Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 139, Issue 8, Pages 3134-3144Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.6b12693
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Funding
- National Science Foundation [NSF-CCF-0832824, NSF-CCF-1317694]
- Gordon and Betty Moore Foundation [GBMF2809]
- Beckman Institute at Caltech (PMTC)
- St Catherine's College, University of Oxford
- John Simon Guggenheim Memorial Foundation
- Balliol College, University of Oxford
- Eastman Visiting Professorship at the University of Oxford
- Division of Computing and Communication Foundations
- Direct For Computer & Info Scie & Enginr [1317694] Funding Source: National Science Foundation
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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.
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