Abstract
The production of sequence-specific copolymers using copolymer templates is fundamental to the synthesis of complex biological molecules and is a promising framework for the synthesis of synthetic chemical complexes. Unlike the superficially similar process of self-assembly, however, the development of synthetic systems that implement templated copying of copolymers under constant environmental conditions has been challenging. The main difficulty has been overcoming product inhibition or the tendency of products to adhere strongly to their templates-an effect that gets exponentially stronger with the template length. We develop coarse-grained models of copolymerization on a finite-length template and analyze them through stochastic simulation. We use these models first to demonstrate that product inhibition prevents reliable template copying and then ask how this problem can be overcome to achieve cyclic production of polymer copies of the right length and sequence in an autonomous and chemically driven context. We find that a simple addition to the model is sufficient to generate far longer polymer products that initially form on, and then separate from, the template. In this approach, some of the free energy of polymerization is diverted into disrupting copy-template bonds behind the leading edge of the growing copy copolymer. By additionally weakening the final copy-template bond at the end of the template, the model predicts that reliable copying with a high yield of full-length, sequence-matched products is possible over large ranges of parameter space, opening the way to the engineering of synthetic copying systems that operate autonomously.
Highlights
Copolymers—polymers formed from two or more types of monomer unit—are ubiquitous in biology
We argue that decoupling the length of a copy from its affinity for the template, by channeling the free energy released in polymerization to the disruption of copy–template bonds as achieved by handhold-mediated DNA strand displacement (HMSD),5 would be sufficient to overcome product inhibition even on long templates in an isothermal environment
Off-rate discrimination is inaccurate for moderate discrimination energies as Unlike the template-copying machinery found in biological systems that can cyclically copy templates under constant environmental conditions,6–16 state-of-the-art synthetic molecular copying systems require external intervention or non-chemical driving35–38,43–46 to operate cyclically
Summary
Copolymers—polymers formed from two or more types of monomer unit—are ubiquitous in biology. In a recent theoretical and experimental work on the pre-enzymatic templated assembly, Rosenberger et al demonstrated that polymer aggregates with increased length can be generated from short building blocks under isothermal conditions, though these polymers were bound up in complexes, not separated from their templates.. A key theoretical result of these works is that separating an accurate copy from its template necessitates producing a state that is extremely far from equilibrium This thermodynamic argument applies to length control: in the absence of residual interactions with a template, an ensemble of copolymers of a specific (but arbitrary and templateselected) length is extraordinarily far from the equilibrium of a broad exponential distribution of lengths. III D, we demonstrate that long and accurate copies of the template can be generated if the correct and incorrect monomers have varying binding rates
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