Chirality-Induced Systematic Gas-Phase Acidity Alternation of Cysteine Polyalanine Oligopeptides

This research endeavor investigates the effects of chirality change on the structures and acidities of cysteine polyalanine oligopeptides in the gas-phase. As the building blocks of proteins, amino acids are small chiral compounds (with the exception of glycine) in which L- and D-enantiomers exist. Forty years ago, scientists still believed that only L-amino acids had effects on biological processes in animals, humans, and nature. However, with further research, D-amino acids have shown to have significant impacts on biological functions. As a distinctive example, myriad studies have demonstrated increased levels of D-amino acids in the brains of patients diagnosed with Alzheimer’s disease. Although much research has been completed on D-amino acids, this field is widely unexplored. One of the major obstacles is the lack of understanding of how D-amino acids affect the conformations and chemical properties of peptides, which is examined in this project. In this project, the gas-phase acidities of designed peptides were determined experimentally and theoretically. To experimentally determine the relative acidity of the peptides with the D-amino acid compared to its L-analog, a charged dimer between two peptides were formed and dissociated. The peptide that more likely takes the charge is the more acidic compound. To examine why one peptide is more acidic, computational studies were performed to obtain the structures and energies of the peptide species using molecular modeling. Experimentally, in this Ac-CAAA series, changing the chirality of the alanine closest to the N-terminal cysteine resulted in the least acidic tetrapeptide. Congruent results were obtained from theoretical studies; the decreasing acidity trend is as follows: Ac-CAADA-NH2, Ac-CADAA-NH2, and Ac-CDAAA-NH2, with their gas-phase acidity values of 321.5, 323.6, and 324.7 kcal/mol, respectively. The elongated hydrogen bonding in peptides with the D-alanine closer to the N-terminus provides less stabilization of the charge and decreases the acidity