One limit on developing complex synthetic gene circuits is the lack of basic components such as transcriptional logic gates that can process combinatorial in-puts. Here we propose a strategy to construct such components based on reusable designs and convergent reengineering of well-studied natural systems. We demon-strated the strategy using variants of the transcription factor LacI and operator Olac that form specifically interacting pairs. Guided by a mathematical model derived from existing quantitative knowledge, rational designs of transcriptional NAND, NOR and NOT gates have been realized. The NAND gates have been de-signed based on direct protein-protein interactions in coupling with DNA looping. We demonstrated that the designs are reusable:a multiplex of logic devices can be readily created using the same designs but different combinations of sequence variants. The designed logic gates are combinable to form compound circuits:a demonstration logic circuit containing all three types of designed logic gates has been synthesized, and the circuit truthfully reproduces the pre-designed input-output logic relations.
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