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Published March 1, 2017 | Supplemental Material + Published
Journal Article Open

Constrained Multistate Sequence Design for Nucleic Acid Reaction Pathway Engineering


We describe a framework for designing the sequences of multiple nucleic acid strands intended to hybridize in solution via a prescribed reaction pathway. Sequence design is formulated as a multistate optimization problem using a set of target test tubes to represent reactant, intermediate, and product states of the system, as well as to model crosstalk between components. Each target test tube contains a set of desired "on-target" complexes, each with a target secondary structure and target concentration, and a set of undesired "off-target" complexes, each with vanishing target concentration. Optimization of the equilibrium ensemble properties of the target test tubes implements both a positive design paradigm, explicitly designing for on-pathway elementary steps, and a negative design paradigm, explicitly designing against off-pathway crosstalk. Sequence design is performed subject to diverse user-specified sequence constraints including composition constraints, complementarity constraints, pattern prevention constraints, and biological constraints. Constrained multistate sequence design facilitates nucleic acid reaction pathway engineering for diverse applications in molecular programming and synthetic biology. Design jobs can be run online via the NUPACK web application.

Additional Information

© 2017 American Chemical Society. ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Received: December 12, 2016; Published: February 13, 2017. This work was funded by the National Science Foundation via the Molecular Programming Project (NSF-CCF-0832824 and NSF-CCF-1317694), by the Gordon and Betty Moore Foundation (GBMF2809), by the Beckman Institute at Caltech (PMTC), by a Christensen Fellowship at St Catherine's College, University of Oxford, by the John Simon Guggenheim Memorial Foundation, by a Professorial Fellowship at Balliol College, University of Oxford, and by the Eastman Visiting Professorship at the University of Oxford. Author Contributions: B.R.W. and N.J.P. contributed equally. The authors declare the following competing financial interest(s): US patents and pending patent applications.

Attached Files

Published - jacs.6b12693.pdf

Supplemental Material - ja6b12693_si_001.pdf


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