Topics

Recent Highlights

10/6/2019  "The power of being explicit: demystifying work, heat, and free energy in the physics of computation" published in "The energetics of computing in life and machines"

Szilard's engine, proposed in 1929, illustrates the fundamental physics of measurement and feedback operations - Szilard himself used it to argue that it is impossible to extract useful work by measuring and then exploiting the fluctuations of an equilibrium system. However, the full device, including the physical mechanism by which measurements are fed back to manipulate the system, was not explicitly described. As a consequence, although Szilard's ideas were correct, there has been great confusion about them ever since. We propose a molecular version of the full device in which all feedback and information-processing is treated explicitly. In "The power of being explicit: demystifying work, heat, and free energy in the physics of computation"we review the literature surrounding Szilard's engine and demonstrate our device in detail, arguing that explicit designs of this kind resolve much of the mystery and confusion surrounding thermodynamics. 

28/5/2019 Rory's paper "Biochemical Szilard engines for memory-limited inference" accepted in New. J. Phys.

Szilard's engine, proposed in 1929, illustrates the fundamental physics of measurement and feedback operations - Szilard himself used it to argue that it is impossible to extract useful work by measuring and then exploiting the fluctuations of an equilibrium system. However, the full device, including the physical mechanism by which measurements are fed back to manipulate the system, was not explicitly described. As a consequence, although Szilard's ideas were correct, there has been great confusion about them ever since. We propose a molecular version of the full device in which all feedback and information-processing is treated explicitly. In "Biochemical Szilard engines for memory-limited inference", we demonstrate the application of modified devices to exploiting order in structured environments. These systems are analogs of simple organisms that must make decisions about feeding in their environment. We show that more complex environments can favour more complex decision-making strategies.

3/5/2019 Abhishek's paper "Optimizing enzymatic catalysts for rapid turnover of substrates with low enzyme sequestration" submitted.

Enzymes must bind to their substrates to perform catalytic turnover. But when they do, they are "sequestered, and can't take part in other reactions. We explore how enzymes might be evolved, or designed by nanotechnologists, to maximize their catalytic activity whilst minimizing their tendency to be sequestered. 

21/2/2019 Jenny's paper "Non-equilibrium correlations in minimal dynamical models of polymer copying" published in PNAS.

The ordering of chemical units within DNA, RNA and proteins carries information about how living cells operate, and copying these sequences accurately is vital. We have a limited understanding of the fundamental physical underpinnings of these processes, since important mechanistic constraints due to the need to separate daughter sequences from their templates have never been investigated in detail. By considering the simplest models that incorporate these constraints, we highlight their profound consequences in terms of the effort that must be expended to make accurate copies. These insights will help us to understand not only life today but also how early replicators may have functioned in the past, and how we might develop synthetic copiers in the future.

26/09/2018 Work with the Turberfield group in Oxford, "Rational design of hidden thermodynamic driving through DNA mismatch repair", submitted.

We propose a new paradigm for the design of synthetic molecular systems, "hidden thermodynamic driving", and demonstrate the possibility of rationally incorporating this motif into nucleic acid-based strand displacement networks through the repair of mismatches during displacement. Hidden thermodynamic driving enables the overall thermodynamics of reactions to be tuned, whilst maintaining tight catalytic control over the rection kinetics. It therefore facilitates the development of complex molecular networks in which reactions must be thermodynamically favourable and yet kinetically frustrated in the absence of catalysts. 

 

 

Functional molecular systems

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.

In this work we collaborate closely with the biochemical networks group of Pieter Rein ten Wolde in Amsterdam, Nick Jones' systems and signals group and Guy Bart-Stan's control engineering synthetic biology group.

Relevant Publications

  1. Ouldridge TW, Brittain RA, ten Wolde PR, 2018, The power of being explicit: demystifying work, heat, and free energy in the physics of computation, in "The Energetics of Computing in Life and Machines", SFI Press.
  2. Deshpande A, Ouldridge TE, 2019, "Optimizing enzymatic catalysts for rapid turnover of substrates with low enzyme sequestration" submitted.
  3. Brittain RA, Jones NS, Ouldridge TE, 2018, Biochemical Szilard engines for memory-limited inferencein press at New J. Phys.
  4. Poulton J, ten Wolde PR and Ouldridge TE, 2019, Non-equilibrium correlations in minimal dynamical models of polymer copying, PNAS: 116,1946-1951.
  5. Deshpande A, Ouldridge  TE, 2017, High rates of fuel consumption are not required by insulating motifs to suppress retroactivity in biochemical circuitsEngineering Biology: 1,86-99.
  6. Poole W, Ortiz-Muñoz A, Behera A, Jones NS,  Ouldridge  TE, Winfree E, Gopalkrishnan M, 2017, Chemical Boltzmann MachinesIn DNA Computing and Molecular Programming. DNA 2017. Lecture Notes in Computer Science: 10467,210-231.
  7. Brittain RA, Jones NS, Ouldridge TE, 2017, What we learn from the learning rateJ. Stat. Mech.: 063592.
  8. Ouldridge TE, 2017, The importance of thermodynamics for molecular systems, and the importance of molecular systems for thermodynamicsNat. Comput.: in press.
  9. Ouldridge TE, ten Wolde PR, 2017, Fundamental costs in the production and destruction of persistent polymer copies, Phys. Rev. Lett.: 118,158103.
  10. Ouldridge TE, Govern CC, ten Wolde PR, 2017, Thermodynamics of computational copying in biochemical systemPhys. Rev. X: 7,021004.
  11. McGrath T, Jones NS, ten Wolde PR, Ouldridge TE, 2017, Biochemical machines for the interconversion of mutual information and workPhys. Rev. Lett.: 118,028101.
  12. ten Wolde PR, Becker NB, Ouldridge TE, Mugler A, 2015, Fundamental Limits to Cellular SensingJ. Stat. Phys.: 162,1395-1424.
  13. Ouldridge TE, ten Wolde PR, 2014, The robustness of proofreading to crowding-induced pseudo-processivity in the MAPK pathwayBiophysical Journal: 107,2425-2435.

Coarse-grained modelling of DNA

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, oxDNA, 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 site.

The oxDNA model was developed in the Doye / Louis groups in Oxford. It has since been applied in collaboration with the Turberfield group in Oxford, the Winfree group in Caltech and the Nir group 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 Turberfield and Kwiatkowska groups in Oxford has led to a less detailed model that can describe the formation of DNA origami structures.

Relevant Publications

  1. Haley NEC, Ouldridge TE, Geraldini A, Louis AA, Bath J and Turberfield AA, 2018, Rational design of hidden thermodynamic driving through DNA mismatch repair, submitted.
  2. Fonseca P, Romano F, Schreck JS, Ouldridge TE, Doye JPK and Louis AA, 2018, Multi-scale coarse-graining for the study of assembly pathways in DNA-brick self assembly, J. Chem. Phys. 148:134910. 
  3. Khara DC, Schreck JS, Tomov TE, Berger Y, Ouldridge TE, Doye JPK and Nir E, 2018, DNA bipedal motor walking dynamics: an experimental and theoretical study of the dependency on step size, Nucl. Acids Res. 46:1553-1561.
  4. Snodin BEK, Romano F, Rovigatti L, Ouldridge TE, Louis AA, and Doye JPK, 2016, Direct Simulation of the Self-Assembly of a Small DNA Origami, ACS Nano: 10,1724-1737.
  5. Dunn KE, Dannenberg F, Ouldridge TE, Kwiatkowska M, Turberfield AJ, Bath J, 2015, Guiding the folding pathway of DNA origami, Nature: 525,82-86.
  6. Dannenberg F, Dunn KE, Bath J, Kwiatkowska M, Turberfield AJ, Ouldridge TE, 2015, Modelling DNA Origami Self-Assembly at the Domain Level, J. Chem. Phys.: 143,165102.
  7. Snodin BEK, Randisi F, Mosayebi M, Sulc P, Schreck JS, Romano F, Ouldridge TE, Tsukanov R, Nir E, Louis AA, Doye JPK, 2015, Introducing improved structural properties and salt dependence into a coarse-grained model of DNA, J. Chem. Phys.: 142,234901.
  8. Schreck JS, Ouldridge TE, Romano F, Sulc P, Shaw L, Louis AA, Doye JPK, 2015, DNA hairpins primarily promote duplex melting rather than inhibiting hybridization, Nucleic Acids Research: 43,6181-6190.
  9. Mosayebi M, Louis AA, Doye JPK, Ouldridge TE, 2015, Force-induced rupture of a DNA duplex, ACS Nano: 9,11993-12003.
  10. Machinek RR, Ouldridge TE, Haley NE, Bath J, Turberfield AJ, 2014, Programmable energy landscapes for kinetic control of DNA strand displacement, Nature Communications: 5,5324.
  11. Doye JPK, Ouldridge TE, Louis AA, Romano F, Sulc P, Matek C, Snodin BEK, Rovigatti L, Schreck JS, Harrison RM, Smith WPJ, 2013, Coarse-graining DNA for simulations of DNA nanotechnology, Physical Chemistry Chemical Physics: 15,20395-20414.
  12. Srinivas N, Ouldridge TE, Sulc P, Schaeffer JM, Yurke B, Louis AA, Doye JPK, Winfree E, 2013, On the biophysics and kinetics of toehold-mediated DNA strand displacement, Nucleic Acids Research: 41,10641-10658.
  13. Ouldridge TE, Sulc P, Romano F, Doye JPK, Louis AA, 2013, DNA hybridization kinetics: Zippering, internal displacement and sequence dependence, Nucleic Acids Research: 41,8886-8895.
  14. Ouldridge TE, Hoare RL, Louis AA, Doye JPK, Bath J, Turberfield AJ, 2013, Optimizing DNA nanotechnology through coarse-grained modeling: A two-footed DNA walker, ACS Nano: 7,2479-2490.
  15. Sulc P, Romano F, Ouldridge TE, Rovigatti L, Doye JPK, Louis AA, 2012, Sequence-dependent thermodynamics of a coarse-grained DNA model, Journal of Chemical Physics: 137,135101.
  16. Ouldridge TE, Louis AA, Doye JPK, 2011, Structural, mechanical, and thermodynamic properties of a coarse-grained DNA model, Journal of Chemical Physics: 134,085101.
  17. Ouldridge TE, Louis AA, Doye JPK, 2010, DNA nanotweezers studied with a coarse-grained model of DNA, Physical Review Letters: 104,178101.

Thermodynamics of small systems

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. Brittain RA, Jones NS, Ouldridge TE, 2019, Biochemical Szilard engines for memory-limited inference, in press at New. J. Phys.
  2. Ouldridge TW, Brittain RA, ten Wolde PR, 2019, The power of being explicit: demystifying work, heat, and free energy in the physics of computation, in "The Energetics of Computing in Life and Machines", SFI Press.
  3. Stopnitzky E, Still S, Ouldridge TE and Altenberg L, 2019,  Physical Limitations of Work Extraction from Temporal Correlations, Phys. Rev. E: 99,042115. 
  4. Poulton J, ten Wolde PR and Ouldridge TE, 2019, Non-equilibrium correlations in minimal dynamical models of polymer copying, PNAS: 116,1946-1951.
  5. Deshpande A, Ouldridge  TE, 2017, High rates of fuel consumption are not required by insulating motifs to suppress retroactivity in biochemical circuitsEngineering Biology: 1,86-99.
  6. Deshpande A, Gopalkrishnan M, Ouldridge TE, Jones NS, 2017,  Designing the Optimal Bit: Balancing Energetic Cost, Speed and ReliabilityProc. Roy. Soc. A.: 473,20170117.
  7. Brittain RA, Jones NS, Ouldridge TE, 2017, What we learn from the learning rateJ. Stat. Mech.: 063592.
  8. Ouldridge TE, 2017, The importance of thermodynamics for molecular systems, and the importance of molecular systems for thermodynamicsNat. Comput.: in press.
  9. Ouldridge TE, ten Wolde PR, 2017, Fundamental costs in the production and destruction of persistent polymer copiesPhys. Rev. Lett.: 118,158103.
  10. Ouldridge TE, Govern CC, ten Wolde PR, 2017, Thermodynamics of computational copying in biochemical systemPhys. Rev. X: 7,021004.
  11. McGrath T, Jones NS, ten Wolde PR, Ouldridge TE, 2017, Biochemical machines for the interconversion of mutual information and workPhys. Rev. Lett.: 118,028101.

Simulation tools and algorithms

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 Doye / Louis groups in Oxford, the biochemical networks group of Pieter Rein ten Wolde in Amsterdam, Michael Tretyakov in Nottingham and Ruslan Davidchack in Leicester, and Oliver Henrich in Strathclyde.

Relevant Publications

  1. Henrich O, Yair AGF, Curk T, Ouldridge TE, 2018, Coarse-grained simulation of DNA using LAMMPS, Eur. Phys. J. E., 41: 57.
  2. Davidchack RL, Ouldridge TE, Tretyakov MV, 2017, Geometric integrator for Langevin systems with quaternion-based rotational degrees of freedom and hydrodynamic interactionsJ. Chem. Phys., 147:224103.
  3. Vijaykumar A, Ouldridge TE, ten Wolde PR, Bolhuis PG 2017, Multiscale simulations of anisotropic particles combining Brownian Dynamics and Green's Function Reaction DynamicsJournal of Chemical Physics: 146,114106.
  4. Davidchack RL, Ouldridge TE, Tretyakov MV, 2015, New Langevin and Gradient Thermostats for Rigid Body DynamicsJournal of Chemical Physics: 142,144114.
  5. Ouldridge TE, 2012, Inferring bulk self-assembly properties from simulations of small systems with multiple constituent species and small systems in the grand canonical ensembleJournal of Chemical Physics: 137,144105.
  6. Ouldridge TE, Louis AA, Doye JPK, 2010, Extracting bulk properties of self-assembling systems from small simulationsJournal of Physics: Condensed Matter: 22,104102.