SHF: Collaborative Research: Biocompatible I/O Interfaces for Robust Bioorthogonal Molecular Computing

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Sugar molecules can exist in two forms that are the mirror image of each other but otherwise indistinguishable, like the left and right hand. All DNA molecules in nature contain right-hand sugars that cause them to assume the well-known double-helix shape with a right-handed twist. Proteins in cells in nature recognize the right-handed DNA in order to perform useful cellular functions, one of which is destroying single-stranded DNA. Over the last decade, DNA has come to be used in synthetic devices for sensing, computing, and diagnosing pathogens and disease. However, when these devices are introduced into a cell, they are prone to being destroyed by these proteins. This project will develop devices using left-handed DNA, which is not found in nature and is resistant to this form of degradation. In particular, the project will develop (1) input interfaces, for signaling from targets of interest, such as small molecules or natural DNA (D-DNA), to left-handed DNA (L-DNA), and (2) output interfaces, for signaling from left-handed DNA back into a relevant natural molecular pathway (such as DNA translation and transcription). This development will enable future devices that can sense multiple markers of the state of a cell (healthy or diseased), then integrate the sensors using DNA computing, and finally act on the cell, for example to destroy it if diseased, but the device itself will consist mainly of left-handed DNA and will therefore be robust in the cell. The project will involve both graduate and undergraduate students. It will be interdisciplinary, involving computer science and biomedical engineering, and will be carried out at the University of New Mexico and Columbia University.The first aim of the project is to study the binding interactions between L-DNA (left-handed DNA) molecular logic devices and naturally occurring molecules. This study will produce a toolbox of basic techniques for implementing input interfaces that can detect naturally occurring target molecules, which in turn, can translate those binding events for information processing within a bio-orthogonal L-DNA logic circuit. This will be done by characterizing the actuation of hybrid L-DNA/D-DNA molecular computing components by pure D-DNA input strands. The second aim of the project is developing output interfaces that will enable L-DNA systems to produce some effect on the environment (i.e., carry out some form of actuation) as a result of their programmed molecular computations. Specifically, the project will focus on one particular mechanism for generating a useful output signal from an L-DNA molecular logic circuit, namely, gene knockdown by the allosteric "activation" of sequestered antisense D-nucleic acids by an L-DNA molecular circuit. Together, these will provide a mechanism for L-DNA molecular logic circuits to actuate via control of gene expression.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.