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PreprintCC BYChemRxiv

Topologically-constrained toehold-mediated strand displacement

  • Andrew Stannard1,2,3,4
  • Aditya Sengar5,2
  • Alexander H. Clowsley6,7,8
  • Christian Soeller6,7,8
  • Thomas E. Ouldridge5,2
  • Lorenzo Di Michele1,2,3,4
8 affiliations
  1. 1Department of Chemistry
  2. 2Imperial College London
  3. 3Department of Chemical Engineering and Biotechnology
  4. 4University of Cambridge
  5. 5Department of Bioengineering and Centre for Engineering Biology
  6. 6Living Systems Institute and Biomedical Physics, University of Exeter
  7. 7Institut für Physiologie
  8. 8Universität Bern
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Abstract

Toehold-mediated strand displacement (TMSD) is regarded as the simplest mechanism through which synthetic nucleicacid nanosystems can be dynamically actuated and is central to applications in biosensing, molecular computing, data storage and retrieval, and synthetic biology. In these implementations, TMSD often occurs in topologically-confined configurations, with the toehold domain being linked to other elements that restrict its conformational freedom. However, the effect of topological confinement on the biophysics of TMSD remains largely unexplored. Here, we study TMSD in a simple, physiologically-encountered configuration in which the toehold domain is located in a DNA ‘bubble’, a region where the two strands of an otherwise continuous DNA duplex are dehybridised. We show that this topological confinement reduces the rate of TMSD by ∼1–3 orders of magnitude as a result of alterations to the TMSD free-energy landscape. We further demonstrate that hybridisation of a short DNA strand to the target complex–away from the toehold domain–speeds up TMSD, hence providing a route for allosteric modulation of the reaction rate. Our results highlight the substantial effect of topological confinement on TMSD. These effects must be considered in the optimal design of dynamic nanostructures and molecular reaction networks while offering convenient strategies for the fine-tuning and modulation of reaction rates.

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Cite

BibTeXRIS
BibTeX
@misc{stannard2026topologicallyconstrained,
  title = {{Topologically-constrained toehold-mediated strand displacement}},
  author = {Andrew Stannard and Aditya Sengar and Alexander H. Clowsley and Christian Soeller and Thomas E. Ouldridge and Lorenzo Di Michele},
  howpublished = {ChemRxiv},
  year = {2026},
  month = sep,
  doi = {10.26434/chemrxiv.15009472/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009472/v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Topologically-constrained toehold-mediated strand displacement
AU  - Andrew Stannard
AU  - Aditya Sengar
AU  - Alexander H. Clowsley
AU  - Christian Soeller
AU  - Thomas E. Ouldridge
AU  - Lorenzo Di Michele
PY  - 2026
DA  - 2026/09/25
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15009472/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009472/v1
AB  - Toehold-mediated strand displacement (TMSD) is regarded as the simplest mechanism through which synthetic nucleicacid nanosystems can be dynamically actuated and is central to applications in biosensing, molecular computing, data storage and retrieval, and synthetic biology. In these implementations, TMSD often occurs in topologically-confined configurations, with the toehold domain being linked to other elements that restrict its conformational freedom. However, the effect of topological confinement on the biophysics of TMSD remains largely unexplored. Here, we study TMSD in a simple, physiologically-encountered configuration in which the toehold domain is located in a DNA ‘bubble’, a region where the two strands of an otherwise continuous DNA duplex are dehybridised. We show that this topological confinement reduces the rate of TMSD by ∼1–3 orders of magnitude as a result of alterations to the TMSD free-energy landscape. We further demonstrate that hybridisation of a short DNA strand to the target complex–away from the toehold domain–speeds up TMSD, hence providing a route for allosteric modulation of the reaction rate. Our results highlight the substantial effect of topological confinement on TMSD. These effects must be considered in the optimal design of dynamic nanostructures and molecular reaction networks while offering convenient strategies for the fine-tuning and modulation of reaction rates.
ER  -