Publications
75 results found
Brittain R, Jones N, Ouldridge T, 2018, Biochemical Szilard engine for memory limited inference
Code and data for figures in 'Biochemical Szilard engine for memory limited inference'
Henrich O, Gutiérrez Fosado YA, Curk T, et al., 2018, Coarse-grained simulation of DNA using LAMMPS : an implementation of the oxDNA model and its applications, European Physical Journal E. Soft Matter, Vol: 41, Pages: 57-57, ISSN: 1292-8941
During the last decade coarse-grained nucleotide models have emerged that allow us to study DNA and RNA on unprecedented time and length scales. Among them is oxDNA, a coarse-grained, sequence-specific model that captures the hybridisation transition of DNA and many structural properties of single- and double-stranded DNA. oxDNA was previously only available as standalone software, but has now been implemented into the popular LAMMPS molecular dynamics code. This article describes the new implementation and analyses its parallel performance. Practical applications are presented that focus on single-stranded DNA, an area of research which has been so far under-investigated. The LAMMPS implementation of oxDNA lowers the entry barrier for using the oxDNA model significantly, facilitates future code development and interfacing with existing LAMMPS functionality as well as other coarse-grained and atomistic DNA models.
Fonseca P, Romano F, Schreck JS, et al., 2018, Multi-scale coarse-graining for the study of assembly pathways in DNA-brick self assembly, Journal of Chemical Physics, Vol: 148, ISSN: 0021-9606
Inspired by recent successes using single-stranded DNA tiles to producecomplex structures, we develop a two-step coarse-graining approach that usesdetailed thermodynamic calculations with oxDNA, a nucleotide-based model ofDNA, to parametrize a coarser kinetic model that can reach the time and lengthscales needed to study the assembly mechanisms of these structures. We test themodel by performing a detailed study of the assembly pathways for atwo-dimensional target structure made up of 334 unique strands each of whichare 42 nucleotides long. Without adjustable parameters, the model reproduces acritical temperature for the formation of the assembly that is close to thetemperature at which assembly first occurs in experiments. Furthermore, themodel allows us to investigate in detail the nucleation barriers and thedistribution of critical nucleus shapes for the assembly of a single targetstructure. The assembly intermediates are compact and highly connected(although not maximally so) and classical nucleation theory provides a good fitto the height and shape of the nucleation barrier at temperatures close towhere assembly first occurs.
Khara DC, Schreck JS, Tomov TE, et al., 2017, DNA bipedal motor walking dynamics: an experimental and theoretical study of the dependency on step size, Nucleic Acids Research, Vol: 46, Pages: 1553-1561, ISSN: 0305-1048
We present a detailed coarse-grained computer simulation and single molecule fluorescence study of the walking dynamics and mechanism of a DNA bipedal motor striding on a DNA origami. In particular, we study the dependency of the walking efficiency and stepping kinetics on step size. The simulations accurately capture and explain three different experimental observations. These include a description of the maximum possible step size, a decrease in the walking efficiency over short distances and a dependency of the efficiency on the walking direction with respect to the origami track. The former two observations were not expected and are non-trivial. Based on this study, we suggest three design modifications to improve future DNA walkers. Our study demonstrates the ability of the oxDNA model to resolve the dynamics of complex DNA machines, and its usefulness as an engineering tool for the design of DNA machines that operate in the three spatial dimensions.
Davidchack RL, Ouldridge TE, Tretyakov MV, 2017, Geometric integrator for Langevin systems with quaternion-based rotational degrees of freedom and hydrodynamic interactions, Journal of Chemical Physics, Vol: 147, ISSN: 0021-9606
We introduce new Langevin-type equations describing the rotational andtranslational motion of rigid bodies interacting through conservative andnon-conservative forces, and hydrodynamic coupling. In the absence ofnon-conservative forces the Langevin-type equations sample from the canonicalensemble. The rotational degrees of freedom are described using quaternions,the lengths of which are exactly preserved by the stochastic dynamics. For theproposed Langevin-type equations, we construct a weak 2nd order geometricintegrator which preserves the main geometric features of the continuousdynamics. A number of numerical experiments are presented to illustrate boththe new Langevin model and the numerical method for it.
Ouldridge TE, 2017, The importance of thermodynamics for molecular systems, and the importance of molecular systems for thermodynamics, Natural Computing, Vol: 17, Pages: 3-29, ISSN: 1567-7818
Improved understanding of molecular systems has only emphasised thesophistication of networks within the cell. Simultaneously, the advance ofnucleic acid nanotechnology, a platform within which reactions can beexquisitely controlled, has made the development of artificial architecturesand devices possible. Vital to this progress has been a solid foundation in thethermodynamics of molecular systems. In this pedagogical review andperspective, I will discuss how thermodynamics determines both the overallpotential of molecular networks, and the minute details of design. I will thenargue that, in turn, the need to understand molecular systems is helping todrive the development of theories of thermodynamics at the microscopic scale.
Deshpande A, Ouldridge TE, 2017, High rates of fuel consumption are not required by insulating motifs to suppress retroactivity in biochemical circuits, Engineering Biology, Vol: 1, Pages: 86-99, ISSN: 2398-6182
Retroactivity arises when the coupling of a molecular network $\mathcal{U}$to a downstream network $\mathcal{D}$ results in signal propagation back from$\mathcal{D}$ to $\mathcal{U}$. The phenomenon represents a breakdown inmodularity of biochemical circuits and hampers the rational design of complexfunctional networks. Considering simple models of signal-transductionarchitectures, we demonstrate the strong dependence of retroactivity on theproperties of the upstream system, and explore the cost and efficacy offuel-consuming insulating motifs that can mitigate retroactive effects. We findthat simple insulating motifs can suppress retroactivity at a low fuel cost bycoupling only weakly to the upstream system $\mathcal{U}$. However, this designapproach reduces the signalling network's robustness to perturbations from leakreactions, and potentially compromises its ability to respond torapidly-varying signals.
Poole W, Ortiz-Muñoz A, Behera A, et al., 2017, Chemical Boltzmann Machines, Lecture Notes in Computer Science, Vol: 10467, Pages: 210-231, ISSN: 0302-9743
How smart can a micron-sized bag of chemicals be? How can an artificial orreal cell make inferences about its environment? From which kinds ofprobability distributions can chemical reaction networks sample? We begintackling these questions by showing four ways in which a stochastic chemicalreaction network can implement a Boltzmann machine, a stochastic neural networkmodel that can generate a wide range of probability distributions and computeconditional probabilities. The resulting models, and the associated theorems,provide a road map for constructing chemical reaction networks that exploittheir native stochasticity as a computational resource. Finally, to show thepotential of our models, we simulate a chemical Boltzmann machine to classifyand generate MNIST digits in-silico.
Deshpande A, Gopalkrishnan M, Ouldridge TE, et al., 2017, Designing the Optimal Bit: Balancing Energetic Cost, Speed and Reliability, Proceedings of the Royal Society A: Mathematical, Physical & Engineering Sciences, Vol: 473, ISSN: 1364-5021
We consider the technologically relevant costs of operating a reliable bitthat can be erased rapidly. We find that both erasing and reliability times arenon-monotonic in the underlying friction, leading to a trade-off betweenerasing speed and bit reliability. Fast erasure is possible at the expense oflow reliability at moderate friction, and high reliability comes at the expenseof slow erasure in the underdamped and overdamped limits. Within a given classof bit parameters and control strategies, we define "optimal" designs of bitsthat meet the desired reliability and erasing time requirements with the lowestoperational work cost. We find that optimal designs always saturate the boundon the erasing time requirement, but can exceed the required reliability timeif critically damped. The non-trivial geometry of the reliability and erasingtime-scales allows us to exclude large regions of parameter space assub-optimal. We find that optimal designs are either critically damped or closeto critical damping under the erasing procedure.
Brittain RA, Jones NS, Ouldridge TE, 2017, What we learn from the learning rate, Journal of Statistical Mechanics-Theory and Experiment, Vol: 2017, ISSN: 1742-5468
The learning rate is an information-theoretical quantity for bipartite Markovchains describing two coupled subsystems. It is defined as the rate at whichtransitions in the downstream subsystem tend to increase the mutual informationbetween the two subsystems, and is bounded by the dissipation arising fromthese transitions. Its physical interpretation, however, is unclear, althoughit has been used as a metric for the sensing performance of the downstreamsubsystem. In this paper we explore the behaviour of the learning rate for anumber of simple model systems, establishing when and how its behaviour isdistinct from the instantaneous mutual information between subsystems. In thesimplest case, the two are almost equivalent. In more complex steady-statesystems, the mutual information and the learning rate behave qualitativelydistinctly, with the learning rate clearly now reflecting the rate at which thedownstream system must update its information in response to changes in theupstream system. It is not clear whether this quantity is the most naturalmeasure for sensor performance, and, indeed, we provide an example in whichoptimising the learning rate over a region of parameter space of the downstreamsystem yields an apparently sub-optimal sensor.
Ouldridge TE, ten Wolde PR, 2017, Fundamental Costs in the production and destruction of persistent polymer copies, Physical Review Letters, Vol: 118, ISSN: 0031-9007
Producing a polymer copy of a polymer template is central to biology, and effective copies must persist after template separation. We show that this separation has three fundamental thermodynamic effects. First, polymer-template interactions do not contribute to overall reaction thermodynamics and hence cannot drive the process. Second, the equilibrium state of the copied polymer is template independent and so additional work is required to provide specificity. Finally, the mixing of copies from distinct templates makes correlations between template and copy sequences unexploitable, combining with copying inaccuracy to reduce the free energy stored in a polymer ensemble. These basic principles set limits on the underlying costs and resource requirements, and suggest design principles, for autonomous copying and replication in biological and synthetic systems.
Ouldridge TE, Govern CC, Wolde PRT, 2017, Thermodynamics of computational copying in biochemical systems, Physical Review X, Vol: 7, ISSN: 2160-3308
Living cells use readout molecules to record the state of receptor proteins, similar to measurements or copies in typical computational devices. But is this analogy rigorous? Can cells be optimally efficient, and if not, why? We show that, as in computation, a canonical biochemical readout network generates correlations; extracting no work from these correlations sets a lower bound on dissipation. For general input, the biochemical network cannot reach this bound, even with arbitrarily slow reactions or weak thermodynamic driving. It faces an accuracy-dissipation trade-off that is qualitatively distinct from and worse than implied by the bound, and more complex steady-state copy processes cannot perform better. Nonetheless, the cost remains close to the thermodynamic bound unless accuracy is extremely high. Additionally, we show that biomolecular reactions could be used in thermodynamically optimal devices under exogenous manipulation of chemical fuels, suggesting an experimental system for testing computational thermodynamics.
Vijaykumar A, Ouldridge TE, ten Wolde PR, et al., 2017, Multiscale simulations of anisotropic particles combining molecular dynamics and Green's function reaction dynamics, Journal of Chemical Physics, Vol: 146, ISSN: 1089-7690
The modeling of complex reaction-diffusion processes in, for instance, cellular biochemical networks or self-assembling soft matter can be tremendously sped up by employing a multiscale algorithm which combines the mesoscopic Green’s Function Reaction Dynamics (GFRD) method with explicit stochastic Brownian, Langevin, or deterministic molecular dynamics to treat reactants at the microscopic scale [A. Vijaykumar, P. G. Bolhuis, and P. R. ten Wolde, J. Chem. Phys. 143, 214102 (2015)]. Here we extend this multiscale MD-GFRD approach to include the orientational dynamics that is crucial to describe the anisotropic interactions often prevalent in biomolecular systems. We present the novel algorithm focusing on Brownian dynamics only, although the methodology is generic. We illustrate the novel algorithm using a simple patchy particle model. After validation of the algorithm, we discuss its performance. The rotational Brownian dynamics MD-GFRD multiscale method will open up the possibility for large scale simulations of protein signalling networks.
McGrath T, Jones NS, Wolde PRT, et al., 2017, A biochemical machine for the interconversion of mutual information and work, Physical Review Letters, Vol: 118, ISSN: 0031-9007
We propose a physically-realisable biochemical device that is coupled to abiochemical reservoir of mutual information, fuel molecules and a chemicalbath. Mutual information allows work to be done on the bath even when the fuelmolecules appear to be in equilibrium; alternatively, mutual information can becreated by driving from the fuel or the bath. The system exhibits diversebehaviour, including a regime in which the information, despite increasingduring the reaction, enhances the extracted work. We further demonstrate that amodified device can function without the need for external manipulation,eliminating the need for a complex and potentially costly control.
ten Wolde PR, Becker NB, Ouldridge TE, et al., 2016, Fundamental Limits to Cellular Sensing, Journal of Statistical Physics, Vol: 162, Pages: 1395-1424, ISSN: 1572-9613
In recent years experiments have demonstrated that living cells can measure low chemical concentrations with high precision, and much progress has been made in understanding what sets the fundamental limit to the precision of chemical sensing. Chemical concentration measurements start with the binding of ligand molecules to receptor proteins, which is an inherently noisy process, especially at low concentrations. The signaling networks that transmit the information on the ligand concentration from the receptors into the cell have to filter this receptor input noise as much as possible. These networks, however, are also intrinsically stochastic in nature, which means that they will also add noise to the transmitted signal. In this review, we will first discuss how the diffusive transport and binding of ligand to the receptor sets the receptor correlation time, which is the timescale over which fluctuations in the state of the receptor, arising from the stochastic receptor-ligand binding, decay. We then describe how downstream signaling pathways integrate these receptor-state fluctuations, and how the number of receptors, the receptor correlation time, and the effective integration time set by the downstream network, together impose a fundamental limit on the precision of sensing. We then discuss how cells can remove the receptor input noise while simultaneously suppressing the intrinsic noise in the signaling network. We describe why this mechanism of time integration requires three classes (groups) of resources—receptors and their integration time, readout molecules, energy—and how each resource class sets a fundamental sensing limit. We also briefly discuss the scheme of maximum-likelihood estimation, the role of receptor cooperativity, and how cellular copy protocols differ from canonical copy protocols typically considered in the computational literature, explaining why cellular sensing systems can never reach the Landauer limit on the optimal trade-o
Snodin BE, Romano F, Rovigatti L, et al., 2016, Direct Simulation of the Self-Assembly of a Small DNA Origami., ACS Nano, Vol: 10, Pages: 1724-1737, ISSN: 1936-086X
By using oxDNA, a coarse-grained nucleotide-level model of DNA, we are able to directly simulate the self-assembly of a small 384-base-pair origami from single-stranded scaffold and staple strands in solution. In general, we see attachment of new staple strands occurring in parallel, but with cooperativity evident for the binding of the second domain of a staple if the adjacent junction is already partially formed. For a system with exactly one copy of each staple strand, we observe a complete assembly pathway in an intermediate temperature window; at low temperatures successful assembly is prevented by misbonding while at higher temperature the free-energy barriers to assembly become too large for assembly on our simulation time scales. For high-concentration systems involving a large staple strand excess, we never see complete assembly because there are invariably instances where copies of the same staple both bind to the scaffold, creating a kinetic trap that prevents the complete binding of either staple. This mutual staple blocking could also lead to aggregates of partially formed origamis in real systems, and helps to rationalize certain successful origami design strategies.
Ouldridge TE, Schreck JS, Romano F, et al., 2016, Precision control of DNA-based molecular reactions
Mosayebi M, Louis AA, Doye JPK, et al., 2015, Force-Induced Rupture of a DNA Duplex: From Fundamentals to Force Sensors, ACS Nano, Vol: 9, Pages: 11993-12003, ISSN: 1936-086X
The rupture of double-stranded DNA under stress is a key process in biophysicsand nanotechnology. In this article, we consider the shear-induced rupture of short DNAduplexes, a system that has been given new importance by recently designed force sensorsand nanotechnological devices. We argue that rupture must be understood as an activatedprocess, where the duplex state is metastable and the strands will separate in a finite timethat depends on the duplex length and the force applied. Thus, the critical shearing forcerequired to rupture a duplex depends strongly on the time scale of observation. We use simplemodels of DNA to show that this approach naturally captures the observed dependence ofthe force required to rupture a duplex within a given time on duplex length. In particular, thiscritical force is zero for the shortest duplexes, before rising sharply and then plateauing in thelong length limit. The prevailing approach, based on identifying when the presence of eachadditional base pair within the duplex is thermodynamically unfavorable rather than allowing for metastability, does not predict a time-scale-dependentcritical force and does not naturally incorporate a critical force of zero for the shortest duplexes. We demonstrate that our findings have importantconsequences for the behavior of a new force-sensing nanodevice, which operates in a mixed mode that interpolates between shearing and unzipping.At a fixed time scale and duplex length, the critical force exhibits a sigmoidal dependence on the fraction of the duplex that is subject to shearing.
Dannenberg F, Dunn KE, Bath J, et al., 2015, Modelling DNA origami self-assembly at the domain level, JOURNAL OF CHEMICAL PHYSICS, Vol: 143, ISSN: 0021-9606
Dunn KE, Dannenberg F, Ouldridge TE, et al., 2015, Guiding the folding pathway of DNA origami, Nature, Vol: 525, Pages: 82-86, ISSN: 0028-0836
DNA origami is a robust assembly technique that folds a single-stranded DNA template into a target structure by annealing it with hundreds of short 'staple' strands. Its guiding design principle is that the target structure is the single most stable configuration. The folding transition is cooperative and, as in the case of proteins, is governed by information encoded in the polymer sequence. A typical origami folds primarily into the desired shape, but misfolded structures can kinetically trap the system and reduce the yield. Although adjusting assembly conditions or following empirical design rules can improve yield, well-folded origami often need to be separated from misfolded structures. The problem could in principle be avoided if assembly pathway and kinetics were fully understood and then rationally optimized. To this end, here we present a DNA origami system with the unusual property of being able to form a small set of distinguishable and well-folded shapes that represent discrete and approximately degenerate energy minima in a vast folding landscape, thus allowing us to probe the assembly process. The obtained high yield of well-folded origami structures confirms the existence of efficient folding pathways, while the shape distribution provides information about individual trajectories through the folding landscape. We find that, similarly to protein folding, the assembly of DNA origami is highly cooperative; that reversible bond formation is important in recovering from transient misfoldings; and that the early formation of long-range connections can very effectively enforce particular folds. We use these insights to inform the design of the system so as to steer assembly towards desired structures. Expanding the rational design process to include the assembly pathway should thus enable more reproducible synthesis, particularly when targeting more complex structures. We anticipate that this expansion will be essential if DNA origami is to continue its rap
Snodin BEK, Randisi F, Mosayebi M, et al., 2015, Introducing improved structural properties and salt dependence into a coarse-grained model of DNA, Journal of Chemical Physics, Vol: 142, ISSN: 1089-7690
Schreck JS, Ouldridge TE, Romano F, et al., 2015, DNA hairpins destabilize duplexes primarily by promoting melting rather than by inhibiting hybridization., Nucleic Acids Research, Vol: 43, Pages: 6181-6190, ISSN: 1362-4962
The effect of secondary structure on DNA duplex formation is poorly understood. Using oxDNA, a nucleotide level coarse-grained model of DNA, we study how hairpins influence the rate and reaction pathways of DNA hybridzation. We compare to experimental systems studied by Gao et al. (1) and find that 3-base pair hairpins reduce the hybridization rate by a factor of 2, and 4-base pair hairpins by a factor of 10, compared to DNA with limited secondary structure, which is in good agreement with experiments. By contrast, melting rates are accelerated by factors of ∼100 and ∼2000. This surprisingly large speed-up occurs because hairpins form during the melting process, and significantly lower the free energy barrier for dissociation. These results should assist experimentalists in designing sequences to be used in DNA nanotechnology, by putting limits on the suppression of hybridization reaction rates through the use of hairpins and offering the possibility of deliberately increasing dissociation rates by incorporating hairpins into single strands.
Davidchack RL, Ouldridge TE, Tretyakov MV, 2015, New Langevin and gradient thermostats for rigid body dynamics, Journal of Chemical Physics, Vol: 142, ISSN: 1089-7690
Sulc P, Ouldridge TE, Romano F, et al., 2015, Modelling Toehold-Mediated RNA Strand Displacement, BIOPHYSICAL JOURNAL, Vol: 108, Pages: 1238-1247, ISSN: 0006-3495
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- Citations: 43
Matek C, Ouldridge TE, Doye JPK, et al., 2015, Plectoneme tip bubbles: Coupled denaturation and writhing in supercoiled DNA, SCIENTIFIC REPORTS, Vol: 5, ISSN: 2045-2322
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- Citations: 60
Schreck JS, Ouldridge TE, Romano F, et al., 2015, Characterizing the bending and flexibility induced by bulges in DNA duplexes, Journal of Chemical Physics, Vol: 142, ISSN: 1089-7690
© 2015 AIP Publishing LLC. Advances in DNA nanotechnology have stimulated the search for simple motifs that can be used to control the properties of DNA nanostructures. One such motif, which has been used extensively in structures such as polyhedral cages, two-dimensional arrays, and ribbons, is a bulged duplex, that is, two helical segments that connect at a bulge loop. We use a coarse-grained model of DNA to characterize such bulged duplexes. We find that this motif can adopt structures belonging to two main classes: one where the stacking of the helices at the center of the system is preserved, the geometry is roughly straight, and the bulge is on one side of the duplex and the other where the stacking at the center is broken, thus allowing this junction to act as a hinge and increasing flexibility. Small loops favor states where stacking at the center of the duplex is preserved, with loop bases either flipped out or incorporated into the duplex. Duplexes with longer loops show more of a tendency to unstack at the bulge and adopt an open structure. The unstacking probability, however, is highest for loops of intermediate lengths, when the rigidity of single-stranded DNA is significant and the loop resists compression. The properties of this basic structural motif clearly correlate with the structural behavior of certain nano-scale objects, where the enhanced flexibility associated with larger bulges has been used to tune the self-assembly product as well as the detailed geometry of the resulting nanostructures. We further demonstrate the role of bulges in determining the structure of a "Z-tile," a basic building block for nanostructures.
Mosayebi M, Romano F, Ouldridge TE, et al., 2014, The Role of Loop Stacking in the Dynamics of DNA Hairpin Formation, JOURNAL OF PHYSICAL CHEMISTRY B, Vol: 118, Pages: 14326-14335, ISSN: 1520-6106
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- Citations: 23
Ouldridge TE, ten Wolde PR, 2014, The Robustness of Proofreading to Crowding-Induced Pseudo-Processivity in the MAPK Pathway, BIOPHYSICAL JOURNAL, Vol: 107, Pages: 2425-2435, ISSN: 0006-3495
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- Citations: 12
Machinek RRF, Ouldridge TE, Haley NEC, et al., 2014, Programmable energy landscapes for kinetic control of DNA strand displacement, Nature Communications, Vol: 5, Pages: 1-9, ISSN: 2041-1723
DNA is used to construct synthetic systems that sense, actuate, move and compute. The operation of many dynamic DNA devices depends on toehold-mediated strand displacement, by which one DNA strand displaces another from a duplex. Kinetic control of strand displacement is particularly important in autonomous molecular machinery and molecular computation, in which non-equilibrium systems are controlled through rates of competing processes. Here, we introduce a new method based on the creation of mismatched base pairs as kinetic barriers to strand displacement. Reaction rate constants can be tuned across three orders of magnitude by altering the position of such a defect without significantly changing the stabilities of reactants or products. By modelling reaction free-energy landscapes, we explore the mechanistic basis of this control mechanism. We also demonstrate that oxDNA, a coarse-grained model of DNA, is capable of accurately predicting and explaining the impact of mismatches on displacement kinetics.
Ouldridge TE, 2014, DNA nanotechnology: understanding and optimisation through simulation, Molecular Physics, Vol: 113, Pages: 1-15, ISSN: 0026-8976
DNA nanotechnology promises to provide controllable self-assembly on the nanoscale, allowing for the design of static structures, dynamic machines and computational architectures. In this article, I review the state-of-the art of DNA nanotechnology, highlighting the need for a more detailed understanding of the key processes, both in terms of theoretical modelling and experimental characterisation. I then consider coarse-grained models of DNA, mesoscale descriptions that have the potential to provide great insight into the operation of DNA nanotechnology if they are well designed. In particular, I discuss a number of nanotechnological systems that have been studied with oxDNA, a recently developed coarse-grained model, highlighting the subtle interplay of kinetic, thermodynamic and mechanical factors that can determine behaviour. Finally, new results highlighting the importance of mechanical tension in the operation of a two-footed walker are presented, demonstrating that recovery from an unintended ‘overstepped’ configuration can be accelerated by three to four orders of magnitude by application of a moderate tension to the walker's track. More generally, the walker illustrates the possibility of biasing strand-displacement processes to affect the overall rate.
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