The role of ring puckering and non-covalent interactions in the conformational chirality of 2,5-diketopiperazines with identical residues: A theoretical study

Abstract

2,5-Diketopiperazines (DKPs) are the smallest cyclic peptides whose six-membered ring can pucker and thus generate conformational chirality in symmetric scaffolds. Here, we investigate how non-covalent interactions (NCIs) govern the emergence of chiral vs achiral conformations and the associated racemization pathways in gas-phase DKPs with identical residues. We combine conformational sampling with geometry optimizations at the density functional theory level, NCI analysis, and simulated spectroscopic features, such as infrared and vibrational circular dichroism (VCD), to determine structure–property relationships in aliphatic and aromatic derivatives. Chirality is quantified using a mirror-optimal root-mean-square deviation (moRMSD), which compares a structure to its mirror image. moRMSD is built on a graph-theoretical atom mapping that identifies each atom by its connectivity and local environment, providing a continuous, chemically informed measure of conformational chirality. When the residues have opposite absolute configuration, our results show that strong intramolecular hydrogen bonds systematically stabilize achiral minima. In contrast, weaker NCIs, such as CH⋯π and NH⋯π contacts, together with steric effects from bulky side chains, promote chiral puckered geometries. Racemization barriers increase with side-chain size, and transition states connecting enantiomers are characterized by (near) planar, centrosymmetric DKP rings. Complementary vibrational chiroptical spectroscopy, specifically VCD, provides insight into conformational preferences: for the most stable geometries in each system, the sign of the VCD νCO couplet tracks the puckering direction, offering a robust spectroscopic handle on ring chirality. These results clarify how specific non-covalent motifs encode puckering-induced conformational chirality in DKP scaffolds.