Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Programming biomolecular self-assembly pathways

Nature volume 451, pages 318–322 (2008)Cite this article

Abstract

In nature, self-assembling and disassembling complexes of proteins and nucleic acids bound to a variety of ligands perform intricate and diverse dynamic functions. In contrast, attempts to rationally encode structure and function into synthetic amino acid and nucleic acid sequences have largely focused on engineering molecules that self-assemble into prescribed target structures, rather than on engineering transient system dynamics1,2. To design systems that perform dynamic functions without human intervention, it is necessary to encode within the biopolymer sequences the reaction pathways by which self-assembly occurs. Nucleic acids show promise as a design medium for engineering dynamic functions, including catalytic hybridization3,4,5,6, triggered self-assembly7 and molecular computation8,9. Here, we program diverse molecular self-assembly and disassembly pathways using a ‘reaction graph’ abstraction to specify complementarity relationships between modular domains in a versatile DNA hairpin motif. Molecular programs are executed for a variety of dynamic functions: catalytic formation of branched junctions, autocatalytic duplex formation by a cross-catalytic circuit, nucleated dendritic growth of a binary molecular ‘tree’, and autonomous locomotion of a bipedal walker.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Programming biomolecular self-assembly pathways.
Figure 2: Programming catalytic geometry: catalytic self-assembly of three-arm and four-arm branched junctions.
Figure 3: Programming catalytic circuitry: autocatalytic duplex formation by a cross-catalytic circuit with exponential kinetics.
Figure 4: Programming nucleated dendritic growth: triggered assembly of quantized binary molecular trees.
Figure 5: Programming autonomous locomotion: stochastic movement of a bipedal walker.

References

  1. Butterfoss, G. L. & Kuhlman, B. Computer-based design of novel protein structures. Annu. Rev. Biophys. Biomol. Struct. 35, 49–65 (2006)

    Article  CAS  Google Scholar 

  2. Seeman, N. C. DNA in a material world. Nature 421, 427–431 (2003)

    Article  ADS  MathSciNet  Google Scholar 

  3. Turberfield, A. J. et al. DNA fuel for free-running nanomachines. Phys. Rev. Lett. 90, 118102 (2003)

    Article  ADS  CAS  Google Scholar 

  4. Bois, J. S. et al. Topological constraints in nucleic acid hybridization kinetics. Nucleic Acids Res. 33, 4090–4095 (2005)

    Article  CAS  Google Scholar 

  5. Green, S. J., Lubrich, D. & Turberfield, A. J. DNA hairpins: Fuel for autonomous DNA devices. Biophys. J. 91, 2966–2975 (2006)

    Article  ADS  CAS  Google Scholar 

  6. Seelig, G., Yurke, B. & Winfree, E. Catalyzed relaxation of a metastable DNA fuel. J. Am. Chem. Soc. 128, 12211–12220 (2006)

    Article  CAS  Google Scholar 

  7. Dirks, R. M. & Pierce, N. A. Triggered amplification by hybridization chain reaction. Proc. Natl Acad. Sci. USA 101, 15275–15278 (2004)

    Article  ADS  CAS  Google Scholar 

  8. Rothemund, P. W. K., Papadakis, N. & Winfree, E. Algorithmic self-assembly of DNA Sierpinski triangles. PLoS Biol. 2, 2041–2053 (2004)

    Article  CAS  Google Scholar 

  9. Seelig, G., Soloveichik, D., Zhang, D. Y. & Winfree, E. Enzyme-free nucleic acid logic circuits. Science 314, 1585–1588 (2006)

    Article  ADS  CAS  Google Scholar 

  10. Yurke, B., Turberfield, A. J., Mills, J. A. P., Simmel, F. C. & Neumann, J. L. A DNA-fuelled molecular machine made of DNA. Nature 406, 605–608 (2000)

    Article  ADS  CAS  Google Scholar 

  11. Winfree, E., Liu, F., Wenzler, L. A. & Seeman, N. C. Design and self-assembly of two-dimensional DNA crystals. Nature 394, 539–544 (1998)

    Article  ADS  CAS  Google Scholar 

  12. Shih, W. M., Quispe, J. D. & Joyce, G. F. A 1.7-kilobase single-stranded DNA that folds into a nanoscale octahedron. Nature 427, 618–621 (2004)

    Article  ADS  CAS  Google Scholar 

  13. Rothemund, P. W. K. Folding DNA to create nanoscale shapes and patterns. Nature 440, 297–302 (2006)

    Article  ADS  CAS  Google Scholar 

  14. Seeman, N. C. Nucleic acid junctions and lattices. J. Theor. Biol. 99, 237–247 (1982)

    Article  CAS  Google Scholar 

  15. Feldkamp, U. & Niemeyer, C. M. Rational design of DNA nanoarchitectures. Angew. Chem. Int. Edn Engl. 45, 1856–1876 (2006)

    Article  CAS  Google Scholar 

  16. Robertson, A., Sinclair, A. J. & Philp, D. Minimal self-replicating systems. Chem. Soc. Rev. 29, 141–152 (2000)

    Article  CAS  Google Scholar 

  17. von Kiedrowski, G. A self-replicating hexadeoxynucleotide. Angew. Chem. Int. Edn Engl. 25, 932–935 (1986)

    Article  Google Scholar 

  18. Paul, N. & Joyce, G. F. A self-replicating ligase ribozyme. Proc. Natl Acad. Sci. USA 99, 12733–12740 (2002)

    Article  ADS  CAS  Google Scholar 

  19. Levy, M. & Ellington, A. D. Exponential growth by cross-catalytic cleavage of deoxyribozymogens. Proc. Natl Acad. Sci. USA 100, 6416–6421 (2003)

    Article  ADS  CAS  Google Scholar 

  20. Lee, D. H., Granja, J. R., Martinez, J. A., Severin, K. & Ghadiri, M. R. A self-replicating peptide. Nature 382, 525–528 (1996)

    Article  ADS  CAS  Google Scholar 

  21. Zhang, D. Y., Turberfield, A. J., Yurke, B. & Winfree, E. Engineering entropy-driven reactions and networks catalyzed by DNA. Science 318, 1121–1125 (2007)

    Article  ADS  CAS  Google Scholar 

  22. Li, Y. et al. Controlled assembly of dendrimer-like DNA. Nature Mater. 3, 38–42 (2004)

    Article  ADS  CAS  Google Scholar 

  23. Yin, P., Yan, H., Daniell, X. G., Turberfield, A. J. & Reif, J. H. A unidirectional DNA walker that moves autonomously along a track. Angew. Chem. Int. Edn Engl. 43, 4906–4911 (2004)

    Article  CAS  Google Scholar 

  24. Tian, Y., He, Y., Chen, Y., Yin, P. & Mao, C. A. DNAzyme that walks processively and autonomously along a one-dimensional track. Angew. Chem. Int. Edn Engl. 44, 4355–4358 (2005)

    Article  CAS  Google Scholar 

  25. Bath, J., Green, S. J. & Turberfield, A. J. A free-running DNA motor powered by a nicking enzyme. Angew. Chem. Int. Edn Engl. 44, 4358–4361 (2005)

    Article  CAS  Google Scholar 

  26. Pei, R. et al. Behavior of polycatalytic assemblies in a substrate-displaying matrix. J. Am. Chem. Soc. 128, 12693–12699 (2006)

    Article  CAS  Google Scholar 

  27. Venkataraman, S., Dirks, R. M., Rothemund, P. W. K., Winfree, E. & Pierce, N. A. An autonomous polymerization motor powered by DNA hybridization. Nature Nanotechnol. 2, 490–494 (2007)

    Article  Google Scholar 

  28. Asbury, C. L. Kinesin: world's tiniest biped. Curr. Opin. Cell Biol. 17, 89–97 (2005)

    Article  CAS  Google Scholar 

  29. Dirks, R. M., Bois, J. S., Schaeffer, J. M., Winfree, E. & Pierce, N. A. Thermodynamic analysis of interacting nucleic acid strands. SIAM Rev. 49, 65–88 (2007)

    Article  ADS  MathSciNet  Google Scholar 

  30. Dirks, R. M., Lin, M., Winfree, E. & Pierce, N. A. Paradigms for computational nucleic acid design. Nucleic Acids Res. 32, 1392–1403 (2004)

    Article  CAS  Google Scholar 

  31. Flamm, C., Fontana, W., Hofacker, I. L. & Schuster, P. RNA folding at elementary step resolution. RNA 6, 325–338 (2000)

    Article  CAS  Google Scholar 

  32. Hansma, H. G. & Laney, D. E. DNA binding to mica correlates with cationic radius: assay by atomic force microscopy. Biophys. J. 70, 1933–1939 (1996)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank the following for discussions: J. S. Bois, R. M. Dirks, M. Grazier G'Sell, R. F. Hariadi, J. A. Othmer, J. E. Padilla, P. W. K. Rothemund, T. Schneider, R. Schulman, M. Schwarzkopf, G. Seelig, D. Sprinzak, S. Venkataraman, E. Winfree, J. N. Zadeh and D. Y. Zhang. We also thank J. N. Zadeh, R. M. Dirks and J. M. Schaeffer for the use of unpublished software, and R. F. Hariadi and S. H. Park for advice on AFM imaging. This work is funded by the NIH, the NSF, the Caltech Center for Biological Circuit Design, the Beckman Institute at Caltech, and the Gates Grubstake Fund at Caltech.

Author information

Authors and Affiliations

  1. Department of Bioengineering,,

    Peng Yin, Harry M. T. Choi, Colby R. Calvert & Niles A. Pierce

  2. Department of Computer Science,,

    Peng Yin

  3. Department of Applied & Computational Mathematics, California Institute of Technology, Pasadena, California 91125, USA,

    Niles A. Pierce

Authors
  1. Peng Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Harry M. T. Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Colby R. Calvert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Niles A. Pierce
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Niles A. Pierce.

Ethics declarations

Competing interests

P.Y. and N.A.P. have applied for a patent on the molecular motif and reaction graph abstraction.

Supplementary information

Supplementary Information

The Supplementary Information is divided into eight sections and contains Supplementary Figures S1-S40 with Legends and additional references. Section 1 contains a summary figure. Section 2 contains reaction graph conventions. Section 3 contains notes on the catalytic geometry systems: hierarchal design process for catalytic formation of a 3-arm junction, execution of the reaction graphs, design and experimental results for catalytic formation of a 4-arm junction, AFM image analysis of 3-/4-arm junctions, design for the catalytic formation of a k-arm junction. Section 4 contains notes on the catalytic circuitry system: execution of the reaction graph, detailed secondary structure mechanism, stepping gel, system kinetic analysis. Section 5 contains notes on the nucleated dendritic growth system: execution of the reaction graph, detailed secondary structure mechanism, quantitative amplification gel, AFM image analysis. Section 6 contains notes on the autonomous locomotion system: execution of the reaction graph, secondary structure of the walker system, detailed secondary structure mechanism, assembly of the walker system, characterization of the fuel system, raw data for the fluorescence quenching experiments, statistical analysis, comparison of walker time scales, control for walker landing effects. Section 7 contains notes on the discussion: leakage and ligation, molecular compiler. Section 8 contains the DNA sequences for all the systems. (PDF 4606 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yin, P., Choi, H., Calvert, C. et al. Programming biomolecular self-assembly pathways. Nature 451, 318–322 (2008). https://doi.org/10.1038/nature06451

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature06451

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing