Self-Sorting in Dynamic Combinatorial Libraries Leads to the Co-Existence of Foldamers and Self-Replicators

Abstract

Nature segregates fundamental tasks such as information storage/transmission and catalysis between two different compound classes (e.g. polynucleotides for replication and folded polyamides for catalysis). This division of labor is likely a product of evolution, raising the question of how simpler systems in which replicators and folded macromolecules co-exist may emerge in the transition from chemistry to biology. In synthetic systems, achieving co-existence of replicators and foldamers in a single molecular network remains an unsolved problem. Previous work on dynamic molecular networks has given rise to either self-replicating fibers or well-defined foldamer structures (or completely un-sorted complex systems). We report a system in which two cross-reactive dithiol (nucleobase- and peptide-based) building blocks self-sort into a replicator fiber and foldamer that both emerge spontaneously and co-exist. The self-sorting behavior remains prevalent across different building block ratios as two phases of emergence occur: replicator growth followed by foldamer formation. This is attributed to the autocatalytic formation of the replicator fiber, followed by enrichment of the system in the remaining building block, which is subsequently incorporated into a foldamer.

Keywords: dynamic combinatorial chemistry; foldamers; self-assembly; self-replicators; self-sorting.

Figure 1

UPLC analysis reveals a) a complex, mixed DCL made from building blocks 1 a (1.0 mM) and 2 (1.0 mM), published previously; ^[14] b) a DCL of macrocycles after 36 hours upon combining 1 b (1.0 mM) and 2 (1.0 mM); c) self‐sorting into two distinct species (1 b)₂ 2₁ and 2₁₅, after the DCL in b was incubated for 7 days; d) 1 b (2.0 mM) selectively forming (1 b)₄ and e) 2 (2.0 mM) selectively forming 2₁₅ after stirring for 10 days in Na₂B₄O₇ buffer (50 mM, pH 8.0, 1.0 M NaCl).

Scheme 1

Cartoon illustration of the self‐sorting process. A DCL made from building blocks 1 b and 2 first forms autocatalytic (1 b)₂ 2₁ fibers, facilitating the formation of a single building block foldamer, 2₁₅, by enriching the remaining products in 2.

Figure 2

a) Kinetics of emergence of replicator (1 b)₂ 2₁ and foldamer 2₁₅ from an equimolar solution of 1 b (1.0 mM) and 2 (1.0 mM) show that 2₁₅ emerges only after formation of (1 b)₂ 2₁ is near complete (shaded area, 96 h). b) Earlier emergence of 2₁₅ is observed in an analogous experiment starting from a different building block ratio (30 % in 1 b), as (1 b)₂ 2₁ growth is complete early at 48 h (shaded area). c) Experiments starting from different ratios of 1 b and 2 show that replicators and foldamers dominate the DCL.

Figure 3

Seeding experiments reveal accelerated formation of (1 b)₂ 2₁ or (1 b)₄ indicative of self‐replication when a) (1 b)₂ 2₁ (6 mol %) seed is added to a solution of 1 b and 2 ([1 b] 1.0 mM, [2]=0.5 mM, red trace) and when b) (1 b)₄ (10 mol %) seed is added to 1 b alone ([1 b]=1.0 mM, green trace) in comparison to non‐seeded samples (black traces). TEM images reveal bundled fibers from samples of c) (1 b)₂ 2₁ and d) (1 b)₄.