Proline N-oxides: modulators of the 3D conformation of linear peptides through “NO-turns”

Abstract

Small peptides are essential mediators of numerous physiological processes. Consequently, there is huge interest in the de novo design of peptides with a predictable folding and related biological activity. In this study, we investigate the possibility of modulating the secondary structure of tetrapeptides through proline N-oxide moieties and N-methylation of the peptide backbone. A series of tetrapeptides were synthesised to investigate the combined effect of Pro N-oxide and N-methylation of the amide bond on the (n + 1) residue in terms of cis- and trans-isomerization, as well as how these modifications direct potential intramolecular hydrogen bonding interactions. The right combination of both these parameters led to a trans to cis-conformational interconversion and a change in the nature of the hydrogen bonding interactions, as demonstrated by NMR spectroscopic, molecular modeling analysis and thermal coefficient studies. Proline N-oxide residues were proposed to induce turns we named as NO-γ-turns and NO-β-turns based on their similarity to traditional γ- and β-turns.

The effect of N-methylation of amino acids (Ac-X-OMe) on solubility and conformation: a DFT study

“…[55,124] A polar solvent, such as DMSO with a large dipolar moment (3.96 D), favours cis-isomers, while less polar solvents, such as water (1.85 D), induce more trans-character. [60] Similar computational [30,32,[47][48][49][50][51][52][53] and other experimental [17,30,47,48,50,51,54,[56][57][58][59] results have been reported, showing that N-methylation of the amide bond increase the cis/trans ratio. [60] Similar computational [30,32,[47][48][49][50][51][52][53] and other experimental [17,30,47,48,50,51,54,[56][57][58][59] results have been reported, showing that N-methylation of the amide bond increase the cis/trans ratio.…”

“…[60] N-Methylation of short cyclic peptides also revealed more rigid behaviour according to NMR solution and molecular dynamics studies. [60] N-Methylation of short cyclic peptides also revealed more rigid behaviour according to NMR solution and molecular dynamics studies.…”

Oxa–diketopiperazines: Access and Conformational Analysis of Potential Turn Inducers

“…Since cyclic scaffolds such as proline analogues and diketopiperazine (DKP), are well known structures exhibiting turn inducer properties, we ambitioned that the 1,2,5‐Oxd skeleton could be defined as an alternative sources of turn inducer. Among the turns present in nature, the β‐turn is one of the major secondary structural element of proteins, playing an essential role in folding and in recognition .…”

Synthesis and structure elucidation using 2D NMR and thermal coefficient investigation on amino acid tethered quinoxalines

“…In aprotic solvents such as DMSO‐ d 6 , −Δ δ /Δ T < 3 ppb K −1 indicates the presence of hydrogen bonding, and at −Δ δ /Δ T > 5 ppb K −1 , hydrogen bonding is not possible . The −Δ δ /Δ T values for selected protons in 4a–n acquired in DMSO‐ d 6 are summarized in Table S1.…”