title: A logical molecular circuit for programmable and autonomous regulation of protein activity using DNA aptamer-protein interactions.
abstract: Researchers increasingly envision an important role for artificial biochemical circuits in biological engineering, much like electrical circuits in electrical engineering. Similar to electrical circuits, which control electromechanical devices, biochemical circuits could be utilized as a type of servomechanism to control nanodevices in vitro, monitor chemical reactions in situ, or regulate gene expressions in vivo. (1)  As a consequence of their relative robustness and potential applicability for controlling a wide range of in vitro chemistries, synthetic cell-free biochemical circuits promise to be useful in manipulating the functions of biological molecules. Here, we describe the first logical circuit based on DNA-protein interactions with accurate threshold control, enabling autonomous, self-sustained and programmable manipulation of protein activity in vitro. Similar circuits made previously were based primarily on DNA hybridization and strand displacement reactions. This new design uses the diverse nucleic acid interactions with proteins. The circuit can precisely sense the local enzymatic environment, such as the concentration of thrombin, and when it is excessively high, a coagulation inhibitor is automatically released by a concentration-adjusted circuit module. To demonstrate the programmable and autonomous modulation, a molecular circuit with different threshold concentrations of thrombin was tested as a proof of principle. In the future, owing to tunable regulation, design modularity and target specificity, this prototype could lead to the development of novel DNA biochemical circuits to control the delivery of aptamer-based drugs in smart and personalized medicine, providing a more efficient and safer therapeutic strategy.
authors.affiliation: Department of Chemistry, Center for Research at the Bio/Nano Interface, Shands Cancer Center and UF Genetics Institute, University of Florida, Gainesville, Florida 32611-7200, USA.
authors.forename: Da
authors.initials: D
authors.lastname: Han
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhu
authors.forename: Cuichen
authors.initials: C
authors.lastname: Wu
authors.forename: Lu
authors.initials: L
authors.lastname: Peng
authors.forename: Leiji
authors.initials: L
authors.lastname: Zhou
authors.forename: Basri
authors.initials: B
authors.lastname: Gulbakan
authors.forename: Guizhi
authors.initials: G
authors.lastname: Zhu
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Williams
authors.forename: Weihong
authors.initials: W
authors.lastname: Tan
mesh_terms: D052157:Aptamers, Nucleotide / Q000378:metabolism*; D001777:Blood Coagulation / Q000187:drug effects; D039301:Computers, Molecular; D006801:Humans; D013917:Thrombin / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D052157:Aptamers, Nucleotide; C081676:thrombin aptamer; D013917:Thrombin