“Bridged” n→π* Interactions Can Stabilize Peptoid Helices

Abstract

Peptoids are an increasingly important class of peptidomimetic foldamers comprised of N-alkylglycine units that have been successfully developed as antimicrobial agents, lung surfactant replacements, enzyme inhibitors, and catalysts, among many other applications. Since peptoid secondary structures can be crucial to their desired functions, significant efforts have been devoted to developing means of modularly controlling peptoid backbone amide cis-trans isomerism using side chains. Strategic engineering of interactions between side chain aromatic rings and backbone cis-amides (n→π*(Ar) interactions) is an attractive strategy for stabilizing helical structures in N-a-chiral aromatic peptoids, which are among the most utilized classes of structured peptoids. Herein, we report the first detailed computational and experimental study of n→π*(Ar) interactions in models of peptoids containing backbone thioamides, which we term "thiopeptoids". Our work has revealed that these interactions significantly affect amide rotamerism in both peptoid and thiopeptoid models via a newly characterized "bridged" mode of interaction mediated by the N-α-C-H σ orbitals. Overall, this work elucidates new strategies for controlling both peptoid and thiopeptoid folding and suggests that thiopeptoids will be highly structured and therefore potentially useful as therapeutics, biological probes, and nanostructural engineering elements.

Log D versus HPLC derived hydrophobicity: The development of predictive tools to aid in the rational design of bioactive peptoids

“…Peptoids have been shown to adopt stable and well defined structures in solution, such as the peptoid helix, threaded loop conformation, peptoid nanosheets, and nanotubes . Unlike peptides where regular backbone hydrogen bonding helps to stabilise the secondary structures adopted, peptoids typically rely upon the local steric or electronic effects of side chains to help stabilise any secondary structures formed. The positioning of the side chains on the nitrogen of the amide (as opposed to the alpha‐carbon) also renders the backbones of peptoid sequences achiral and the tertiary amides are more easily isomerised between cis and trans conformations than the secondary amides of a peptide (see Figure ).…”

Endothioxopeptides: A conformational overview

“…The intramolecular O…CO distance should be less than 3.2 Å and the corresponding bond angle 100°–120°. More recently, Raines and coworkers extended this investigation to endothioxopeptides (through the detailed NMR determination of their trans / cis ratios) and others to endothioxopeptoids. In the former compounds, theoretical analyses demonstrated that the energy of the n → π * interaction is higher when the donor atom is sulfur (as compared to oxygen).…”

“…On the other hand, in endothioxopeptide a computational investigation revealed that a different type of n → π * interaction, where in this case π * refers to orbitals of an electron poor aromatic ring located in the side chain (linked to the N α ‐atom), does take place, stabilizing the cis ‐rotamer of the donor thionamide group . In these compounds, the n → π * (aromatic) interaction is operative via a new “bridged” mode facilitated by the NαCH orbitals.…”

Unconstrained peptoid tetramer exhibits a predominant conformation in aqueous solution

“…To design effective drugs or protein mimetic materials from peptoids, it is essential to understand and control their conformation. Thus, researchers have developed a variety of methods to constrain peptoid structure, including macrocyclization, steric congestion, side chain chirality, and electronic interactions . Most of these rely on bulky, hydrophobic groups, which can dominate the molecular properties and restrict water solubility, hindering the development of biological applications.…”