Paradigms for computational nucleic acid design

Creators: Dirks, Robert M.; Lin, Milo; Winfree, Erik; Pierce, Niles A.

Abstract

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.

Additional Information

© 2004 Oxford University Press. Received December 14, 2003; Revised and Accepted January 28, 2004. The authors wish to thank D. Baker, A. Condon, S. L. Mayo, N. C. Seeman and R. Schulman for comments on the manuscript, and I. Hofacker for providing the kinetic simulation package Kinfold. The following research support is gratefully acknowledged: NSF graduate research fellowship (R.M.D.), Caltech Axline SURF (M.L.), DARPA and Air Force Research Laboratory under agreement F30602-01020561 (R.M.D., E.W. and N.A.P.) and Ralph M. Parsons Foundation (N.A.P.).

Attached Files

Published - 1392.full.pdf

Supplemental Material - design_nar2004_supplemental.pdf

Supplemental Material - sequences/README

Supplemental Material - sequences/dna_large_multiloop/sm3_62.seq1

Supplemental Material - sequences/dna_large_multiloop/sm3_62.seq2

Supplemental Material - sequences/dna_large_multiloop/sm3_62.seq3

Supplemental Material - sequences/dna_large_multiloop/sm3_62.seq4

Supplemental Material - sequences/dna_large_multiloop/sm3_62.seq5

Supplemental Material - sequences/dna_large_multiloop/sm3_62.seq6

Supplemental Material - sequences/dna_large_multiloop/sm3_62.seq7

Supplemental Material - sequences/dna_multiloop/ML4_40.seq1

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Paradigms for computational nucleic acid design

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