Nucleic Acids for Computation

  • Joanne Macdonald
  • Milan N. Stojanovic
Part of the Integrated Analytical Systems book series (ANASYS)


Nucleic acids have many features that are ideal for molecular computation. Using nucleic acids, we have constructed a full set of molecular logic gates, with modular stem-loop-controlled deoxyribozymes as switches and single-stranded oligonucleotides as inputs and outputs. These gates have been combined to form basic computational circuits, including a half- and a full-adder, and can also be assembled into automata to perform complex computational tasks such as game playing. Our most advanced automaton to-date integrates more than 100 nucleic acid logic gates to play a complete game of tic-tac-toe encompassing 76 possible game plays. Inputs and outputs can also be coupled with upstream and downstream components, such as aptamers, sensors, secondary gate activation, and small-molecule release, indicating the potential for nucleic acid computation in the engineering of autonomous therapeutic and diagnostic molecular devices.


Human Move Logic Gate Molecular Computation Human Player Input Molecule 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This material is based upon work supported by the National Science Foundation under Grants IIS-0324845, CCF-0523317, and CHE-0533065, Searle Fellowship to M.N.S. Milan Stojanovic is a Lymphoma and Leukemia Society Fellow.


  1. 1.
    Adleman, L.M. (1994) Molecular computation of solutions to combinatorial problems. Science 266:1021–1024.CrossRefGoogle Scholar
  2. 2.
    Stojanovic, M.N., Mitchell, T.E. and Stefanovic, D. (2002) Deoxyribozyme-based logic gates. J. Am. Chem. Soc. 124:3555–3561.CrossRefGoogle Scholar
  3. 3.
    James, K.D., Boles, A.R., Henckel, D. and Ellington, A.D. (1998) The fidelity of template-directed oligonucleotide ligation and its relevance to DNA computation. Nucleic Acids Res. 26:5203–5211.CrossRefGoogle Scholar
  4. 4.
    Stojanovic, M.N. and Stefanovic, D. (2003) Deoxyribozyme-based half-adder. J. Am. Chem. Soc. 125:6673–6676.CrossRefGoogle Scholar
  5. 5.
    Stojanovic, M.N. and Stefanovic, D. (2003) A deoxyribozyme-based molecular automaton. Nat. Biotechnol. 21:1069–1074.CrossRefGoogle Scholar
  6. 6.
    Lederman, H., Macdonald, J., Stefanovic, D. and Stojanovic, M.N. (2006) Deoxyribozyme-based three-input logic gates and construction of a molecular full adder. Biochemistry 45:1194–1199.CrossRefGoogle Scholar
  7. 7.
    Macdonald, J., Li, Y., Sutovic, M., Lederman, H., Pendri, K., Lu, W., Andrews, B.L., Stefanovic, D. and Stojanovic, M.N. (2006) Medium scale integration of molecular logic gates in an automaton. Nano Lett. 6:2598–2603.CrossRefGoogle Scholar
  8. 8.
    Macdonald, J., Li, Y., Sutovic, M., Stefanovic, D. and Stojanovic, M. (2006) Genomes to systems conference 2006. Manchester, UK, p. BN-2.Google Scholar
  9. 9.
    Stojanovic, M.N., Semova, S., Kolpashchikov, D., Macdonald, J., Morgan, C. and Stefanovic, D. (2005) Deoxyribozyme-based ligase logic gates and their initial circuits. J. Am. Chem. Soc. 127:6914–6915.CrossRefGoogle Scholar
  10. 10.
    de Silva, A.P., Leydet, Y., Lincheneau, C. and McClenaghan, N.D. (2006) Chemical approaches to nanometre-scale logic gates. J. Phys. Condensed Matter 18:S1847–S1872.CrossRefGoogle Scholar
  11. 11.
    Breaker, R.R. and Joyce, G.F. (1995) A DNA enzyme with Mg(2+)-dependent RNA phos-phoesterase activity. Chem. Biol. 2:655–660.CrossRefGoogle Scholar
  12. 12.
    Yurke, B., Turberfield, A.J., Mills, A.P., Jr., Simmel, F.C. and Neumann, J.L. (2000) A DNA-fuelled molecular machine made of DNA. Nature (Lond.) 406:605–608.CrossRefGoogle Scholar
  13. 13.
    Santoro, S.W. and Joyce, G.F. (1997) A general purpose RNA-cleaving DNA enzyme. Proc. Natl. Acad. Sci. USA 94:4262–4266.CrossRefGoogle Scholar
  14. 14.
    Cuenoud, B. and Szostak, J.W. (1995) A DNA metalloenzyme with DNA ligase activity. Nature (Lond.) 375:611–614.CrossRefGoogle Scholar
  15. 15.
    Hartig, J.S. and Famulok, M. (2002) Reporter ribozymes for real-time analysis of domain-specific interactions in biomolecules: HIV-1 reverse transcriptase and the primer-template complex. Angew. Chem. Int. Ed. 41:4263–4266.CrossRefGoogle Scholar
  16. 16.
    Singh, K.K., Parwaresch, R. and Krupp, G. (1999) Rapid kinetic characterization of hammerhead ribozymes by real-time monitoring of fluorescence resonance energy transfer (FRET). RNA (New York) 5:1348–1356.Google Scholar
  17. 17.
    Stojanovic, M.N., de Prada, P. and Landry, D.W. (2000) Homogeneous assays based on deoxyribozyme catalysis. Nucleic Acids Res. 28:2915–2918.CrossRefGoogle Scholar
  18. 18.
    McCluskey, E.J. (1986) Logic design principles: with emphasis on testable semicustom circuits. Prentice Hall, Englewood Cliffs, NJ.Google Scholar
  19. 19.
    Macdonald, J., Stefanovic, D. and Stojanovic, M.N. (2006) Solution-phase molecular-scale computation with deoxyribozyme-based logic gates and fluorescent readouts. In: Didenko, V. V. (ed.) Fluorescent energy transfer nucleic acid probes: designs and protocols, vol. 335. Humana Press, Totowa, NJ, pp. 343–363.CrossRefGoogle Scholar
  20. 20.
    Noireaux, V., Bar-Ziv, R. and Libchaber, A. (2003) Principles of cell-free genetic circuit assembly. Proc. Natl. Acad. Sci. USA 100:12672–12677.CrossRefGoogle Scholar
  21. 21.
    Seelig, G., Soloveichik, D., Zhang, D.Y. and Winfree, E. (2006) Enzyme-free nucleic acid logic circuits. Science 314:1585–1588.CrossRefGoogle Scholar
  22. 22.
    Penchovsky, R. and Breaker, R.R. (2005) Computational design and experimental validation of oligonucleotide-sensing allosteric ribozymes. Nat. Biotechnol. 23:1424–1433.23.CrossRefGoogle Scholar
  23. 23.
    Kolpashchikov, D.M. and Stojanovic, M.N. (2005) Boolean control of aptamer binding states. J. Am. Chem. Soc. 127:11348–11351.CrossRefGoogle Scholar
  24. 24.
    Dirks, R.M. and Pierce, N.A. (2004) Triggered amplification by hybridization chain reaction. Proc. Natl. Acad. Sci. USA 101:15275–15278.CrossRefGoogle Scholar
  25. 25.
    Dittmer, W.U., Reuter, A. and Simmel, F.C. (2004) A DNA-based machine that can cyclically bind and release thrombin. Angew. Chem. Int. Ed. 43:3550–3553.CrossRefGoogle Scholar
  26. 26.
    Nutiu, R. and Li, Y. (2003) Structure-switching signaling aptamers. J. Am. Chem. Soc. 125: 4771–4778.CrossRefGoogle Scholar
  27. 27.
    Benenson, Y., Gil, B., Ben-Dor, U., Adar, R. and Shapiro, E. (2004) An autonomous molecular computer for logical control of gene expression. Nature (Lond.) 429:423–429.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Joanne Macdonald
    • 1
  • Milan N. Stojanovic
    • 1
  1. 1.The National Science Foundation Center for Molecular Cybernetics; Division of Experimental Therapeutics, Department of MedicineColumbia UniversityNew YorkUSA

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