Characterization of a Novel Dynamic Combinatorial Depsipeptide System with Implications for the Origin of Biopolymers

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C, Martin
Hud, Nicholas V.
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Proteins are a class of functional macromolecules whose components, amino acids, are thought to have been present on the ancient Earth—long before biology inhabited the planet. However, the orderly association of these monomers to form functional covalent biopolymers under simulated early Earth conditions has proven difficult, if not impossible. A further complication is that the peptide bonds holding proteins together are not easily broken in plausibly prebiotic settings, a kinetic limitation that strongly inhibits dynamic sequence space sampling for peptides and proteins even in modern-day laboratory applications. This hardened chemical nature of proteins suggests that although their constituent amino acids may have been available in prebiotic times, proteins could very well be a product of evolution. Recently, it has been shown that prebiotic peptide bond formation challenges can be overcome by introduction of hydroxy acids, which are able to join the amino acids in robust dry-heating co-polymerizations to form depsipeptides. These hybrid polymers contain both ester and amide bonds, which each possess dissimilar aqueous lifetimes. We speculated that the relative lability of the ester bond under most aqueous conditions could be harnessed to recycle large depsipeptides down to smaller copolymer units that were comprised primarily of amide bonds, and terminated with hydroxyl groups. These recycled N-(α-hydroxyacyl)-peptides would then be able to form new ester bonds with other similar units upon dry-heating, allowing for a re-sampling of sequence space. Herein, we explore the potential for synthetic N-(α-hydroxyacyl)-peptide units to function as building blocks for dynamic combinatorial chemistry using hydration-dehydration “environmental” cycles. The building blocks’ hydroxyl groups allow for dynamic ester chemistry in water while preserving the thermo-mechanical and self-assembly properties inherent to amides in the product depsipeptide polymers. We determine that a simple amide linked heterodimeric unit is the optimal dynamic building block size and demonstrate kinetic polymerization and depolymerization properties owing to cyclic morpholinedione intermediates that are applicable across a wide range of building blocks which incorporate a variety of hydroxy and amino acid side chains. We demonstrate that depsipeptides formed from amphiphilic building blocks are able to form self-assembling polymers that exhibit unprecedented aqueous solution-state assemblies of depsipeptides in addition to substrate-surface assemblies whose presence is in-phase with the hydration-dehydration cycles. In light of the difficulties with the abiotic formation of any well-defined length or sequence of peptides, we demonstrate how versatile the closely-related depsipeptides are, and how they might serve to fill historically significant voids in the understanding of the prebiotic milieu on early Earth.
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