Computational Design of Nucleic Acid Feedback Control Circuits

Abstract

The design of synthetic circuits for controlling molecular-scale processes is an important goal of synthetic biology, with potential applications in future in vitro and in vivo biotechnology. In this paper, we present a computational approach for designing feedback control circuits constructed from nucleic acids. Our approach relies on an existing methodology for expressing signal processing and control circuits as biomolecular reactions. We first extend the methodology so that circuits can be expressed using just two classes of reactions: catalysis and annihilation. We then propose implementations of these reactions in three distinct classes of nucleic acid circuits, which rely on DNA strand displacement, DNA enzyme and RNA enzyme mechanisms, respectively. We use these implementations to design a Proportional Integral controller, capable of regulating the output of a system according to a given reference signal, and discuss the trade-offs between the different approaches. As a proof of principle, we implement our methodology as an extension to a DNA strand displacement software tool, thus allowing a broad range of nucleic acid circuits to be designed and analyzed within a common modeling framework.

Biomolecular implementation of a quasi sliding mode feedback controller based on DNA strand displacement reactions

“…In the control literature it is well known that nonlinear systems are in general more difficult to control than linear systems. Also, previous work on the implementation of linear feedback controllers using nucleic acids considered only a static process to be controlled [8], [9], [10]. The system described here…”

Biologically inspired design of feedback control systems implemented using DNA strand displacement reactions

“…An emerging design framework that uses abstract chemical reaction networks (CRNs) in the implementation of enzymefree, entropy driven DNA reactions has recently attracted much attention in the Synthetic Biology community following a number of successful studies [1]- [3]. The basic idea underlying this approach is to design biomolecular circuitry using abstract chemical reactions as a programming language.…”

“…Sophisticated CAD tools are also now becoming available to facilitate the design of synthetic circuits using this approach [5]. Examples of complex biomolecular circuits successfully designed and implemented through this approach include predator-prey dynamics [6], oscillators [7], and both linear and nonlinear feedback controllers [3], [8], [9].…”

“…In [8] and [3], a classical proportional-integral (PI) controller was successfully designed using the above framework to control a biomolecular process. However, one issue that could potentially disrupt the transition from theoretical design to wet-lab implementation for such controllers is the large number of abstract chemical reactions that are required.…”

Biomolecular implementation of nonlinear system theoretic operators

“…Recently, the direct use of nucleic acids for performing computation has emerged as a promising approach for addressing the above problems [7]- [10]. For these type of systems, the sequences of nucleic acid components dictate their interactions through the well-known Watson-Crick base-pairing mechanism, which enables a precise programming of molecular interactions by the choice of relevant sequences.…”