Influence of Proline Chirality on Neighbouring Azaproline Residue Stereodynamic Nitrogen Preorganization

• Published in: Chemistry, an Asian journal an Asian journal, 2023-01, Vol.18 (1), p.e202201023-n/a
• Main Authors: Lal, Jhajan, Prajapati, Gurudayal, Meena, Rachana, Kant, Ruchir, Sankar Ampapathi, Ravi, Reddy, Damodara N.
• Format: Article
• Language: English
• Subjects: azaproline; Chemistry; Chirality; Crystal structure; Crystallography; Density functional theory; Magnetic Resonance Spectroscopy; Molecular orbitals; Nitrogen; NMR; Nuclear magnetic resonance; n→π interactions; Peptides; Peptides - chemistry; Proline; Proline - chemistry; proline editing; Protein Conformation; Residues; Stereochemistry; Titration; β-turn
• ISSN: 1861-4728; 1861-471X
• DOI: 10.1002/asia.202201023

We report herein the first systematic crystal structural investigation of azaproline incorporated in homo‐ and heterochiral diprolyl peptides. The X‐ray crystallography data of peptides 1–5 illustrates that stereodynamic nitrogen in azaproline adopted the stereochemistry of neighbouring proline residue without depending on its position in the peptide sequence. Natural bond orbital analysis of crystal structures indicates OazPro−C′Pro of peptides 4 and 5 participating in n→π* interaction with stabilization energy about 1.21–1.33 kcal/mol. Density functional theory calculations suggested that the endo‐proline ring puckering favoured over exo‐conformation by 6.72–7.64 kcal/mol. NBO and DFT data reveals that the n→π* interactions and proline ring puckering stabilize azaproline chirality with the neighbouring proline stereochemistry. The CD, solvent titration, variable‐temperature and 2D NMR experimental results further supported the crystal structures conformation. The X‐ray crystallography data of an azaproline residue embedded within homo‐ and heterochiral diprolyl peptides 1–5 demonstrated that the chirality of the stereodynamic nitrogen of the azaproline residue adopts the neighbouring proline stereochemistry. NBO and DFT calculations suggest that the n→π* interactions and proline ring puckering stabilize azaproline with the neighbouring proline chirality.