experimentally and theoretically in model systems and the dipeptide LysTyr. Gas-phase ion-molecule reactions were carried out between radical cations of several aromatic nitrogen bases with the neutrals nitric oxide and n -propyl thiol. Reactivity of radical cations 4–6 correlated with the spin density. The possibility of hydrogen bonding was explored in compounds which allowed four-, five-, and six-membered rings to be formed between the protonated nitrogen and the phenoxyl oxygen, while possessing similar spin density at the oxygen atom. The N + -H⋯O bond length was calculated to decrease in the series ( 1–3 ), consistent with the theoretical calculations finding weak hydrogen bonding in 2 and strong hydrogen bonding in 3 . This coincided with the decrease in reaction rates of 1–3 with both nitric oxide and n -propyl thiol. DFT calculations found that the lowest energy structure of the distonic radical cation of the dipeptide [LysTyr(O )] + has a short hydrogen bond between the protonated Lys side chain and the phenoxyl oxygen, 1.70 A, which is consistent with its low reactivity.

The single-conformation spectroscopy and infrared-induced conformational isomerization of a model protonated pentapeptide [YGPAA + H]+ is studied under cryo-cooled conditions in the gas phase. Building on recent results (DeBlase, A. F.; J. Am. Chem. Soc. 2017, 139, 5481−5493), firm assignments are established for the presence of two conformer families with distinct infrared and ultraviolet spectra, using IR–UV depletion spectroscopy. Families (A and B) share a similar structure near the N-terminus but differ in the way that the C-terminal COOH group configures itself (cis versus trans) in forming H-bonds with the peptide backbone. Infrared population transfer (IR-PT) spectroscopy is used to study the IR-induced conformational isomerization following single-conformer infrared excitation. IR-induced isomerization is accomplished in both directions (A → B and B → A) in the hydride stretch region and is used to determine fractional abundances for the two conformer families (FA = 0.65 ± 0.04, FB = 0.35 ± 0.04,...

Incorporation of the unnatural d-proline (DP) stereoisomer into a polypeptide sequence is a typical strategy to encourage formation of β-hairpin loops because natural sequences are often unstructured in solution. Using conformation-specific IR and UV spectroscopy of cold (≈10 K) gas-phase ions, we probe the inherent conformational preferences of the DP and LP diastereomers in the protonated peptide [YAPAA+H]+, where only intramolecular interactions are possible. Consistent with the solution-phase studies, one of the conformers of [YADPAA+H]+ is folded into a charge-stabilized β-hairpin turn. However, a second predominant conformer family containing two sequential γ-turns is also identified, with similar energetic stability. A single conformational isomer of the LP diastereomer, [YALPAA+H]+, is found and assigned to a structure that is not the anticipated “mirror image” β-turn. Instead, the LP stereocenter promotes a cis-alanine–proline amide bond. The assigned structures contain clues that the preference ...

Incorporation of the unnatural d-proline (

The radical cation of cytosine (Cyt.+ ) is generated by dissociative oxidation from a ternary CuII complex in the gas phase. The radical cation is characterized by infrared multiple photon dissociation (IRMPD) spectroscopy in the fingerprint region, UV/Vis photodissociation (UVPD) spectroscopy, ion-molecule reactions, and theoretical calculations (density functional theory and ab initio). The experimental IRMPD spectrum features diagnostic bands for two enol-amino and two keto-amino tautomers of Cyt.+ that are calculated to be among the lowest energy isomers, in agreement with a previous study. Although the UVPD action spectrum can also be matched to a combination of the four lowest energy tautomers, the presence of a nonclassical distonic radical cation cannot be ruled out. Its formation is, however, unlikely due to the high energy of this isomer and the respective ternary CuII complex. Gas-phase ion-molecule reactions showed that Cyt.+ undergoes hydrogen-atom abstraction from 1-propanethiol, radical recombination reactions with nitric oxide, and electron transfer from dimethyl disulfide.

Intramolecular hydrogen atom transfer (HAT) was examined in homocysteine (Hcy) thiyl radical/alkali metal ion complexes in the gas phase by combination of experimental techniques (ion‐molecule reactions and infrared multiple photon dissociation spectroscopy) and theoretical calculations. The experimental results unequivocally show that metal ion complexation (as opposed to protonation) of the regiospecifically generated Hcy thiyl radical promotes its rapid isomerisation into an α‐carbon radical via HAT. Theoretical calculations were employed to calculate the most probable HAT pathway and found that in alkali metal ion complexes the activation barrier is significantly lower, in full agreement with the experimental data. This is, to our knowledge, the first example of a gas‐phase thiyl radical thermal rearrangement into an α‐carbon species within the same amino acid residue and is consistent with the solution phase behaviour of Hcy radical.

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