Designing cooperatively folded abiotic uni- and multimolecular helix bundles

Abstract

Abiotic foldamers, that is foldamers that have backbones chemically remote from peptidic and nucleotidic skeletons, may give access to shapes and functions different to those of peptides and nucleotides. However, design methodologies towards abiotic tertiary and quaternary structures are yet to be developed. Here we report rationally designed interactional patterns to guide the folding and assembly of abiotic helix bundles. Computational design facilitated the introduction of hydrogen-bonding functionalities at defined locations on the aromatic amide backbones that promote cooperative folding into helix-turn-helix motifs in organic solvents. The hydrogen-bond-directed aggregation of helices not linked by a turn unit produced several thermodynamically and kinetically stable homochiral dimeric and trimeric bundles with structures that are distinct from the designed helix-turn-helix. Relative helix orientation within the bundles may be changed from parallel to tilted on subtle solvent variations. Altogether, these results prefigure the richness and uniqueness of abiotic tertiary structure behaviour.

Parallel Homochiral and Anti‐Parallel Heterochiral Hydrogen‐Bonding Interfaces in Multi‐Helical Abiotic Foldamers

“…The 1 HNMR spectrum of 2a in CDCl 3 shows two sets of signals,s uggesting the coexistence of PM and PP/MM conformers in solution ( Figure S1a in the Supporting Information), as was previously observed for structures containing T1. [6,9] On the contrary,t he deprotected sequence 2b shows one set of sharp NMR signals including for OH resonances (Figure 3c). Thes pectrum is similar to that of 1 (Figure 3b) Ahydrogen-bond array between parallel homochiralh elices (left) can be transformed in an equivalent array between anti-parallel heterochiralh elices (right).…”

“…[5] We have recently introduced the first abiotic tertiary folds,t hat is,f rom backbones that do not relate to peptides or nucleotides. [6] We used the stable helices formed by aromatic oligoamides of 8-amino-quinolinecarboxylic acid [7] (Q in Figure 1) and 6-aminomethylpyridine carboxylic acid [8] as well-defined modules and introduced hydroxy groups at precise positions at their periphery (X and Y in Figure 1) to promote inter-helix hydrogen bonding with amide carbonyl groups (Figure 2a). Va rious types of helix bundling were observed, including parallel trimers and dimers,a nd tilted dimers.…”

“…Va rious types of helix bundling were observed, including parallel trimers and dimers,a nd tilted dimers. [6,9] As opposed to biotic tertiary folds that form in water and are often driven by hydrophobic effects,t hese folds form in organic solvents.A ll these assemblies were homochiral, that is,t hey involved helices that have the same handedness.F urther progress in tertiary structures design will primarily rest on the orchestration of interactions between secondary folds,afar-from-trivial endeavor.H erein we introduce ab inding interface between helices of opposite handedness.U nlike what was recently shown in heterochiral peptide bundling, [10] we demonstrate the equivalence of parallel homochiral and anti-parallel heterochiral abiotic helix association. We also show how the two patterns can be combined within the same tertiary fold without having to consider the stereochemistry at each unit, as it would in apeptide.…”

“…Tu rn unit T1 ( Figure 1) has been shown to promote homochiral parallel helix bundling between two identical helical segments attached at their C-terminus as,for example in sequence 1 (Figure 1). [6] Molecular modelling was used to design 1:i ta llowed us to adjust the positions of hydrogenbond donors and led to the replacement of some X units by Y to avoid possible steric repulsions.Adiagram of the helixhelix interface illustrates how the hydrogen-bond donors and acceptors may face each other (Figure 2c,left). This diagram also shows that hydrogen bonding occurs despite the helices having the same handedness:the slope of the main chain (i.e.…”

Light‐Controlled Conformational Switch of an Aromatic Oligoamide Foldamer

“…[12] In addition, guest binding to,orrelease from, ahelical host may be associated with single helix-double helix equilibrium, [13] with al ight stimulus, [14] or with the ring contraction of am ain-chain aromatic unit. [16] Recent progress includes the consistent spatial arrangement of several abiotic helices, [17] as well as aromatic helix and sheet combinations. [16] Recent progress includes the consistent spatial arrangement of several abiotic helices, [17] as well as aromatic helix and sheet combinations.…”