Subtle chirality effects of a D/l-Cysteine on the intrinsic acidity and conformation of isomeric tripeptides ACA and AdCA

Abstract

Chirality effects on the intrinsic acidity of oligopeptides have been studied using a pair of stereoisomeric tripeptides containing two alanine (A) residues and either an L- or a d-cysteine, ACA and AdCA, where the C-terminus is amidated. The gas-phase acidities were determined by mass spectrometry measurements. The extended kinetic method yielded the deprotonation enthalpy (ΔacidH) and the gas-phase acidity (ΔacidG) of ACA to be 328.0 and 322.7 kcal/mol (1372.4 and 1350.2 kJ/mol), and of AdCA to be 327.8 and 322.4 kcal/mol (1371.5 and 1348.9 kJ/mol), respectively. Although the quantitative difference is small, the branching ratio bracketing experiments clearly indicate that AdCA is a stronger gas-phase acid than ACA. Conformations were obtained via a step-wise conformational search, followed by geometry and frequency calculations at the B3LYP/6-311 + G (d,p) level of theory. Theoretical gas-phase acidities are in good agreement with the experiments, which also suggests that AdCA is a stronger gas-phase acid. The enhanced acidity of the d-cysteine containing peptide is likely due to the adoption of a unique bent conformation upon deprotonation at the thiol group, which enables more favorable hydrogen bonding interactions within the peptide ion. The findings imply that chirality change on a single amino acid residue may have a notable effect on the biochemical properties of peptides.