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Crystal structures reveal that the sterically hindered pivaloyl-cisProlyl amide bond is energetically frustrated

Banerjee, S and Gupta, SK and Pal, S and Prabhakaran, EN (2024) Crystal structures reveal that the sterically hindered pivaloyl-cisProlyl amide bond is energetically frustrated. In: Peptide Science .

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Official URL: https://doi.org/10.1002/pep2.24337


Background: CisPro/transPro isomerism at the prolyl amide bond is a fundamental dynamism governing protein folding, structure, and functions. Since cisPro crystal structures are rare, the interactions influencing their structures are less understood, unlike transPro. Crystal data for the sterically hindered pivaloyl-cisProlyl amide bond (2,2-dimethyl-1-(1-pyrrolidinyl)-1-propanone, Piv-cisPro) were particularly lacking for decades. Here we introduce Piv-Pro-Xaa-OMe dipeptides which crystallize with the elusive Piv-cisPro (Xaa is Leu/Ile) and the abundant Piv-transPro (Xaa is Gly/Phe) conformers. Results: Natural bond orbital, quantum theory of atoms in molecules, and density functional theory calculations performed on these crystal structures and on the rotamers of the pivaloyl group reveal the presence of two constant n��* interactions and a network of varying van der Waals interactions with unfavorable energies influencing this cisPro/transPro dynamism. Both conformers are hence energetically frustrated. The Piv-cisPro amide bond distorts significantly to lower its energy by avoiding hard sphere clashes. Still, only in a narrow range of 12° of rotation along the CαPiv-CβPiv bond, the Piv-cisPro energies are relatively more favorable than Piv-transPro. Piv-cisPro crystallizes within this range. Conclusions: Interactions that constrain the CαPiv-CβPiv bond within this 12° range can further stabilize Piv-cisPro in crystals. Current results provide the first insights into interactions governing Piv-Pro amide bond isomerism. © 2024 Wiley Periodicals LLC.

Item Type: Journal Article
Publication: Peptide Science
Publisher: John Wiley and Sons Inc
Additional Information: The copyright for this article belongs to author
Keywords: Amides; Chemical bonds; Crystal atomic structure; Crystals; Isomers; Quantum theory; Stereochemistry; Van der Waals forces, Amide bond; Cisproline; Crystals structures; Energy; N��* interaction; Pivaloyl; Protein functions; Proteins structures; Van der Waal; �-interactions, Density functional theory
Department/Centre: Others
Date Deposited: 01 Mar 2024 09:34
Last Modified: 01 Mar 2024 09:34
URI: https://eprints.iisc.ac.in/id/eprint/83991

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