Sequence-selective dynamic covalent assembly of information-bearing oligomers

Samuel C Leguizamon,Timothy F Scott

doi:10.1038/s41467-020-14607-3

Abstract

Relatively robust dynamic covalent interactions have been employed extensively to mediate molecular self-assembly reactions; however, these assembly processes often do not converge to a thermodynamic equilibrium, instead yielding mixtures of kinetically-trapped species. Here, we report a dynamic covalent self-assembly process that mitigates kinetic trapping such that multiple unique oligomers bearing covalently coreactive pendant groups are able to undergo simultaneous, sequence-selective hybridization with their complementary strands to afford biomimetic, in-registry molecular ladders with covalent rungs. Analogous to the thermal cycling commonly employed for nucleic acid melting and annealing, this is achieved by raising and lowering the concentration of a multi-role reagent to effect quantitative dissociation and subsequently catalyze covalent bond rearrangement, affording selective assembly of the oligomeric sequences. The hybridization specificity afforded by this process further enabled information encoded in oligomers to be retrieved through selective hybridization with complementary, mass-labeled sequences.

Highlights

Robust dynamic covalent interactions have been employed extensively to mediate molecular self-assembly reactions; these assembly processes often do not converge to a thermodynamic equilibrium, instead yielding mixtures of kinetically-trapped species
Efforts to improve the stability of double-stranded, nucleic acid-like duplexes include the utilization of abiotic, neutral backbones[12,13,14], the integration of isostere nucleobase mimetics[15,16], and the incorporation of photoinduced cross-links[17,18]; the assembly processes for these duplexes remain mediated by intermolecular interactions
These oligomers were synthesized as binary sequences of amine and aldehyde pendant groups alternating with inert spacer residues such that, owing to the zig-zag ‘Σ-strand’ conformation adopted by the constituent peptoid chains, the reactive groups were presented on the same side of the peptoid backbone[33]

Summary

Introduction

Robust dynamic covalent interactions have been employed extensively to mediate molecular self-assembly reactions; these assembly processes often do not converge to a thermodynamic equilibrium, instead yielding mixtures of kinetically-trapped species. To examine the effect of Sc3+ concentration on molecular ladder dissociation, varying amounts of scandium triflate were added to post-annealed, in-registry 10101 × 01010 reaction mixtures which were heated at 60 °C for 6 h, left to stand at room temperature overnight to ensure system equilibration, and characterized by mass spectrometry (Supplementary Fig. 7).

Results

Conclusion