Gas phase acidity of a cysteine residue in small oligopeptides

The conformational effects on the gas-phase acidities of small cysteine-containing peptides were examined using ten oligopeptides. The gas-phase deprotonation enthalpies were measured using the extended Cooks kinetic method with full entropy analysis. The experiments were carried out using a triple quadrupole mass spectrometer. The values of ΔacidH were determined to be 335.6 ± 1.7 kcal/mol (AlaCysNH2), 334.6 ± 1.8 kcal/mol (Ala2CysNH2), 331.2 ± 1.8 kcal/mol (CysAlaNH2), 330.5 ± 2.0 kcal/mol (CysAla2NH2), 329.7 ± 1.8 kcal/mol (AlaCysAlaNH2), 335.3 ± 1.8 kcal/mol (GlyCysNH2), 334.6 ± 1.7 kcal/mol (Gly2CysNH2), 330.4 ± 1.8 kcal/mol (CysGlyNH2), 329.7 ± 1.8 kcal/mol (CysGly2NH2), and 327.3 ± 2.0 kcal/mol (GlyCysGlyNH2). The gas-phase acidities (ΔacidG) and the deprotonation entropies (ΔacidS) for these peptides were determined accordingly. These results suggested that the tripeptides were more acidic than the corresponding dipeptides by about 1 kcal/mol, and the N-cysteine peptides were more acidity than the isomeric C-cysteine peptides by about 4 kcal/mol. The initial conformations of the peptides were modeled via a conformational search using the MMFF method. The final geometries and energies were calculated at the B3LYP/6-31++G(d,p) level of theory. The calculated enthalpies of deprotonation agreed reasonably well with the experimental results. The conformations of the deprotonated N-cysteine peptides were more compact than those of the C-cysteine analogues. The more compact conformations allowed more efficient multiple hydrogen-bonding interactions between the thiolate anion and the nearby NH bonds. The greater acidities of the N-cysteine peptides were likely the results of the more favorable hydrogen-bonding and charge–amide dipole interactions that stabilized the thiolate anions more efficiently.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (160 K)Download as PowerPoint slideHighlights► The gas-phase acidities of small cysteine-containing peptides showed large variation. ► Tripeptides were slightly more acidic than the corresponding dipeptides. ► The N-cysteine peptides were more acidity than the isomeric C-cysteine ones. ► The differences in the gas-phase acidities were largely due to conformational effects.