Conformational Preferences of Proline Derivatives Incorporated into Vasopressin Analogues: NMR and Molecular Modelling Studies

Abstract

In this study, arginine vasopressin analogues modified with proline derivatives - indoline-2-carboxylic acid (Ica), (2S,4R)-4-(naphthalene-2-ylmethyl)pyrrolidine-2-carboxylic acid (Nmp), (2S,4S)-4-aminopyroglutamic acid (APy) and (2R,4S)-4-aminopyroglutamic acid, (Apy) - were examined using NMR spectroscopy and molecular modelling methods. The results have shown that Ica is involved in the formation of the cis peptide bond. Moreover, it reduces to a great extent the conformational flexibility of the peptide. In turn, incorporation of (2S,4R)-Nmp stabilizes the backbone conformation, which is heavily influenced by the pyrrolidine ring. However, the aromatic part of the Nmp side chain exhibits a high degree of conformational freedom. With analogues IV and V, introduction of the 4-aminopyroglumatic acid reduces locally conformational space of the peptides, but it also results in weaker interactions with the dodecylphosphocholine/sodium dodecyl sulphate micelle. Admittedly, both analogues are adsorbed on the micelle's surface but they do not penetrate into its core. With analogue V, the interactions between the peptide and the micelle seem to be so weak that conformational equilibrium is established between different bound states.

Design, Synthesis and Structure–Activity Relationship of New Arginine Vasopressin Analogues Containing Proline Derivatives in Position 2

“…Both non‐coded amino acids, Nmp and Ppc, have an aromatic and bulky planar side chain (naphthalene or phenyl moiety, respectively); however, in the case of Nmp in comparison with Ppc, the more bulky group is linked to the proline ring with –CH 2 – connection; thus, it is more distant and has higher flexibility. More light on the pressor antagonism of Nmp‐modified analogues is shed by NMR and molecular modelling studies recently conducted by our research group (34). These studies namely showed that the aromatic part of the Nmp side chain, despite its bulkiness, exhibits a high degree of conformational freedom, which might help the peptide to adopt the conformation required for the interaction with the V 1A receptor.…”

“…Results of these studies demonstrated also that Ica 2 substitution in analogue [Mpa 1 , Ica 2 , D‐Arg 8 ]VP ( IV ) reduces to a great extent the conformational flexibility of the peptide, which may be important for its selective activity. For detailed explanation of NMR and molecular modelling studies see reference (34).…”