Computational design of synchronous sequential structures in biological systems

- Biological implementation of edge-triggered D flip-flop is proposed.
- Genetic algorithms are applied to its optimisation.
- Robustness is assessed with global sensitivity and parameter sweep analyses.
- Proposed structure is applied to the design of biological Johnson counter.

Numerous applications of synthetic biology require the implementation of scalable and robust biological circuits with information processing capabilities. Basic logic structures, such as logic gates, have already been implemented in prokaryotic as well as in eukaryotic cells. Biological memory structures have also been implemented either in vitro or in vivo. However, these implementations are still in their infancy compared to their electronic equivalents. Their response is mainly asynchronous. We may learn from electronic computer systems that robust and scalable computing devices can be implemented only with edge-triggered synchronous sequential structures. Implementation of such structures, however, has yet to be performed in the synthetic biological systems even on the conceptual level.Herein we describe the computational design and analysis of edge-triggered D flip-flop in master-slave configuration based on transcriptional logic. We assess the robustness of the proposed structure with its global sensitivity as well as parameter sweep analysis. Furthermore, we describe the design of a robust Johnson counter, which can count up to 2n cellular events using a sequence of n flip-flops. Changing the state of the counter is edge-triggered either with synchronization, i.e. clock signal, or with a pulse, which corresponds to the occurrence of observed event within the cellular environment. To the best of our knowledge this represents the design of the first biological synchronous sequential structure on such level of complexity.