Probability 1 computation with chemical reaction networks

The computational power of stochastic chemical reaction networks (CRNs) varies significantly with the output convention and whether or not error is permitted. Focusing on probability 1 computation, we demonstrate a striking difference between stable computation that converges to a state where the output cannot change, and the notion of limit-stable computation where the output eventually stops changing with probability 1. While stable computation is known to be restricted to semilinear predicates (essentially piecewise linear), we show that limit-stable computation encompasses the set of predicates ϕ:N→{0,1} in Δ^0_2 in the arithmetical hierarchy (a superset of Turing-computable). In finite time, our construction achieves an error-correction scheme for Turing universal computation. We show an analogous characterization of the functions f:N→N computable by CRNs with probability 1, which encode their output into the count of a certain species. This work refines our understanding of the tradeoffs between error and computational power in CRNs

Probability 1 computation with chemical reaction networks

The computational power of stochastic chemical reaction networks (CRNs) varies significantly with the output convention and whether or not error is permitted. Focusing on probability 1 computation, we demonstrate a striking difference between stable computation that converges to a state where the output cannot change, and the notion of limit-stable computation where the output eventually stops changing with probability 1. While stable computation is known to be restricted to semilinear predicates (essentially piecewise linear), we show that limit-stable computation encompasses the set of predicates ϕ:N→{0,1} in Δ^0_2 in the arithmetical hierarchy (a superset of Turing-computable). In finite time, our construction achieves an error-correction scheme for Turing universal computation. We show an analogous characterization of the functions f:N→N computable by CRNs with probability 1, which encode their output into the count of a certain species. This work refines our understanding of the tradeoffs between error and computational power in CRNs

Optimal Information Encoding in Chemical Reaction Networks

Discrete chemical reaction networks formalize the interactions of molecular species in a well-mixed solution as stochastic events. Given their basic mathematical and physical role, the computational power of chemical reaction networks has been widely studied in the molecular programming and distributed computing communities. While for Turing-universal systems there is a universal measure of optimal information encoding based on Kolmogorov complexity, chemical reaction networks are not Turing universal unless error and unbounded molecular counts are permitted. Nonetheless, here we show that the optimal number of reactions to generate a specific count x ? ? with probability 1 is asymptotically equal to a "space-aware" version of the Kolmogorov complexity of x, defined as K?s(x) = min_p {|p|/log|p| + log(space(?(p))) : ?(p) = x}, where p is a program for universal Turing machine ?. This version of Kolmogorov complexity incorporates not just the length of the shortest program for generating x, but also the space usage of that program. Probability 1 computation is captured by the standard notion of stable computation from distributed computing, but we limit our consideration to chemical reaction networks obeying a stronger constraint: they "know when they are done" in the sense that they produce a special species to indicate completion. As part of our results, we develop a module for encoding and unpacking any b bits of information via O(b/log{b}) reactions, which is information-theoretically optimal for incompressible information. Our work provides one answer to the question of how succinctly chemical self-organization can be encoded - in the sense of generating precise molecular counts of species as the desired state

Rate-Independent Computation in Continuous Chemical Reaction Networks

Coupled chemical interactions in a well-mixed solution are commonly formalized as chemical reaction networks (CRNs). However, despite the widespread use of CRNs in the natural sciences, the range of computational behaviors exhibited by CRNs is not well understood. Here we study the following problem: what functions f:R^k --> R can be computed by a CRN, in which the CRN eventually produces the correct amount of the "output" molecule, no matter the rate at which reactions proceed? This captures a previously unexplored, but very natural class of computations: for example, the reaction X1 + X2 --> Y can be thought to compute the function y = min(x1, x2). Such a CRN is robust in the sense that it is correct no matter the kinetic model of chemistry, so long as it respects the stoichiometric constraints. We develop a reachability relation based on "what could happen" if reaction rates can vary arbitrarily over time. We define *stable computation* analogously to probability 1 computation in distributed computing, and connect it with a seemingly stronger notion of rate-independent computation based on convergence under a wide class of generalized rate laws. We also consider the "dual-rail representation" that can represent negative values as the difference of two concentrations and allows the composition of CRN modules. We prove that a function is rate-independently computable if and only if it is piecewise linear (with rational coefficients) and continuous (dual-rail representation), or non-negative with discontinuities occurring only when some inputs switch from zero to positive (direct representation). The many contexts where continuous piecewise linear functions are powerful targets for implementation, combined with the systematic construction we develop for computing these functions, demonstrate the potential of rate-independent chemical computation.Comment: preliminary version appeared in ITCS 2014: http://doi.org/10.1145/2554797.255482

Programmability of Chemical Reaction Networks

Motivated by the intriguing complexity of biochemical circuitry within individual cells we study Stochastic Chemical Reaction Networks (SCRNs), a formal model that considers a set of chemical reactions acting on a finite number of molecules in a well-stirred solution according to standard chemical kinetics equations. SCRNs have been widely used for describing naturally occurring (bio)chemical systems, and with the advent of synthetic biology they become a promising language for the design of artificial biochemical circuits. Our interest here is the computational power of SCRNs and how they relate to more conventional models of computation. We survey known connections and give new connections between SCRNs and Boolean Logic Circuits, Vector Addition Systems, Petri Nets, Gate Implementability, Primitive Recursive Functions, Register Machines, Fractran, and Turing Machines. A theme to these investigations is the thin line between decidable and undecidable questions about SCRN behavior

Synthesizing and tuning chemical reaction networks with specified behaviours

We consider how to generate chemical reaction networks (CRNs) from functional specifications. We propose a two-stage approach that combines synthesis by satisfiability modulo theories and Markov chain Monte Carlo based optimisation. First, we identify candidate CRNs that have the possibility to produce correct computations for a given finite set of inputs. We then optimise the reaction rates of each CRN using a combination of stochastic search techniques applied to the chemical master equation, simultaneously improving the of correct behaviour and ruling out spurious solutions. In addition, we use techniques from continuous time Markov chain theory to study the expected termination time for each CRN. We illustrate our approach by identifying CRNs for majority decision-making and division computation, which includes the identification of both known and unknown networks.Comment: 17 pages, 6 figures, appeared the proceedings of the 21st conference on DNA Computing and Molecular Programming, 201

Simulation and inference algorithms for stochastic biochemical reaction networks: from basic concepts to state-of-the-art

Stochasticity is a key characteristic of intracellular processes such as gene regulation and chemical signalling. Therefore, characterising stochastic effects in biochemical systems is essential to understand the complex dynamics of living things. Mathematical idealisations of biochemically reacting systems must be able to capture stochastic phenomena. While robust theory exists to describe such stochastic models, the computational challenges in exploring these models can be a significant burden in practice since realistic models are analytically intractable. Determining the expected behaviour and variability of a stochastic biochemical reaction network requires many probabilistic simulations of its evolution. Using a biochemical reaction network model to assist in the interpretation of time course data from a biological experiment is an even greater challenge due to the intractability of the likelihood function for determining observation probabilities. These computational challenges have been subjects of active research for over four decades. In this review, we present an accessible discussion of the major historical developments and state-of-the-art computational techniques relevant to simulation and inference problems for stochastic biochemical reaction network models. Detailed algorithms for particularly important methods are described and complemented with MATLAB implementations. As a result, this review provides a practical and accessible introduction to computational methods for stochastic models within the life sciences community

Robust Stochastic Chemical Reaction Networks and Bounded Tau-Leaping

The behavior of some stochastic chemical reaction networks is largely unaffected by slight inaccuracies in reaction rates. We formalize the robustness of state probabilities to reaction rate deviations, and describe a formal connection between robustness and efficiency of simulation. Without robustness guarantees, stochastic simulation seems to require computational time proportional to the total number of reaction events. Even if the concentration (molecular count per volume) stays bounded, the number of reaction events can be linear in the duration of simulated time and total molecular count. We show that the behavior of robust systems can be predicted such that the computational work scales linearly with the duration of simulated time and concentration, and only polylogarithmically in the total molecular count. Thus our asymptotic analysis captures the dramatic speedup when molecular counts are large, and shows that for bounded concentrations the computation time is essentially invariant with molecular count. Finally, by noticing that even robust stochastic chemical reaction networks are capable of embedding complex computational problems, we argue that the linear dependence on simulated time and concentration is likely optimal