title: Biophysically inspired rational design of structured chimeric substrates for DNAzyme cascade engineering.
abstract: The development of large-scale molecular computational networks is a promising approach to implementing logical decision making at the nanoscale, analogous to cellular signaling and regulatory cascades. DNA strands with catalytic activity (DNAzymes) are one means of systematically constructing molecular computation networks with inherent signal amplification. Linking multiple DNAzymes into a computational circuit requires the design of substrate molecules that allow a signal to be passed from one DNAzyme to another through programmed biochemical interactions. In this paper, we chronicle an iterative design process guided by biophysical and kinetic constraints on the desired reaction pathways and use the resulting substrate design to implement heterogeneous DNAzyme signaling cascades. A key aspect of our design process is the use of secondary structure in the substrate molecule to sequester a downstream effector sequence prior to cleavage by an upstream DNAzyme. Our goal was to develop a concrete substrate molecule design to achieve efficient signal propagation with maximal activation and minimal leakage. We have previously employed the resulting design to develop high-performance DNAzyme-based signaling systems with applications in pathogen detection and autonomous theranostics.
authors.affiliation: Department of Computer Science, University of New Mexico, Albuquerque, New Mexico, United States of America.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Lakin
authors.affiliation: Center for Biomedical Engineering, University of New Mexico, Albuquerque, New Mexico, United States of America.
authors.forename: Carl W
authors.initials: CW
authors.lastname: Brown
authors.affiliation: Center for Biomedical Engineering, University of New Mexico, Albuquerque, New Mexico, United States of America.
authors.forename: Eli K
authors.initials: EK
authors.lastname: Horwitz
authors.affiliation: Department of Computer Science, University of New Mexico, Albuquerque, New Mexico, United States of America.
authors.forename: M Leigh
authors.initials: ML
authors.lastname: Fanning
authors.affiliation: Center for Biomedical Engineering, University of New Mexico, Albuquerque, New Mexico, United States of America.
authors.forename: Hannah E
authors.initials: HE
authors.lastname: West
authors.affiliation: Department of Computer Science, University of New Mexico, Albuquerque, New Mexico, United States of America; Center for Biomedical Engineering, University of New Mexico, Albuquerque, New Mexico, United States of America.
authors.forename: Darko
authors.initials: D
authors.lastname: Stefanovic
authors.affiliation: Center for Biomedical Engineering, University of New Mexico, Albuquerque, New Mexico, United States of America; Department of Chemical and Biological Engineering, University of New Mexico, Albuquerque, New Mexico, United States of America.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Graves
mesh_terms: D001703:Biophysics; D002384:Catalysis; D021881:DNA, Catalytic / Q000737:chemistry* / Q000378:metabolism; D005818:Genetic Engineering; D009690:Nucleic Acid Conformation; D021281:Quantitative Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D021881:DNA, Catalytic