A New Chirality Phenomenon in Amino Acid and Peptide Derivatives

Amino acids and peptides are essential molecules that play pivotal roles in biology, medicine, and chemistry, particularly in drug design and discovery. Peptide-based drugs are increasingly favored due to their high solubility in aqueous biological systems, ease of structural modification, and the non-toxic nature of their metabolites. For most peptide drugs, the chirality of their higher structures determines both their functionality and biological activities. To date, nearly all amino acid residues in peptide structures exhibit central chirality, although axial chirality has occasionally been observed in peptides. In this study, we report the discovery of a new form of chirality, termed turbo chirality, which consists of two propeller blades and coexists alongside central chirality in amino acids and peptides. Specifically, we found that di-propeller structures in amino acids and peptides can exist in either M,M- or P,P-configurations, depending on the orientation of their chiral centers, which are controlled by (S)- and (R)-configurations, respectively. Computational studies were conducted to explore the relative energies of rotational barriers for conversion between M,M- and P,P-configurations, as well as the transition pathways between the two enantiomers, yielding results that align with our expectations. This discovery is expected to have broad implications for amino acid and peptide research, particularly in structure-activity relationship (SAR) studies of peptides and peptidomimetics. As a result, our findings are anticipated to make a significant impact across multiple disciplines, including chemistry, biomedicine, and materials science.