Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 14, Pages 5386-5391Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1222807110
Keywords
amplifier; enzyme-free; DNA circuitry
Categories
Funding
- National Institutes of Health [R01 AI092839-01]
- Defense Advanced Research Projects Agency [5-35830]
- Gates Foundation [OPP1028808]
- Welch Foundation [F-1654]
- Cancer Prevention Research Institute of Texas
- Bill and Melinda Gates Foundation [OPP1028808] Funding Source: Bill and Melinda Gates Foundation
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Signal amplification schemes that do not rely on protein enzymes show great potential in areas as abstruse as DNA computation and as applied as point-of-care molecular diagnostics. Toehold-mediated strand displacement, a programmable form of dynamic DNA hybridization, can be used to design powerful amplification cascades that can achieve polynomial or exponential amplification of input signals. However, experimental implementation of such amplification cascades has been severely hindered by circuit leakage due to catalyst-independent side reactions. In this study, we systematically analyzed the origins, characteristics, and outcomes of circuit leakage in amplification cascades and devised unique methods to obtain high-quality DNA circuits that exhibit minimal leakage. We successfully implemented a two-layer cascade that yielded 7,000-fold signal amplification and a two-stage, four-layer cascade that yielded upward of 600,000-fold signal amplification. Implementation of these unique methods and design principles should greatly empower molecular programming in general and DNA-based molecular diagnostics in particular.
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