Stabilizing Bifurcated Hydrogen Bond in 8‐Aminoquinoline Appended Peptides

• Published in: Chemistry, an Asian journal an Asian journal, 2024-07, Vol.19 (14), p.e202400248-n/a
• Main Authors: Shekhar, Shashank, Meena, Rachana, Lal, Jhajan, Yadav, Mukul, Kant, Ruchir, Reddy, Damodara N.
• Format: Article
• Language: English
• Subjects: 8-Aminoquinoline; Amino acids; Aminoquinolines; Bifurcated hydrogen bonding; Crystal structure; C−H⋅⋅⋅O Hydrogen bond; Hirshfeld Surface analysis; Hydrogen bonding; Hydrogen bonds; Nitrogen; NMR; Nuclear magnetic resonance; N−H⋅⋅⋅N hydrogen bond; Peptides; Quinoline; Residues
• ISSN: 1861-4728; 1861-471X; 1861-471X
• DOI: 10.1002/asia.202400248

The hydrogen bonding interaction between an amide N−H and the amide N of the preceding residue is prevalent in proline‐containing proteins and peptides. However, the N−H⋅⋅⋅N hydrogen bonding interaction is rare in non‐prolyl natural peptides due to restricted dihedral angles. Herein, we stabilize this type of interaction in 8‐aminoquinoline appended non‐prolyl peptides through bifurcated N⋅⋅⋅H⋅⋅⋅N hydrogen bond. The 8‐aminoquinoline‐incorporated model peptides 2 a–i were designed, synthesized, and the crystal structures of 2 a–c and 2 i were solved. Analysis of crystal data reveals that the amide N−H of aminoquinoline is involved in bifurcated hydrogen bonding interaction with the nitrogen of the preceding amino acid residue and the nitrogen in quinoline. Analysis of crystal packing, Hirshfeld surface and fingerprint plots confirms that the intermolecular O⋅⋅⋅H contacts significantly contribute to stabilizing bifurcated N⋅⋅⋅H⋅⋅⋅N hydrogen bonding interaction. Furthermore, NMR experiments and CD spectroscopy were conducted to examine the preferred conformation in solution, and the data corroborate with the crystal structure conformation. The crystal structural analysis of various 8‐aminoquinoline appended peptides revealed that the amide N−H involvement in bifurcated N⋅⋅⋅H⋅⋅⋅N hydrogen bond with the nitrogen of the preceding residue and with the imine of quinoline, while analysis of crystal packing, Hirshfeld surface, and fingerprint plots confirms significant contribution of intramolecular CH⋅⋅⋅O interaction and intermolecular O⋅⋅⋅H contacts are energetically significant and substantially influences the peptide conformation.