Gas-phase H/D exchange experiments with CD 3 OD and D 2 O and quantum chemical ab initio G3(MP2) calculations were carried out on protonated histidine and protonated histidine methyl ester in order to elucidate their bonding and structure. The H/D exchange experiments show that both ions have three equivalent fast hydrogens and one appreciably slower exchangeable hydrogen assigned to the protonated amino group participating in a strong intramolecular hydrogen bond (IHB) with the nearest N(sp 2 ) nitrogen of the imidazole fragment and to the distal ring NH-group, respectively. It is taken for granted that the proton exchange in the IHB is much faster than the H/D exchange. Unlike in other protonated amino acids (glycine, proline, phenylalanine, tyrosine, and tryptophan) studied earlier, the exchange rate of the carboxyl group in protonated histidine is slower than that of the amino group. The most stable conformers and the enthalpies of neutral and protonated histidine and its methyl ester are calculated at the G3(MP2) level of theory. It is shown that strong intramolecular hydrogen bonding between the amino group and the imidazole ring nitrogen sites is responsible for the stability and specific properties of the protonated histidine. It is found that the proton fluctuates between the amino and imidazole groups in the protonated form across an almost vanishing barrier. Proton affinity (PA) of histidine calculated by the G3(MP2) method is 233.2 and 232.4 kcal mol -1 for protonation at the imidazole ring and at the amino group nitrogens, respectively, which is about 3-5 kcal mol -1 lower than the reported experimental value.

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Gas-phase interaction of LysH + with D 2 O has been investigated in order to elucidate the H/D exchange reaction mechanism and possibility of water assisted ion-zwitterion structure formation. The proceed of the interaction is modeled by DFT calculations. Potential energy profiles for: the perturbation from ion-molecule to ion-zwitterion structure, the "flip-flop" and the "bridging" mechanism are presented. Analysis of H/D exchange kinetics results for LysH + with D 2 O and CD 3 OD measured in a Fourier transform ion cyclotron resonance (FTICR) mass spectrometer agree with ion-molecule structure of LysH + . Both experimental and theoretical findings suggest that during interaction of LysH + with D 2 O isotopic exchange is favored over the water assisted conformational change from ion-molecule into ion-zwitterion structure.

Site-specific rate constants for the gas-phase hydrogen/deuterium (H/D) exchange of four, three, five and five hydrogen atoms in protonated phenylalanine (Phe), proline (Pro), tyrosine (Tyr) and tryptophan (Trp), respectively, were determined from matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance mass spectrometry (MALDI-FTICRMS) experiments with D 2 O, D 2 S, and CH 3 OD as deuterating agents. No H/D exchange was observed with D 2 S. For exchange with both CD 3 OD and D 2 O, which is about ten times slower in the latter, results indicate for all compounds protonation of the a-amino group in agreement with theoretical results. Also, with both reagents, all compounds exchange at the COOH site more than ten times faster than at the protonation site, with OH and NH sites of Tyr and Trp, respectively, exchanging slowest. The observation of H/D exchange despite the high differences in proton affinities between the amino acids and deuterating agent exceeding 200 kJ mol À1 is in agreement with lowering of the barrier for proton transfer through hydrogen bonding proposed by Lebrilla and coworkers.