Unconstrained peptoid tetramer exhibits a predominant conformation in aqueous solution

Abstract

Conformational control in peptoids, N‐substituted glycines, is crucial for the design and synthesis of biologically‐active compounds and atomically‐defined nanomaterials. While there are a growing number of structural studies in solution, most have been performed with conformationally‐constrained short sequences (e.g., sterically‐hindered sidechains or macrocyclization). Thus, the inherent degree of heterogeneity of unconstrained peptoids in solution remains largely unstudied. Here, we explored the folding landscape of a series of simple peptoid tetramers in aqueous solution by NMR spectroscopy. By incorporating specific 13C‐probes into the backbone using bromoacetic acid‐2‐13C as a submonomer, we developed a new technique for sequential backbone assignment of peptoids based on the 1,n‐Adequate pulse sequence. Unexpectedly, two of the tetramers, containing an N‐(2‐aminoethyl)glycine residue (Nae), had preferred conformations. NMR and molecular dynamics studies on one of the tetramers showed that the preferred conformer (52%) had a trans‐cis‐trans configuration about the three amide bonds. Moreover, >80% of the ensemble contained a cis amide bond at the central amide. The backbone dihedral angles observed fall directly within the expected minima in the peptoid Ramachandran plot. Analysis of this compound against similar peptoid analogs suggests that the commonly used Nae monomer plays a key role in the stabilization of peptoid structure via a side‐chain‐to‐main‐chain interaction. This discovery may offer a simple, synthetically high‐yielding approach to control peptoid structure, and suggests that peptoids have strong intrinsic conformational preferences in solution. These findings should facilitate the predictive design of folded peptoid structures, and accelerate application in areas ranging from drug discovery to biomimetic nanoscience.

Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution

“…Progress in foldamer design has thus relied much on computational modeling, with successful design efforts resulting from the tight collaboration of both experiment and theory. 30,[38][39][40][41] One approach to foldamer prediction and design has been to use ab initio modeling to construct rotamer libraries of residue types that can be used with existing tools for protein design such as Rosetta. 38,[42][43][44] While this enables fast searching of sequence and structure space, the main drawback is the difficulty of parameterization.…”

Cooperative Intramolecular Hydrogen Bonding Strongly Enforces cis-Peptoid Folding

“…We commenced our study by synthesizing and analyzing peptoids that feature a potential NH–O hydrogen-bonding interaction. Previous studies have hinted that side-chains with primary amine or ammonium functionalities tethered to the backbone by an alkyl linker, such as N -aminoethyl (Nae), N -aminopropyl (Nap), and N -aminobutyl (Nab), may be capable of inducing the cis -amide geometry in peptoid structures, though these studies did not quantify the extent of cis induction. , Moreover, the mentioned side-chains are widely used in peptoid structures such as in nanosheets and helices. ,, Peptoid monomer derivatives, 1 – 3 , containing Nae, Nap, and Nab, respectively, were synthesized to test this hypothesis, along with other peptoids as controls, N -hydroxyethyl (Nhe) ( 4 ), N -guanidinylethyl (Ngue) ( 5 ), N -2picolyl (N2pic) ( 6 ), and N -3picolyl (N3pic) ( 7 ) (Chart ). Indeed, most of these side-chains favor the cis -amide geometry moderately ( K cis/trans up to 5.4), with the exception of Nhe ( 4 ), which slightly favors the trans rotamer ( K cis/trans = 0.9 in CDCl 3 , 0.5 in MeOD and D 2 O), and Nab ( 3 ), which shows almost no preference for either geometry in all solvents ( K cis/trans ≈ 1) (Table ).…”

“…Previous studies have hinted that side-chains with primary amine or ammonium functionalities tethered to the backbone by an alkyl linker, such as N-aminoethyl (Nae), N-aminopropyl (Nap), and N-aminobutyl (Nab), may be capable of inducing the cis-amide geometry in peptoid structures, though these studies did not quantify the extent of cis induction. 34,35 Moreover, the mentioned side-chains are widely used in peptoid structures such as in nanosheets and helices. 10,12,36 Peptoid monomer derivatives, 1−3, containing Nae, Nap, and Nab, respectively, were synthesized to test this hypothesis, along with other peptoids as controls, N-hydroxyethyl (Nhe) (4), N-guanidinylethyl (Ngue) (5), N-2picolyl (N2pic) (6), and N-3picolyl (N3pic) (7) (Chart 1).…”

Guidelines for designing peptoid structures: Insights from the Peptoid Data Bank

“…However, several properties of the peptoid backbone make NMR data challenging to interpret. [ 46 ] First, the lack of an amide NH group frustrates assignment strategies familiar to peptide chemists. Second, isomerization of the amide bond is slow on the NMR time scale, leading to multiple sets of peaks.…”