Gas-Phase Acidities of the Cysteine-Polyalanine Peptides I: A\u3csub\u3e3,4\u3c/sub\u3eCSH and HSCA\u3csub\u3e3,4\u3c/sub\u3e

The gas-phase acidities of four cysteine-polyalanine peptides, A3,4CSH and HSCA3,4, were determined using the extended Cooks kinetic method with full entropy analysis. A triple-quadrupole mass spectrometer with an electrospray interface was employed for the experimental study. The ion activation was achieved via collision-induced dissociation (CID) experiments. The deprotonation enthalpies (ΔacidH) of the peptides were determined to be 332.2 ± 2.0 kcal/mol (A3CSH), 325.9 ± 2.0 kcal/mol (A4CSH), 319.3 ± 3.0 kcal/mol (HSCA3), and 319.2 ± 4.0 kcal/mol (HSCA4). The deprotonation entropies (ΔacidS) of the peptides were estimated based on the entropy term (Δ(ΔS)) and the deprotonation entropies of the reference acids. By using the deprotonation enthalpies and entropies, the gas-phase acidities (ΔacidG) of the peptides were derived: 325.0 ± 2.0 kcal/mol (A3CSH), 320.2 ± 2.0 kcal/mol (A4CSH), 316.3 ± 3.0 kcal/mol (HSCA3), and 315.4 ± 4.0 kcal/mol (HSCA4). Conformations and energetic information of the peptides were calculated through simulated annealing (Tripos), geometry optimization (AM1), and single-point energy calculations (B3LYP/6-31+G(d)), respectively. The calculated theoretical deprotonation enthalpies (ΔacidH) of 334.2 kcal/mol (A3CSH), 327.7 kcal/mol (A4CSH), 320.6 kcal/mol (HSCA3), and 318.6 kcal/mol (HSCA4) are in good agreement with the experimentally determined values. Both the experimental and computational studies suggest that the two N-terminal cysteine peptides, HSCA3,4, are significantly more acidic than the corresponding C-terminal ones, A3,4CSH. The high acidities of the former are likely due to the helical conformational effects for which the thiolate anion may be strongly stabilized by the interaction with the helix macrodipole