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Programming biomolecular self-assembly pathways


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.

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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.


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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 We also thank J. N. Zadeh, R. M. Dirks and J. M. Schaeffer for the use of unpublished software, and R. F. Hariadi and S. H. Park for advice on AFM imaging.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.

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Correspondence to Niles A. Pierce.

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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)

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Yin, P., Choi, H., Calvert, C. et al. Programming biomolecular self-assembly pathways. Nature 451, 318–322 (2008).

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