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published in Newton

Cells assemble complex molecules such as proteins using template polymers with information-carrying sequences. These sequences are used to direct the ordered assembly of a set of molecular building blocks to form exactly the right product, such as a specific protein, on demand. A crucial feature of this process is that the templates act catalytically, since they accelerate the assembly of a specific product without being consumed in the process. A single template can then be used to direct the assembly of many copies of a product. It has long been suspected that this transfer of information from catalytic templates to products must be associated with a minimal energy cost, in the same way that computation has lower bounds on energy input. To explore this hypothesis further, this work considers arbitrarily complex templating networks involving many assembly and disassembly processes. We show that the accuracy with which a specific set of products can be maintained is, indeed, constrained by energetic properties of the underlying network. Surprisingly, the operation of the most efficient templating networks is completely different from the behavior observed in nature, where molecules such as proteins are overwhelmingly assembled by templates and degraded in a distinct, template-free fashion. Instead, the most efficient approach, which both achieves the highest accuracy and has a negligible energetic cost, is to disassemble products via a reversal of the pathway by which they were formed. This observation raises interesting questions about why nature does not operate in this way and whether synthetic templating systems can be built that exploit this approach.

published in Nature Chemistry

Information propagation by sequence-specific, template-catalysed molecular assembly is a key process facilitating life’s biochemical complexity, yielding thousands of sequence-defined proteins from only 20 distinct building blocks. However, exploitation of catalytic templating is rare in non-biological contexts, particularly in enzyme-free environments, where even the template-catalysed formation of dimers is challenging. Typically, product inhibition—the tendency of products to bind to templates more strongly than individual monomers—prevents catalytic turnover. Here we present a rationally designed enzyme-free system in which a DNA template catalyses, with weak product inhibition, the production of sequence-specific DNA dimers. We demonstrate selective templating of nine different dimers with high specificity and catalytic turnover, then we show that the products can participate in downstream reactions, and finally that the dimerization can be coupled to covalent bond formation. Most importantly, our mechanism demonstrates a design principle for constructing synthetic molecular templating systems, a first step towards applying this powerful motif in non-biological contexts to construct many complex molecules and materials from a small number of building blocks.

Biochemical networks within cells achieve remarkable functionality, including sensing, signalling, information-processing and replication. We aim to understand the fundamental physical principles that set the scope of this behaviour, allowing development of engineering principles for artificial analogs of these systems.

Since these systems of interest typically involve small numbers of molecules, randomness plays an important role. This work often touches on the deep connections between two bodies of work that deal explicitly with randomness: information theory, which describes the role of randomness in communication, and statistical mechanics, through which randomness is related to thermodynamics.

Recently, we've started to translate our basic understanding into the engineering of synthetic, nucleic acid-based analogs of these natural systems within our own lab here at 911½ñÈÕºÚÁÏ. To get a taste, check out , or a . 

Relevant Publications

1. Plesa T, Dack A, Ouldridge TE, 2023 "", J. Math. Chem.
2. Qureshi, B., Juritz, J., Poulton, J. M., Beersing-Vasquez, A., & Ouldridge, T. E. (2023). . The Journal of Chemical Physics.
3. JM Lawrence et al., 2022, , Science Advances. 
4. Catala AC, Ouldridge TE, Stan GBV, Bae W, 2022, "", ACS Synthetic Biology.
5. Juritz J, Poulton JM, Ouldridge TE, 2021, "", The Journal of Chemical Physics.
6. Bae W, Stan GBV, Ouldridge TE, 2021, "", Nano Lett.
7. Cabello-Garcia J, Bae W, Stan GBV, Ouldridge TE, 2021, "", ACS Nano.
   
8. Poulton JM, Ouldridge TE, 2021, "", New J. Phys.
   
9. Lankinen A, Mullor Ruiz I, Ouldridge TE, 2020, , 26th International Conference on DNA Computing and Molecular Programming (DNA 26).
10. Plesa T, Stan G-BV, Ouldridge TE, Bae W, 2021, "", J. R. Soc. Interface.
11. Deshpande A, Ouldridge TE, 2020, "". Biological Cybernetics.
12. Brittain RA, Jones NS, Ouldridge TE, 2019, , New J. Phys. 
13. Poulton J, ten Wolde PR and Ouldridge TE, 2019, , PNAS.
14. Ouldridge TE, Brittain RA, ten Wolde PR, 2018, , in , SFI Press.
15. Deshpande A, Ouldridge  TE, 2017, , Engineering Biology.
16. Poole W, Ortiz-Muñoz A, Behera A, Jones NS,  Ouldridge  TE, Winfree E, Gopalkrishnan M, 2017, , In DNA Computing and Molecular Programming (DNA 2017).
17. Brittain RA, Jones NS, Ouldridge TE, 2017, , J. Stat. Mech.
18. Ouldridge TE, 2017, , Nat. Comput.
19. Ouldridge TE, ten Wolde PR, 2017, , Phys. Rev. Lett.
20. Ouldridge TE, Govern CC, ten Wolde PR, 2017, , Phys. Rev. X.
21. McGrath T, Jones NS, ten Wolde PR, Ouldridge TE, 2017, , Phys. Rev. Lett.
22. ten Wolde PR, Becker NB, Ouldridge TE, Mugler A, 2015, , J. Stat. Phys.
23. Ouldridge TE, ten Wolde PR, 2014, , Biophysical Journal.

The elegant selectivity of Watson-Crick base-pairing makes DNA an extremely useful tool for the construction of nanoscale objects and machines. Stable structures and mechanical cycles can be programmed into a system of single strands by careful choice of the sequences of bases. I'm particularly interested in using nucleic acids to design artificial analogs of complex cellular systems, to enable careful exploration of the design principles and engineering possibilities.

Despite the experimental successes, there is no clear theoretical description of the processes involved. We have developed a nucleotide-level coarse grained model of DNA,, which is detailed enough to capture the essential physics of assembly processes, yet simple enough to be applicable over long time scales. Code, user guides and examples for simulating the model can be downloaded from this

The oxDNA model was developed in the / groups in Oxford. It has since been applied in collaboration with the in Oxford, the in Caltech and the at the Ben-Gurion University of Negev, as well as being used independently by other researchers.

Even with oxDNA, it is still not practical to simulate the formation of very large structures. A collaboration with the and groups in Oxford has led to a less detailed model that can describe the formation of DNA origami structures.

Relevant Publications

1. Sengar A, Ouldridge TE, Henrich O, Rovigatti L, Sulc P, 2021, "", Frontiers in Molecular Biosciences.
2. Irmisch P, Ouldridge TE, Seidel R, 2020, , J. Am. Chem. Soc.
   
3. Haley NEC, Ouldridge TE, Mullor Ruiz I, Geraldini A, Louis AA, Bath J and Turberfield AA, 2020, , Nat. Comms.
4. Fonseca P, Romano F, Schreck JS, Ouldridge TE, Doye JPK and Louis AA, 2018, , J. Chem. Phys. 
5. Khara DC, Schreck JS, Tomov TE, Berger Y, Ouldridge TE, Doye JPK and Nir E, 2018, , Nucl. Acids Res.
6. Snodin BEK, Romano F, Rovigatti L, Ouldridge TE, Louis AA, and Doye JPK, 2016, , ACS Nano.
7. Dunn KE, Dannenberg F, Ouldridge TE, Kwiatkowska M, Turberfield AJ, Bath J, 2015, , Nature.
8. Dannenberg F, Dunn KE, Bath J, Kwiatkowska M, Turberfield AJ, Ouldridge TE, 2015, , J. Chem. Phys.
9. Snodin BEK, Randisi F, Mosayebi M, Sulc P, Schreck JS, Romano F, Ouldridge TE, Tsukanov R, Nir E, Louis AA, Doye JPK, 2015, , J. Chem. Phys.
10. Schreck JS, Ouldridge TE, Romano F, Sulc P, Shaw L, Louis AA, Doye JPK, 2015, , Nucleic Acids Research.
11. Mosayebi M, Louis AA, Doye JPK, Ouldridge TE, 2015, , ACS Nano.
12. Machinek RR, Ouldridge TE, Haley NE, Bath J, Turberfield AJ, 2014, , Nature Communications.
13. Doye JPK, Ouldridge TE, Louis AA, Romano F, Sulc P, Matek C, Snodin BEK, Rovigatti L, Schreck JS, Harrison RM, Smith WPJ, 2013, , Physical Chemistry Chemical Physics.
14. Srinivas N, Ouldridge TE, Sulc P, Schaeffer JM, Yurke B, Louis AA, Doye JPK, Winfree E, 2013, , Nucleic Acids Research.
15. Ouldridge TE, Sulc P, Romano F, Doye JPK, Louis AA, 2013, , Nucleic Acids Research.
16. Ouldridge TE, Hoare RL, Louis AA, Doye JPK, Bath J, Turberfield AJ, 2013, , ACS Nano.
17. Sulc P, Romano F, Ouldridge TE, Rovigatti L, Doye JPK, Louis AA, 2012, , Journal of Chemical Physics.
18. Ouldridge TE, Louis AA, Doye JPK, 2011, , Journal of Chemical Physics.
19. Ouldridge TE, Louis AA, Doye JPK, 2010, , Physical Review Letters.

Thermodynamics, the science of heat and energy transfer, emerged as a field in the 19th century, motivated by the need to describe the engines that powered the industrial revolution. One of the challenges of modern science is to adapt and extend the theory to describe microscopic systems in which fluctuations play a key role. Biological and biologically-inspired systems are a key arena for these new ideas, due both to the need to understand natural molecular analogues of the engines and processes that we are familiar with at much larger length scales, and the possibility of developing artificial devices ourselves.

Not only does thermodynamics provide understanding of biological systems, but the study of real biophysical devices in turn provides us with a deeper understanding of the thermodynamic principles at play. In particular, the natural diffusive behaviour of biomolecules allows us to study complex systems that do not require external manipulation to function.

Relevant Publications

1. Ouldridge TE and Wolpert DH, 2023. T. New Journal of Physics.  
2. Seet I, Ouldridge TE, Doye JPK, 2023, , Physical Review E.
3. Qureshi B, Juritz J, Poulton JM, Beersing-Vasquez A, Ouldridge, TE, 2023, . The Journal of Chemical Physics.
4. Juritz J, Poulton JM, Ouldridge TE, 2021, "", The Journal of Chemical Physics.
5. Poulton JM, Ouldridge TE, 2021, "", New J. Phys.
6. Ouldridge TE, 2020, , Reseach Outreach. 
7. Brittain RA, Jones NS, Ouldridge TE, 2019, , New. J. Phys.
8. Ouldridge TW, Brittain RA, ten Wolde PR, 2019, , in , SFI Press.
9. Stopnitzky E, Still S, Ouldridge TE and Altenberg L, 2019,  , Phys. Rev. E. 
10. Poulton J, ten Wolde PR and Ouldridge TE, 2019, , PNAS.
11. Deshpande A, Ouldridge  TE, 2017, , Engineering Biology: 1.
12. Deshpande A, Gopalkrishnan M, Ouldridge TE, Jones NS, 2017, , Proc. Roy. Soc. A.
13. Brittain RA, Jones NS, Ouldridge TE, 2017, , J. Stat. Mech.
14. Ouldridge TE, 2017, , Nat. Comput.
15. Ouldridge TE, ten Wolde PR, 2017, , Phys. Rev. Lett.
16. Ouldridge TE, Govern CC, ten Wolde PR, 2017, , Phys. Rev.
17. McGrath T, Jones NS, ten Wolde PR, Ouldridge TE, 2017, , Phys. Rev. Lett.

Our work often involves systems that are too complex to be treated analytically. This means that simulations are a key tool in our research, and we are interested in simulation techniques and analysis tools for systems involving biomolecular reactions.

In this work we collaborate with the  /  groups in Oxford, the  of Pieter Rein ten Wolde in Amsterdam,  in Nottingham and  in Leicester, and  in Strathclyde.

Relevant Publications

1. Qureshi B, Juritz J, Poulton JM, Beersing-Vasquez A, & Ouldridge TE, 2023, . The Journal of Chemical Physics.
2. Sengar A, Ouldridge TE, Henrich O, Rovigatti L, Sulc P, 2021, "", Frontiers in Molecular Biosciences.
3. Henrich O, Yair AGF, Curk T, Ouldridge TE, 2018, , Eur. Phys. J. E.
4. Davidchack RL, Ouldridge TE, Tretyakov MV, 2017, , J. Chem. Phys.
5. Vijaykumar A, Ouldridge TE, ten Wolde PR, Bolhuis PG, 2017, ,  Journal of Chemical Physics.
6. Davidchack RL, Ouldridge TE, Tretyakov MV, 2015, , Journal of Chemical Physics.
7. Ouldridge TE, 2012, , Journal of Chemical Physics.
8. Ouldridge TE, Louis AA, Doye JPK, 2010, , Journal of Physics: Condensed Matter.

We've recently acquired our own (small) lab within the synthetic biology space at 911½ñÈÕºÚÁÏ. We're using this lab to actually put our theoretical ideas into practice, engineering functional molecular systems from nucleic acids. These systems are both useful test-beds for our theory and engineering platforms for synthetic biology.

Our work currently focusses on engineering non-equilibrium information processing systems, analogs of the signalling and transcription/translation machinery in cells.  To get a taste, check out , or a . 

 Below we list papers that present data obtained in our lab.

Relevant Publications

1. Catala AC, Ouldridge TE, Stan GBV, Bae W, 2022, "", ACS Synthetic Biology,
2. Bae W, Stan GBV, Ouldridge TE, 2021, "", Nano Lett.
3. Cabello-Garcia J, Bae W, Stan GBV, Ouldridge TE, 2021, "", ACS Nano.
4. Haley NEC, Ouldridge TE, Mullor Ruiz I, Geraldini A, Louis AA, Bath J and Turberfield AA, 2020, , Nat. Comms.