Automated exploration of DNA-based structure self-assembly networks.

Finding DNA sequences capable of folding into specific nanostructures is a hard problem, as it involves very large search spaces and complex nonlinear dynamics. Typical methods to solve it aim to reduce the search space by minimizing unwanted interactions through restrictions on the design (e.g. staples in DNA origami or voxel-based designs in DNA Bricks). Here, we present a novel methodology that aims to reduce this search space by identifying the relevant properties of a given assembly system to the emergence of various families of structures (e.g. simple structures, polymers, branched structures). For a given set of DNA strands, our approach automatically finds chemical reaction networks (CRNs) that generate sets of structures exhibiting ranges of specific user-specified properties, such as length and type of structures or their frequency of occurrence. For each set, we enumerate the possible DNA structures that can be generated through domain-level interactions, identify the most prevalent structures, find the best-performing sequence sets to the emergence of target structures, and assess CRNs' robustness to the removal of reaction pathways. Our results suggest a connection between the characteristics of DNA strands and the distribution of generated structure families.

High-resolution mapping of bifurcations in nonlinear biochemical circuits.

Analog molecular circuits can exploit the nonlinear nature of biochemical reaction networks to compute low-precision outputs with fewer resources than digital circuits. This analog computation is similar to that employed by gene-regulation networks. Although digital systems have a tractable link between structure and function, the nonlinear and continuous nature of analog circuits yields an intricate functional landscape, which makes their design counter-intuitive, their characterization laborious and their analysis delicate. Here, using droplet-based microfluidics, we map with high resolution and dimensionality the bifurcation diagrams of two synthetic, out-of-equilibrium and nonlinear programs: a bistable DNA switch and a predator-prey DNA oscillator. The diagrams delineate where function is optimal, dynamics bifurcates and models fail. Inverse problem solving on these large-scale data sets indicates interference from enzymatic coupling. Additionally, data mining exposes the presence of rare, stochastically bursting oscillators near deterministic bifurcations.