Studies of the Gas-phase Acidity of D/L-Cysteine-Containing Polyalanine Peptides with Computational Chemistry and Mass Spectrometry

D-amino acids have been found in nearly all living organics, including humans. However, the chemistry of the D-amino acids is largely unknown. Conversion of an amino acid from the L-form to the D-form often modifies the biological activity of the peptides, and in many cases, enhances their biological functions. Gas-phase acidity represents the intrinsic property of peptides containing ionizable amino acid residues. This study focused on characterization of several important parameters affecting the gas-phase acidity of oligopeptides consisting of one D/L-configuration cysteine residue and a polyalanine backbone. The gas-phase acidities were determined using a tandem quadrupole mass spectrometer by applying the CID bracketing experiments and the extended kinetic method. The conformations and the energetics of model peptides were obtained computationally using a series of approaches. Conformational search was performed using the CREST program, which gives a pool of low-energy conformations. Subsequent geometry optimization and frequency calculations were carried out using the density functional theory at ωB97xD/6-311+G(d,p) level, which yields the final pool of lowest energy conformations. Theoretical gas-phase acidities were calculated based on Boltzmann averaged free energies of the final pool of conformations. Noncovalent interactions were examined using the reduced density gradient analysis.