Probabilistic switching circuits in DNA

Significance Biological organisms exhibit sophisticated control over the stochastic states of individual cells, but the understanding of underlying molecular mechanisms remains incomplete. It has been argued that unbiased choices are easy to achieve, but choices biased with specific probabilities are much harder. These natural phenomena raise an engineering challenge: Does there exist a simple method to program molecular systems that control arbitrary probabilities for individual molecular events? Here we show a molecular circuit architecture, using just a simple DNA strand displacement building block that functions as an unbiased switch, for creating a circuit output with any desired probability. We constructed several DNA circuits with multiple layers and feedback, demonstrating complex molecular information processing that exploits the inherent stochasticity of molecular interactions. A natural feature of molecular systems is their inherent stochastic behavior. A fundamental challenge related to the programming of molecular information processing systems is to develop a circuit architecture that controls the stochastic states of individual molecular events. Here we present a systematic implementation of probabilistic switching circuits, using DNA strand displacement reactions. Exploiting the intrinsic stochasticity of molecular interactions, we developed a simple, unbiased DNA switch: An input signal strand binds to the switch and releases an output signal strand with probability one-half. Using this unbiased switch as a molecular building block, we designed DNA circuits that convert an input signal to an output signal with any desired probability. Further, this probability can be switched between 2n different values by simply varying the presence or absence of n distinct DNA molecules. We demonstrated several DNA circuits that have multiple layers and feedback, including a circuit that converts an input strand to an output strand with eight different probabilities, controlled by the combination of three DNA molecules. These circuits combine the advantages of digital and analog computation: They allow a small number of distinct input molecules to control a diverse signal range of output molecules, while keeping the inputs robust to noise and the outputs at precise values. Moreover, arbitrarily complex circuit behaviors can be implemented with just a single type of molecular building block.