Quantum chemical mass spectrometry: Ab initio study of b₂‐ion formation mechanisms for the singly protonated Gln‐His‐Ser tripeptide

Abstract

Rationale: Both amide bond protonation triggering peptide fragmentations and the controversial b 2 -ion structures have been subjects of intense research. The involvement of histidine (H), with its imidazole side chain that induces specific dissociation patterns involving inter-side-chain (ISC) interactions, in b 2 -ion formation was investigated, focusing on the QHS model tripeptide. Methods:To identify the effect of histidine on fragmentations issued from ISC interactions, QHS was selected for a comprehensive analysis of the pathways leading to the three possible b 2 -ion structures, using quantum chemical calculations performed at the DFT/B3LYP/6-311+G* level of theory. Electrospray ionization ion trap mass spectrometry allowed the recording of MS 2 and MS 3 tandem mass spectra, whereas the Quantum Chemical Mass Spectrometry for Materials Science (QCMS 2 ) method was used to predict fragmentation patterns. Results:Whereas it is very difficult to differentiate among protonated oxazolone, diketopiperazine, or lactam b 2 -ions using MS 2 and MS 3 mass spectra, the calculations indicated that the QH b 2 -ion (detected at m/z 266) is probably a mixture of the lactam and oxazolone structures formed after amide nitrogen protonation, making the formation of diketopiperazine less likely as it requires an additional step for its formation. Conclusions:In contrast to glycine-histidine-containing b 2 -ions, known to be issued from the backbone-imidazole cyclization, we found that interactions between the side chains were not obvious to perceive, neither from a thermodynamics nor from a fragmentation perspective, emphasizing the importance of the whole sequence on the dissociation behavior usually demonstrated from simple glycine-containing tripeptides.

Structure and collision-induced dissociation of the protonated cyclo His-Phe dipeptide: mechanistic studies and stereochemical effects

“…This aspect has been recently discussed based on MS 3 experiments coupled with quantum chemical calculations, which suggest the coexistence of oxazolone and lactam for the singly protonated Gln-His-Ser tripeptide, the DKP being disfavored by an additional reaction step. 53 The fragmentation mechanism of protonated DKP dipeptides isolated in an ion trap has been questioned too. The CID of protonated model DKPs like cyclo Gly-Gly, cyclo Ala-Ala, or cyclo Ala-Gly, 52,54 has been widely debated, based on the experimental evidence that protonated cyclo Ala-Ala loses CO and CO+NH 3 , while protonated cyclo Gly-Gly loses 2 CO at higher energy.…”

How change in chirality prevents β-amyloid type interaction in a protonated cyclic dipeptide dimer

“…52 In contrast to peptides containing aliphatic residues, peptides containing histidine show diketopiperazine or lactam in addition to oxazolone fragments. 51,53,54 We recently showed that the CID of cyclo (Phe-His)H + shows a very high sensitivity of CO loss efficiency to the chirality of the residues, due to the proton shuttling mechanism from the imidazole substituent to the amide. 45 We determine here the structure of the protonated dimer of cyclo (LPhe-LHis) and cyclo (LPhe-DHis), noted in short (c-LL) 2 H + and (c-LD) 2 H + , in a room-temperature ion trap, by Infra-Red Multiple Photons Dissociation (IRMPD) and compare them to quantum chemical calculations in the frame of the density functional theory (DFT).…”