Kinetics and Equilibria of Cis/Trans Isomerization of Backbone Amide Bonds in Peptoids

Abstract

The biological activities of N-substituted glycine oligomers (peptoids) have been the subject of extensive research. As compared to peptides, both the cis and trans conformations of the backbone amide bonds of peptoids can be significantly populated. Thus, peptoids are mixtures of configurational isomers, with the number of isomers increasing by a factor of 2 with each additional monomer residue. Here we report the results of a study of the kinetics and equilibria of cis/trans isomerization of the amide bonds of N-acetylated peptoid monomers, dipeptoids, and tripeptoids by NMR spectroscopy. Resonance intensities indicate the cis conformation of the backbone amide bonds of the peptoids studied is more populated than is generally the case for the analogous secondary amide bond to proline residues in acyclic peptides. Rate constants were measured by inversion-magnetization transfer techniques over a range of temperatures, and activation parameters were derived from the temperature dependence of the rate constants. The rate of cis/trans isomerization by rotation around the amide bonds in the peptoids studied is generally slower than that around amide bonds to proline residues and takes place on the NMR inversion-magnetization transfer time scale only by rotation around the amide bond to the C-terminal peptoid residue.

Structural Modeling and Conformational Analysis of Aromatic Polypeptoid Models Confined to Different Environmental Conditions

“…In our study all atoms of the system were considered explicitly. The simulation results obtained by GROMOS force field have been found to be in good agreement with the experimental results on β peptides and peptoids [26,27,52]. The Dundee-PRODRG2 server [53] was used to obtain the GROMACS topology and coordinate files.…”

“…Peptoids are generally synthesized by coupling a haloacetic acid and a primary amine by using DMF or DMSO as solvents [25]. Due to the hydrophobic nature of peptoids compared to the corresponding amino acids they are difficult to crystallize and their structural studies have mainly been carried out by circular dichroism-a low resolution technique and NMR spectroscopy [23,[26][27][28][29][30][31]. Also, crystallographic studies are mostly on cyclic peptoids and there are only a few studies on linear peptoids [32][33][34][35][36].…”

“…It may also be mentioned that in poly N-methylated α-peptides the amide bond geometry has also been shown to be trans by crystallographic results [28,29]. A careful analysis of literature leads to an interesting observation that when peptoids were synthesized using dimethyl formamide (DMF) [31,32,[34][35][36][37], or dimethyl sulphoxide (DMSO) [25,26,27] as solvents during the coupling reactions; the results obtained on amide bond geometry are at variance including crystallographic studies and hence the adopted structures. This implies that the nature of amide bond geometry is influenced by the solvents being used during peptoid synthesis at the coupling stage.…”

Chemical Modulation of Peptoids: Synthesis and Conformational Studies on Partially Constrained Derivatives

“…Second, both molecules have shown interesting biological properties as inhibitors of the formation of the apoptosome. [21, 27a] The main feature in the By considering previous studies on peptoids and the identity of the 1 H NMR signals that were split more significantly, [16] we proposed the cis/trans isomerization around the exocyclic tertiary amide bond to be the dynamic process responsible for this conformational behavior (Scheme 3).…”

“…By taking advantage of the intensive research into short peptoids as a result of their potential application in drug discovery, Borchardt and Rabenstein recently reported the use of NMR spectroscopic techniques to study cis/trans isomerization by rotation around the amide bonds of small peptoid models. [16] These authors observed a slow cis/trans exchange rate for even the most labile of the amide bonds between the two C-terminal residues. This feature can be of importance with respect to the on/off rates for the ligand/receptor binding or when facing undesired interactions with other targets.…”