Improving the Performance of DNA Strand Displacement Circuits by Shadow Cancellation

DNA strand displacement circuits are powerful tools that can be rationally engineered to implement molecular computing tasks because they are programmable, cheap, robust, and predictable. A key feature of these circuits is the use of catalytic gates to amplify signal. Catalytic gates tend to leak; that is, they generate output signal even in the absence of intended input. Leaks are harmful to the performance and correct operation of DNA strand displacement circuits. Here, we present "shadow cancellation", a general-purpose technique to mitigate leak in catalytic DNA strand displacement circuits. Shadow cancellation involves constructing a parallel shadow circuit that mimics the primary circuit and has the same leak characteristics. It is situated in the same test tube as the primary circuit and produces "anti-background" DNA strands that cancel "background" DNA strands produced by leak. We demonstrate the feasibility and strength of the shadow leak cancellation approach through a challenging test case, a cross-catalytic feedback DNA amplifier circuit that leaks prodigiously. Shadow cancellation dramatically reduced the leak of this circuit and improved the signal-to-background difference by several fold. Unlike existing techniques, it makes no modifications to the underlying amplifier circuit and is agnostic to its leak mechanism. Shadow cancellation also showed good robustness to concentration errors in multiple scenarios. This work introduces a direction in leak reduction techniques for DNA strand displacement amplifier circuits and can potentially be extended to other molecular amplifiers.