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Constrained Multistate Sequence Design for Nucleic Acid Reaction Pathway Engineering

Wolfe, Brian R. and Porubsky, Nicholas J. and Zadeh, Joseph N. and Dirks, Robert M. and Pierce, Niles A. (2017) Constrained Multistate Sequence Design for Nucleic Acid Reaction Pathway Engineering. Journal of the American Chemical Society, 139 (8). pp. 3134-3144. ISSN 0002-7863. doi:10.1021/jacs.6b12693.

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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.

Item Type:Article
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Pierce, Niles A.0000-0003-2367-4406
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.
Funding AgencyGrant Number
Gordon and Betty Moore FoundationGBMF2809
Caltech Beckman InstituteUNSPECIFIED
St Catherine’s College, University of OxfordUNSPECIFIED
John Simon Guggenheim FoundationUNSPECIFIED
Balliol College, University of OxfordUNSPECIFIED
Eastman Visiting Professorship, University of OxfordUNSPECIFIED
Issue or Number:8
Record Number:CaltechAUTHORS:20170213-164458132
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Official Citation:Constrained Multistate Sequence Design for Nucleic Acid Reaction Pathway Engineering Brian R. Wolfe, Nicholas J. Porubsky, Joseph N. Zadeh, Robert M. Dirks, and Niles A. Pierce Journal of the American Chemical Society 2017 139 (8), 3134-3144 DOI: 10.1021/jacs.6b12693
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:74283
Deposited By: George Porter
Deposited On:14 Feb 2017 15:41
Last Modified:11 Nov 2021 05:26

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