Software-controlled assembly of oligomers

Lead Research Organisation: University of Southampton
Department Name: School of Chemistry

Abstract

We propose to create a molecular machine that will build new materials under software control. The output of the machine will be chains of building blocks linked by covalent bonds. The machine is modular and is designed to accept many different building blocks, from small molecules to nanoparticles, with a wide range of physical and chemical properties. In order to drive its development we will concentrate on using it to create two target products: a molecular wire, capable of transporting energy and electrical charge, and a catalyst. Software control starts with specification by the end-user of a sequence of building blocks. The target sequence is encoded in an instruction tape which can be read by the machine: the tape is itself a molecule, a synthetic DNA oligomer. The target sequence of building blocks is automatically converted into a control sequence of DNA bases, and the tape is produced by commercial solid-phase synthesis. The job of the machine is to read the instruction tape and to form the bonds between building blocks in the specified sequence. Every component of this molecular factory is itself a molecule: our ambition is to develop the system to the point where it could be distributed to end users as chemicals in plastic vials.

Publications

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McKee ML (2011) Peptidomimetic bond formation by DNA-templated acyl transfer. in Organic & biomolecular chemistry

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Coomber D (2010) Programmed assembly of peptide-functionalized gold nanoparticles on DNA templates. in Langmuir : the ACS journal of surfaces and colloids

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McKee ML (2012) Programmable one-pot multistep organic synthesis using DNA junctions. in Journal of the American Chemical Society

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Griffith A (2013) Fluorescent hydrogel formation from carboxyphenyl-terpyridine. in Chemical communications (Cambridge, England)

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Milnes PJ (2012) Sequence-specific synthesis of macromolecules using DNA-templated chemistry. in Chemical communications (Cambridge, England)

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McKee ML (2010) Multistep DNA-templated reactions for the synthesis of functional sequence controlled oligomers. in Angewandte Chemie (International ed. in English)

 
Description We intend to create a nanoscale chemical factory in which the machines, like the products, are molecules. The products will be linear molecules produced by linking together smaller building blocks in a defined sequence - at each stage the molecular machinery will be capable of choosing the correct building block from a range of possibilities. The system will be capable of synthesizing a library of molecules with different sequences and selecting 'successful' molecules for their fitness to perform a specified task. We have developed systems, based on nanostructures made from DNA, that control the routing of a cargo within a branched track network. Under a linked grant, we have developed methods for controlling sequential chemical reactions using DNA. We have also worked on designs for more powerful systems in which the molecular machinery responsible for chemical synthesis has internal computing power and can direct its own operation. Many of the components for our nanoscale factory are therefore in place: we have DNA-directed chemistry and DNA assembly lines with controlled routing that will enable control of the molecular product formed.
Exploitation Route See 'Exploitation routes' To achieve their full potential impact, the ideas contained in this proposal will require research and development well beyond the scope of this proposal. In the initial stages of this project (covered by this proposal) the principal beneficiary will be the academic community - particularly in the field of molecular nanotechnology, also in synthetic biology. We anticipate that successful development of an intelligent molecular manufacturing processes would lead to industrial interest, particularly in the following sectors: pharmaceutical (enzyme inhibitors, cyclic peptides), chemical manufacturing (catalyst development) and electronic (optoelectronic components, electronic wires). Commercial adoption and development has the potential to contribute to the UK economy and to public health and standard of living, for example through innovations in drug development, manufacture and delivery, and in the development of novel prototyping and manufacturing techniques.
Sectors Chemicals

 
Description Peer Review Panel
Geographic Reach Asia 
Policy Influence Type Membership of a guideline committee
Impact The peer review panel selects the proposals of highest impact for science and societal issues.
 
Description Steering committee
Geographic Reach Asia 
Policy Influence Type Membership of a guideline committee
Impact The steering committee of Diamond Light Source has helped to improve the beamline B23 service and accessibility to both UK and international academic and industrial based researchers, who are working in health care, materials, biotechnology and energy/electronics.
 
Description Evaluation of a platform technology for manipulation of gene expression
Amount £20,000 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2016 
End 04/2016
 
Description Functional DNA nanomaterials
Amount € 231,283 (EUR)
Funding ID FP7 MSCA-IEF NANO-DNA 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 10/2013 
End 09/2015
 
Description B23 CD 
Organisation Diamond Light Source
Country United Kingdom 
Sector Private 
PI Contribution Synthesis of modified DNA for high-end CD spectroscopy analysis using SRCD, data evaluation, writing of publications.
Collaborator Contribution Providing support in CD measurements using synchrotron based CD spectrometer, help in data evaluation and writing of publications.
Impact Multi-disciplinary projects, including synthetic chemistry, spectroscopy, biology and materials science. To date a total of 18 sessions were successfully applied for and obtained. Output: DOI: 10.1039/c5ob01681a DOI: 10.1039/c0ob00535e dx.doi.org/10.1002/anie.200805657 Theses: Porphyrin - DNA as a scaffold for nanoarchitecture and nanotechnology; TN. Nguyen, 2010 Supramolecular porphyrin arrays on DNA and SWNT scaffolds; A. J. Brewer, 2011 Functionalised DNA - Introducing & Applying a Versatile Porphyrin Molecular Ruler; J. R. Burns, 2011 Porphyrin substituted DNA: Building blocks for novel nanostructures; D. G. Singleton, 2012 The Structural Analysis of Porphyrin Modified DNA and the Construction of a Molecular Wire; J. W. Wood, 2015
Start Year 2009
 
Description B23 PhD 
Organisation Diamond Light Source
Country United Kingdom 
Sector Private 
PI Contribution Design and synthesis of DNA origami platform for enzyme analysis; modifying enzymes with DNA; data acquisition and analysis; writing of publications.
Collaborator Contribution Support in data acquisition, data evaluation and writing of publications. Providing synchrotron based CD spectrometer.
Impact No outputs yet. Multi-disciplinary project involving organic chemistry, biology, spectroscopy and materials science.
Start Year 2016
 
Description Cancer res Singapore 
Organisation National Research Foundation Singapore
Country Singapore 
Sector Charity/Non Profit 
PI Contribution Development and synthesis of modified DNA origami nanopores, data evaluation, writing reports and publications.
Collaborator Contribution Performance of clinical trials towards specific targeting of cancer cells, data evaluation, help in writing publications.
Impact No outputs yet. Multidisciplinary project involving chemistry and medicine.
Start Year 2014
 
Description Sensors Singapore 
Organisation National Research Foundation Singapore
Country Singapore 
Sector Charity/Non Profit 
PI Contribution Providing modified DNA samples for the development of novel multisensors for cancer genes and cancer markers, data evaluation, writing publications.
Collaborator Contribution Development of sensors to detect early cancer markers from biological samples, data evaluation, help in writing publications.
Impact dx.doi.org/10.1016/j.bios.2014.05.017 Multi-disciplinary project involving chemistry and materials science (microfluidics).
Start Year 2012
 
Description Supramolecular nanoscale arrays of fluorophores 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Undergraduate students
Results and Impact Dissemination of results in form of poster presentation at the Southampton Nanofabrication Centre Open Day, Sept. 2009, Southampton.

Discussions about potential future research collaborations.
Year(s) Of Engagement Activity 2009