Exploring the Conformation of Mixed Cis–Trans α,β-Oligopeptoids: A Joint Experimental and Computational Study

Abstract

The synthesis and conformational preferences of a set of new synthetic foldamers that combine both the α,β-peptoid backbone and side chains that alternately promote cis- and trans-amide bond geometries have been achieved and addressed jointly by experiment and molecular modeling. Four sequence patterns were thus designed and referred to as cis-β- trans-α, cis-α- trans-β, trans-β- cis-α, and trans-α- cis-β. α- and β NtBu monomers were used to enforce cis-amide bond geometries and α- and β NPh monomers to promote trans-amides. NOESY and molecular modeling reveal that the trans-α- cis-β and cis-β- trans-α tetramers show a similar pattern of intramolecular weak interactions. The same holds for the cis-α- trans-β and trans-β- cis-α tetramers, but the interactions are different in nature than those identified in the trans-α- cis-β-based oligomers. Interestingly, the trans-α- cis-β peptoid architecture allows establishment of a larger amount of structure-stabilizing intramolecular interactions.

Relating circular dichroism to atomic structure by means of MD simulations and computed CD spectra with α-peptoids as an example

“…This is in accordance with our previous results where such interactions are omnipresent when two α-peptoid monomers are concerned. 33 Some amount of backbone (i)C=O ... (i+1)C=O interactions are also observed during the simulations. The last type interactions studied in the present work is that between main chain carbonyl oxygen and side-chain chiral carbon.…”

The Challenge of Conformational Isomerism in Cyclic Peptoids

“…Finally, the alternated ct secondary structure in [ 31a· Na] + showed a unique CPM 2 loop structure with classic ϕ ≈ ±70° and ψ ≈ ±170° torsional angles but rare cis ‐ trans arrangement of the peptoid backbone reminiscent of the peptoid ribbon‐like structure, the “?‐helix ” , or the mixed cis ‐ trans α,β‐oligopeptoids secondary structures.…”

Increasing the Functional Group Diversity in Helical β-Peptoids: Achievement of Solvent- and pH-Dependent Folding

“…Inspired by detailed studies of the trans-cis-amide equilibria of proline residues, [35][36][37][38] efforts have also been directed towards the development of methods to control these ratios in and -peptoids. [39][40][41][42][43][44][45][46][47][48][49] Still, only a limited number of examples of high-resolution structures of folded oligomers have been solved, [50][51][52][53][54][55][56][57][58] underlining the continued challenge of achieving structure-based design of oligomeric peptoids. We reported the N-(S)-1-(1-naphthyl)ethyl (Ns1npe, 1) side chain to promote formation of triangular prism-shaped -peptoid helical structure of oligomer 2, 31,53 and recently elaborated upon this highly cis-amide bond-inducing side chain to incorporate longer hydrocarbons (3) and amino groups.…”