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Published online 27 February 2004

Nucleic Acids Research, 2004, Vol. 32, No. 4 1392-1403
© 2004 Oxford University Press

Paradigms for computational nucleic acid design

Robert M. Dirks, Milo Lin1, Erik Winfree2,3 and Niles A. Pierce*,3,4

Chemistry Department, 1 Physics Department, 2 Computer Science and Computation and Neural Systems Departments, 3 Bioengineering Department and 4 Applied and Computational Mathematics Department, California Institute of Technology, Pasadena, CA 91125, USA

*To whom correspondence should be addressed. Tel: +1 626 395 8086; Fax: +1 626 395 8845; Email: niles{at}caltech.edu

The design of DNA and RNA sequences is critical for many endeavors, from DNA nanotechnology, to PCR-based applications, to DNA hybridization arrays. Results in the literature rely on a wide variety of design criteria adapted to the particular requirements of each application. Using an extensively studied thermodynamic model, we perform a detailed study of several criteria for designing sequences intended to adopt a target secondary structure. We conclude that superior design methods should explicitly implement both a positive design paradigm (optimize affinity for the target structure) and a negative design paradigm (optimize specificity for the target structure). The commonly used approaches of sequence symmetry minimization and minimum free-energy satisfaction primarily implement negative design and can be strengthened by introducing a positive design component. Surprisingly, our findings hold for a wide range of secondary structures and are robust to modest perturbation of the thermodynamic parameters used for evaluating sequence quality, suggesting the feasibility and ongoing utility of a unified approach to nucleic acid design as parameter sets are refined further. Finally, we observe that designing for thermodynamic stability does not determine folding kinetics, emphasizing the opportunity for extending design criteria to target kinetic features of the energy landscape.


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