Oligo(N‐alkoxy glycines): Trans substantiating peptoid conformations

Abstract

Peptoid oligomers possess many desirable attributes bioactive peptidomimetic agents, including their ease of synthesis, chemical diversity, and capability for molecular recognition. Ongoing efforts to develop functional peptoids will necessitate improved capability for control of peptoid structure, particularly of the backbone amide conformation. We introduce alkoxyamines as a new reagent for solid phase peptoid synthesis. Herein, we describe the synthesis of N-alkoxy peptoids, and present NMR data indicating that the oligomers adopt a single stable conformation featuring trans amide bonds. These findings, combined with results from computational modeling, suggest that N-alkoxy peptoid oligomers have a strong propensity to adopt a polyproline II type secondary structure.

α‐Aminoxy Peptoids: A Unique Peptoid Backbone with a Preference for cis‐Amide Bonds

“…The relative free energies of the α‐aminoxy peptoid 1 as a function of the backbone dihedral angles ϕ , θ , and ψ computed from the frequency of occurrence of the conformations during the MD simulations allowed us to identify the preferred backbone conformations of the α‐aminoxy peptoid 1 (Figure S24 in the Supporting Information); given the almost identical torsion angle distributions (Figures S17, S18, and S19 in the Supporting Information), similar conformations are expected to be favorable also for the other α‐aminoxy peptoids. The lack of mirror symmetry in the θ / ϕ and θ / ψ projections of the relative free energy is compatible with the observation that the amide nitrogen atom shows a certain degree of pyramidalization, which is in agreement with findings of Jordan and co‐workers, leading to a transient chirality . Superimposing the low‐energy conformations of the α‐aminoxy peptoids 1 , 2 , and 3 extracted from the respective MD simulations onto the crystal structure of the α‐aminoxy peptoid 1 results in backbone‐atom root mean square deviations (RMSD)≤0.6 Å (Figure A–C).…”

“…The MD simulations reached equilibrium with respect to conformational preferences of the angels ϕ , θ , and ψ , as indicated by highly symmetric torsion angle distributions (Figures S17, S18, and S19 in the Supporting Information) and frequent transitions between energetically preferred states (Figures S20, S21, and S22 in the Supporting Information). In contrast, for the α‐aminoxy peptoids 1 , 2 , or 3 started either with a cis ‐ or trans ‐amide conformation, a transition in the ω torsion angle between the two conformers was not observed, which is in line with an energetic barrier separating the two conformers (Figure S16 in the Supporting Information for the N ‐ethoxyformamide model compound; Figure S23 in the Supporting Information for the α‐aminoxy peptoid 30 ( N , N ‐dimethyl‐2‐(( N ‐methylacetamido)‐oxy)acetamide) for probing the effect of an acetyl cap group and an N ‐methyl side chain) and previous work . In addition, our calculations show that the cis conformer is preferred over the trans conformer by approximately 2.8 kcal mol −1 for peptoid 30 , whereas the cis and trans conformers are virtually isoenergetic for the N ‐ethoxyformamide model compound (Figures S23 and S16 in the Supporting Information, respectively), which is consistent with cis / trans energy differences of up to 1.4 kcal mol −1 in regular (not α‐aminoxy) peptoids, as reported by Yoo and Kirshenbaum .…”

Polypeptoids: A perfect match for molecular definition and macromolecular engineering?

“…Kirshenbaum and coworkers have made substantial contributions to our understanding on the possibilities to introduce turns into peptoids . In fact, recently de novo structure prediction of peptoids oligomers has been demonstrated …”

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

“…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.…”