Engineering molecular systems that exhibit complex behavior requires the design of kinetic barriers. For example, an effective catalytic pathway must have a large barrier when the catalyst is absent. While programming such energy barriers seems to require knowledge of the specific molecular substrate, we develop a novel substrate-independent approach. We extend the recently-developed model known as thermodynamic binding networks, demonstrating programmable kinetic barriers that arise solely from the thermodynamic driving forces of bond formation and the configurational entropy of forming separate complexes. Our kinetic model makes relatively weak assumptions, which implies that energy barriers predicted by our model would exist in a wide variety of systems and conditions. We demonstrate that our model is robust by showing that several variations in its definition result in equivalent energy barriers. We apply this model to design catalytic systems with an arbitrarily large energy barrier to uncatalyzed reactions. Our results could yield robust amplifiers using DNA strand displacement, a popular technology for engineering synthetic reaction pathways, and suggest design strategies for preventing undesired kinetic behavior in a variety of molecular systems.

Biological regulatory networks depend upon chemical interactions to process information. Engineering such molecular computing systems is a major challenge for synthetic biology and related fields. The chemical reaction network (CRN) model idealizes chemical interactions, allowing rigorous reasoning about the computational power of chemical kinetics. Here we focus on function computation with CRNs, where we think of the initial concentrations of some species as the input and the equilibrium concentration of another species as the output. Specifically, we are concerned with CRNs that are rate-independent (the computation must be correct independent of the reaction rate law) and composable ( f°g can be computed by concatenating the CRNs computing f and g). Rate independence and composability are important engineering desiderata, permitting implementations that violate mass-action kinetics, or even "well-mixedness", and allowing the systematic construction of complex computation via modular design. We show that to construct composable rate-independent CRNs, it is necessary and sufficient to ensure that the output species of a module is not a reactant in any reaction within the module. We then exactly characterize the functions computable by such CRNs as superadditive, positive-continuous, and piecewise rational linear. Thus composability severely limits rate-independent computation unless more sophisticated input/output encodings are used.

Embedding computation in molecular contexts incompatible with traditional electronics is expected to have wide ranging impact in synthetic biology, medicine, nanofabrication and other fields. A key remaining challenge lies in developing programming paradigms for molecular computation that are well-aligned with the underlying chemical hardware and do not attempt to shoehorn ill-fitting electronics paradigms. We discover a surprisingly tight connection between a popular class of neural networks (binary-weight ReLU aka BinaryConnect) and a class of coupled chemical reactions that are absolutely robust to reaction rates. The robustness of rate-independent chemical computation makes it a promising target for bioengineering implementation. We show how a BinaryConnect neural network trained in silico using well-founded deep learning optimization techniques, can be compiled to an equivalent chemical reaction network, providing a novel molecular programming paradigm. We illustrate such translation on the paradigmatic IRIS and MNIST datasets. Toward intended applications of chemical computation, we further use our method to generate a chemical reaction network that can discriminate between different virus types based on gene expression levels. Our work sets the stage for rich knowledge transfer between neural network and molecular programming communities.

Inspired by nature and motivated by a lack of top-down tools for precise nanoscale manufacture, self-assembly is a bottom-up process where simple, unorganized components autonomously combine to form larger more complex structures. Such systems hide rich algorithmic properties - notably, Turing universality - and a self-assembly system can be seen as both the object to be manufactured as well as the machine controlling the manufacturing process. Thus, a benchmark problem in self-assembly is the unique assembly of shapes: to design a set of simple agents which, based on aggregation rules and random movement, self-assemble into a particular shape and nothing else. We use a popular model of self-assembly, the 2-handed or hierarchical tile assembly model, and allow the existence of repulsive forces, which is a well-studied variant. The technique utilizes a finely-tuned temperature (the minimum required affinity required for aggregation of separate complexes). We show that calibrating the temperature and the strength of the aggregation between the tiles, one can encode the shape to be assembled without increasing the number of distinct tile types. Precisely, we show one tile set for which the following holds: for any finite connected shape S, there exists a setting of binding strengths between tiles and a temperature under which the system uniquely assembles S at some scale factor. Our tile system only uses one repulsive glue type and the system is growth-only (it produces no unstable assemblies). The best previous unique shape assembly results in tile assembly models use O(K(S)/(log K(S))) distinct tile types, where K(S) is the Kolmogorov (descriptional) complexity of the shape S.

We analyze the number of tile types t, bins b, and stages necessary to assemble $$n \times n$$ squares and scaled shapes in the staged tile assembly model. For $$n \times n$$ squares, we prove $$\mathcal {O}\left( \frac{\log {n} - tb - t\log t}{b^2} + \frac{\log \log b}{\log t}\right) $$ stages suffice and $$\varOmega \left( \frac{\log {n} - tb - t\log t}{b^2}\right) $$ are necessary for almost all n. For shapes S with Kolmogorov complexity K(S), we prove $$\mathcal {O}\left( \frac{K(S) - tb - t\log t}{b^2} + \frac{\log \log b}{\log t}\right) $$ stages suffice and $$\varOmega \left( \frac{K(S) - tb - t\log t}{b^2}\right) $$ are necessary to assemble a scaled version of S, for almost all S. We obtain similarly tight bounds when the more powerful flexible glues are permitted.

We show how to design a universal shape replicator in a self- assembly system with both attractive and repulsive forces. More precisely, we show that there is a universal set of constant-size objects that, when added to any unknown holefree polyomino shape, produces an unbounded number of copies of that shape (plus constant-size garbage objects). The constant-size objects can be easily constructed from a constant number of individual tile types using a constant number of preprocessing self-assembly steps. Our construction uses the well-studied 2-Handed Assembly Model (2HAM) of tile self-assembly, in the simple model where glues interact only with identical glues, allowing glue strengths that are either positive (attractive) or negative (repulsive), and constant temperature (required glue strength for parts to hold together). We also require that the given shape has specified glue types on its surface, and that the feature size (smallest distance between nonincident edges) is bounded below by a constant. Shape replication necessarily requires a self-assembly model where parts can both attach and detach, and this construction is the first to do so using the natural model of negative/repulsive glues (also studied before for other problems such as fuel-efficient computation); previous replication constructions require more powerful global operations such as an “enzyme” that destroys a subset of the tile types.