Stereochemical Sequence Ion Selectivity: Proline versus Pipecolic-acid-containing Protonated Peptides

Substitution of proline by pipecolic acid, the six-membered ring congener of proline, results in vastly different tandem mass spectra. The well-known proline effect is eliminated and amide bond cleavage C-terminal to pipecolic acid dominates instead. Why do these two ostensibly similar residues produce dramatically differing spectra? Recent evidence indicates that the proton affinities of these residues are similar, so are unlikely to explain the result [Raulfs et al., J. Am. Soc. Mass Spectrom. 25, 1705–1715 (2014)]. An additional hypothesis based on increased flexibility was also advocated. Here, we provide a computational investigation of the “pipecolic acid effect,” to test this and other hypotheses to determine if theory can shed additional light on this fascinating result. Our calculations provide evidence for both the increased flexibility of pipecolic-acid-containing peptides, and structural changes in the transition structures necessary to produce the sequence ions. The most striking computational finding is inversion of the stereochemistry of the transition structures leading to “proline effect”-type amide bond fragmentation between the proline/pipecolic acid-congeners: R (proline) to S (pipecolic acid). Additionally, our calculations predict substantial stabilization of the amide bond cleavage barriers for the pipecolic acid congeners by reduction in deleterious steric interactions and provide evidence for the importance of experimental energy regime in rationalizing the spectra.

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Why are a 3 ions rarely observed?

It has been determined experimentally that a(3) ions are generally not observed in the tandem mass spectroscopic (MS/MS) spectra of b(3) ions. This is in contrast to other b(n) ions, which often have the corresponding a(n) ion as the base peak in their MS/MS spectra. Although this might suggest a different structure for b(3) ions compared to that of other b(n) ions, theoretical calculations indicate the conventional oxazolone structure to be the lowest energy structure for the b(3) ion of AAAAR, as it is for other b(n) ions of this peptide. However, it has been determined theoretically that the a(3) ion is lower in energy than other a(n) ions, relative to the corresponding b ions. Furthermore, the a(3) --> b(2) transition structure (TS) is lower in energy than other a(n) --> b(n-1) TSs of AAAAR, compared with the corresponding b ions. Consequently, it is suggested that the b(3) ion does fragment to the a(3) ion, but that the a(3) ion then immediately fragments (to b(2) and a(3)) because of the excess internal energy arising from its relatively low energy and the facile a(3) --> b(2) reaction. That is why a(3) ions are not observed in the MS/MS spectra of b(3) ions.     

NONCOOPERATIVE MANAGEMENT OF THE NORTHEAST ATLANTIC COD FISHERY: A FIRST MOVER ADVANTAGE

The point of departure for this analysis is Bjørndal and Lindroos [2012], who developed an empirical bioeconomic model to analyze cooperative and noncooperative management of Northeast Atlantic cod. In their analysis, only constant strategies were analyzed for noncooperative games. In this paper, nonconstant strategies are considered. Moreover, the fishery in question is characterized by cooperative management. What may happen in the real world is that one nation breaks the cooperative agreement by fishing in excess of its quota. Often, it takes time for the other agent to detect this and respond. In this paper, we allow this kind of delayed response into a two‐agent noncooperative game so that, if country 2 exceeds its quota, there will be a time lag before this is detected by country 1; moreover, there may also be a delay until country 1 is able to respond. Results show that the outcome critically depends on the length of these two lags as well as initial conditions.     

Structure of the [M + H - H2O]+ ion from tetraglycine: a revisit by means of density functional theory and isotope labeling

Collision-induced dissociations of protonated (18)O-labeled tetraglycines labeled separately at either the first or the second amide bond established that water loss from the backbone occurs from the N-terminal residue. Density functional theory at B3LYP/6-311++G(d,p) predicted that the low-energy [G(4) + H - H(2)O](+) product ion is an N(1)-protonated 3,5-dihydro-4H-imidazol-4-one. The ion at the lowest energy, III, is 24.8 kcal mol(-1) lower than the protonated oxazole structure, II, proposed by Bythell et al. (J. Phys. Chem A2010, 114, 5076-5082). In addition, structure III has a predicted IR spectrum that provides a better match with the published experimental IRMPD spectrum than that of structure II.