77 results found
Ouldridge T, Hertel S, Spinney R, et al., 2022, The stability and number of nucleating interactions determine DNA hybridisation rates in the absence of secondary structure, Nucleic Acids Research, Vol: 50, Pages: 7829-7841, ISSN: 0305-1048
The kinetics of DNA hybridisation are fundamental to biological processes and DNA-based technologies.However, the precise physical mechanisms that determine why different DNA sequences hybridise at differentrates are not well understood. Secondary structure is one predictable factor that influences hybridisation ratesbut is not sufficient on its own to fully explain the observed sequence-dependent variance. In this context, wemeasured hybridisation rates of 43 different DNA sequences that are not predicted to form secondarystructure and present a parsimonious physically justified model to quantify our observations. Accounting onlyfor the combinatorics of complementary nucleating interactions and their sequence-dependent stability, themodel achieves good correlation with experiment with only two free parameters. Our results indicate thatgreater repetition of Watson-Crick pairs increases the number of initial states able to proceed to fullhybridisation, with the stability of those pairings dictating the likelihood of such progression, thus providingnew insight into the physical factors underpinning DNA hybridisation rates.
Ouldridge T, Doye J, Louis A, et al., 2022, Free energy landscapes of DNA and its assemblies: perspectives from coarse-grained modelling, Energy Landscapes of Nanoscale Systems, Publisher: Elsevier, Pages: 195-210, ISBN: 9780128244067
This chapter will provide an overview of how characterising free energy landscapes can provide insights into the biophysical properties of DNA, as well as into the behaviour of the DNA assemblies used in the field of DNA nanotechnology. The landscapes for these complex systems are accessible through the use of accurate coarse-grained descriptions of DNA. Particular foci will be the landscapes associated with DNA self-assembly and mechanical deformation, where the latter can arise from either externally imposed forces or internal stresses.
Ledesma Amaro R, Ouldridge T, O'Hare D, et al., 2022, Synthetic biology and bioelectrochemical tools for electrogenetic system engineering, Science Advances, Vol: 8, ISSN: 2375-2548
Synthetic biology research and its industrial applications rely on deterministic spatiotemporal control of gene expression. Recently, electrochemical control of gene expression has been demonstrated in electrogenetic systems (redox-responsive promoters used alongside redox inducers and electrodes), allowing for the direct integration of electronics with biological processes. However, use of electrogenetic systems is limited by poor activity, tunability and standardisation. In this work we developed a strong, unidirectional, redox-responsive promoter before deriving a mutant promoter library with a spectrum of strengths. We constructed genetic circuits with these parts and demonstrated their activation by multiple classes of redox molecules. Finally, we demonstrated electrochemical activation of gene expression in aerobic conditions using a novel, modular bioelectrochemical device. These genetic and electrochemical tools facilitate the design and improve the performance of electrogenetic systems. Furthermore, the genetic design strategies used can be applied to other redox-responsive promoters to further expand the available tools for electrogenetics.
Climent-Catala A, Ouldridge TE, Stan G-BV, et al., 2022, Building an RNA-based toggle switch using inhibitory RNA aptamers, ACS Synthetic Biology, Vol: 11, Pages: 562-569, ISSN: 2161-5063
Synthetic RNA systems offer unique advantages such as faster response, increased specificity, and programmability compared to conventional protein-based networks. Here, we demonstrate an in vitro RNA-based toggle switch using RNA aptamers capable of inhibiting the transcriptional activity of T7 or SP6 RNA polymerases. The activities of both polymerases are monitored simultaneously by using Broccoli and malachite green light-up aptamer systems. In our toggle switch, a T7 promoter drives the expression of SP6 inhibitory aptamers, and an SP6 promoter expresses T7 inhibitory aptamers. We show that the two distinct states originating from the mutual inhibition of aptamers can be toggled by adding DNA sequences to sequester the RNA inhibitory aptamers. Finally, we assessed our RNA-based toggle switch in degrading conditions by introducing controlled degradation of RNAs using a mix of RNases. Our results demonstrate that the RNA-based toggle switch could be used as a control element for nucleic acid networks in synthetic biology applications.
Juritz J, Poulton JM, Ouldridge TE, 2022, Minimal mechanism for cyclic templating of length-controlled copolymers under isothermal conditions, Journal of Chemical Physics, Vol: 156, ISSN: 0021-9606
The production of sequence-specific copolymers using copolymer templates is fundamental to the synthesis of complex biological molecules and is a promising framework for the synthesis of synthetic chemical complexes. Unlike the superficially similar process of self-assembly, however, the development of synthetic systems that implement templated copying of copolymers under constant environmental conditions has been challenging. The main difficulty has been overcoming product inhibition or the tendency of products to adhere strongly to their templates—an effect that gets exponentially stronger with the template length. We develop coarse-grained models of copolymerization on a finite-length template and analyze them through stochastic simulation. We use these models first to demonstrate that product inhibition prevents reliable template copying and then ask how this problem can be overcome to achieve cyclic production of polymer copies of the right length and sequence in an autonomous and chemically driven context. We find that a simple addition to the model is sufficient to generate far longer polymer products that initially form on, and then separate from, the template. In this approach, some of the free energy of polymerization is diverted into disrupting copy–template bonds behind the leading edge of the growing copy copolymer. By additionally weakening the final copy–template bond at the end of the template, the model predicts that reliable copying with a high yield of full-length, sequence-matched products is possible over large ranges of parameter space, opening the way to the engineering of synthetic copying systems that operate autonomously.
Liu H, Hong F, Smith F, et al., 2021, Kinetics of RNA and RNA:DNA hybrid strand displacement, ACS Synthetic Biology, Vol: 10, Pages: 3066-3073, ISSN: 2161-5063
In nucleic acid nanotechnology, strand displacement is a widely used mechanism where one strand from a hybridized duplex is exchanged with an invading strand that binds to a toehold, a single-stranded region on the duplex. It is used to perform logic operations on a molecular level, initiate cascaded reactions, or even for in vivo diagnostics and treatments. While systematic experimental studies have been carried out to probe the kinetics of strand displacement in DNA with different toehold lengths, sequences, and mismatch positions, there has not been a comparable investigation of RNA or RNA-DNA hybrid systems. Here, we experimentally study how toehold length, toehold location (5' or 3' end of the strand), and mismatches influence the strand displacement kinetics. We observe reaction acceleration with increasing toehold length and placement of the toehold at the 5' end of the substrate. We find that mismatches closer to the interface of toehold and duplex slow down the reaction more than remote mismatches. A comparison of RNA and DNA displacement with hybrid displacement (RNA invading DNA or DNA invading RNA) is partly explainable by the thermodynamic stabilities of the respective toehold regions, but also suggests that the rearrangement from B-form to A-form helix in the case of RNA invading DNA might play a role in the kinetics.
Poulton JM, Ouldridge TE, 2021, Edge-effects dominate copying thermodynamics for finite-length molecular oligomers, New Journal of Physics, Vol: 23, Pages: 1-14, ISSN: 1367-2630
A signature feature of living systems is their ability to produce copies ofinformation-carrying molecular templates such as DNA. These copies are madeby assembling a set of monomer molecules into a linear macromolecule with a sequence determined by the template. The copies produced have a finite length –they are often “oligomers”, or short polymers – and must eventually detach fromtheir template. We explore the role of the resultant initiation and termination ofthe copy process in the thermodynamics of copying. By splitting the free-energychange of copy formation into informational and chemical terms, we show that,surprisingly, copy accuracy plays no direct role in the overall thermodynamics. Instead, finite-length templates function as highly-selective engines that interconvertchemical and information-based free energy stored in the environment; it is thermodynamically costly to produce outputs that are more similar to the oligomersin the environment than sequences obtained by randomly sampling monomers. Incontrast to previous work that neglects separation, any excess free energy stored incorrelations between copy and template sequences is lost when the copy fully detaches and mixes with the environment; these correlations therefore do not featurein the overall thermodynamics. Previously-derived constraints on copy accuracytherefore only manifest as kinetic barriers experienced while the copy is templateattached; these barriers are easily surmounted by shorter oligomers.
Sengar A, Ouldridge TE, Henrich O, et al., 2021, A primer on the oxDNA model of DNA: When to use it, how to simulate it and how to interpret the results, Frontiers in Molecular Biosciences, Vol: 8, Pages: 1-22, ISSN: 2296-889X
The oxDNA model of DNA has been applied widely to systems in biology,biophysics and nanotechnology. It is currently available via two independentopen source packages. Here we present a set of clearly-documented exemplarsimulations that simultaneously provide both an introduction to simulating themodel, and a review of the model's fundamental properties. We outline howsimulation results can be interpreted in terms of -- and feed into ourunderstanding of -- less detailed models that operate at larger length scales,and provide guidance on whether simulating a system with oxDNA is worthwhile.
Plesa T, Stan G-B, Ouldridge TE, et al., 2021, Quasi-robust control of biochemical reaction networks via stochastic morphing., Journal of the Royal Society Interface, Vol: 18, Pages: 1-14, ISSN: 1742-5662
One of the main objectives of synthetic biology is the development of molecular controllers that can manipulate the dynamics of a given biochemical network that is at most partially known. When integrated into smaller compartments, such as living or synthetic cells, controllers have to be calibrated to factor in the intrinsic noise. In this context, biochemical controllers put forward in the literature have focused on manipulating the mean (first moment) and reducing the variance (second moment) of the target molecular species. However, many critical biochemical processes are realized via higher-order moments, particularly the number and configuration of the probability distribution modes (maxima). To bridge the gap, we put forward the stochastic morpher controller that can, under suitable timescale separations, morph the probability distribution of the target molecular species into a predefined form. The morphing can be performed at a lower-resolution, allowing one to achieve desired multi-modality/multi-stability, and at a higher-resolution, allowing one to achieve arbitrary probability distributions. Properties of the controller, such as robustness and convergence, are rigorously established, and demonstrated on various examples. Also proposed is a blueprint for an experimental implementation of stochastic morpher.
Cabello-Garcia J, Bae W, Stan G-BV, et al., 2021, Handhold-mediated strand displacement: a nucleic acid based mechanism for generating far-from-equilibrium assemblies through templated reactions., ACS Nano, Vol: 15, Pages: 3272-3283, ISSN: 1936-0851
The use of templates is a well-established method for the production of sequence-controlled assemblies, particularly long polymers. Templating is canonically envisioned as akin to a self-assembly process, wherein sequence-specific recognition interactions between a template and a pool of monomers favor the assembly of a particular polymer sequence at equilibrium. However, during the biogenesis of sequence-controlled polymers, template recognition interactions are transient; RNA and proteins detach spontaneously from their templates to perform their biological functions and allow template reuse. Breaking template recognition interactions puts the product sequence distribution far from equilibrium, since specific product formation can no longer rely on an equilibrium dominated by selective copy-template bonds. The rewards of engineering artificial polymer systems capable of spontaneously exhibiting nonequilibrium templating are large, but fields like DNA nanotechnology lack the requisite tools; the specificity and drive of conventional DNA reactions rely on product stability at equilibrium, sequestering any recognition interaction in products. The proposed alternative is handhold-mediated strand displacement (HMSD), a DNA-based reaction mechanism suited to producing out-of-equilibrium products. HMSD decouples the drive and specificity of the reaction by introducing a transient recognition interaction, the handhold. We measure the kinetics of 98 different HMSD systems to prove that handholds can accelerate displacement by 4 orders of magnitude without being sequestered in the final product. We then use HMSD to template the selective assembly of any one product DNA duplex from an ensemble of equally stable alternatives, generating a far-from-equilibrium output. HMSD thus brings DNA nanotechnology closer to the complexity of out-of-equilibrium biological systems.
Berengut J, Kui Wong C, Berengut J, et al., 2020, Self-limiting polymerization of DNA origami subunits with strain accumulation, ACS Nano, Vol: 14, Pages: 17428-17441, ISSN: 1936-0851
Biology demonstrates how a near infinite array of complex systems and structures at many scales can originate from the self-assembly of component parts on the nanoscale. But to fully exploit the benefits of self-assembly for nanotechnology, a crucial challenge remains: How do we rationally encode well-defined global architectures in subunits that are much smaller than their assemblies? Strain accumulation via geometric frustration is one mechanism that has been used to explain the self-assembly of global architectures in diverse and complex systems a posteriori. Here we take the next step and use strain accumulation as a rational design principle to control the length distributions of self-assembling polymers. We use the DNA origami method to design and synthesize a molecular subunit known as the PolyBrick, which perturbs its shape in response to local interactions via flexible allosteric blocking domains. These perturbations accumulate at the ends of polymers during growth, until the deformation becomes incompatible with further extension. We demonstrate that the key thermodynamic factors for controlling length distributions are the intersubunit binding free energy and the fundamental strain free energy, both which can be rationally encoded in a PolyBrick subunit. While passive polymerization yields geometrical distributions, which have the highest statistical length uncertainty for a given mean, the PolyBrick yields polymers that approach Gaussian length distributions whose variance is entirely determined by the strain free energy. We also show how strain accumulation can in principle yield length distributions that become tighter with increasing subunit affinity and approach distributions with uniform polymer lengths. Finally, coarse-grained molecular dynamics and Monte Carlo simulations delineate and quantify the dominant forces influencing strain accumulation in a molecular system. This study constitutes a fundamental investigation of the use of strain accumula
Ouldridge T, Stan G-B, Bae W, 2020, In situ generation of RNA complexes for synthetic molecular strand displacement circuits in autonomous systems, Nano Letters: a journal dedicated to nanoscience and nanotechnology, Vol: 21, Pages: 265-271, ISSN: 1530-6984
Synthetic molecular circuits implementing DNA or RNA strand-displacement reactions can be used to build complex systems such as molecular computers and feedback control systems. Despite recent advances, application of nucleic acid-based circuits in vivo remains challenging due to a lack of efficient methods to produce their essential components, namely, multistranded complexes known as gates, in situ, i.e., in living cells or other autonomous systems. Here, we propose the use of naturally occurring self-cleaving ribozymes to cut a single-stranded RNA transcript into a gate complex of shorter strands, thereby opening new possibilities for the autonomous and continuous production of RNA strands in a stoichiometrically and structurally controlled way.
Deshpande A, Ouldridge T, 2020, Optimizing enzymatic catalysts for rapid turnover of substrates with low enzyme sequestration, Biological Cybernetics: communication and control in organisms and automata, Vol: 114, Pages: 653-668, ISSN: 0340-1200
Enzymes are central to both metabolism and information processing in cells. In both cases, an enzyme’s ability to accelerate a reaction without being consumed in the reaction is crucial. Nevertheless, enzymes are transiently sequestered when they bind to their substrates; this sequestration limits activity and potentially compromises information processing and signal transduction. In this article, we analyse the mechanism of enzyme–substrate catalysis from the perspective of minimizing the load on the enzymes through sequestration, while maintaining at least a minimum reaction flux. In particular, we ask: which binding free energies of the enzyme–substrate and enzyme–product reaction intermediates minimize the fraction of enzymes sequestered in complexes, while sustaining a certain minimal flux? Under reasonable biophysical assumptions, we find that the optimal design will saturate the bound on the minimal flux and reflects a basic trade-off in catalytic operation. If both binding free energies are too high, there is low sequestration, but the effective progress of the reaction is hampered. If both binding free energies are too low, there is high sequestration, and the reaction flux may also be suppressed in extreme cases. The optimal binding free energies are therefore neither too high nor too low, but in fact moderate. Moreover, the optimal difference in substrate and product binding free energies, which contributes to the thermodynamic driving force of the reaction, is in general strongly constrained by the intrinsic free-energy difference between products and reactants. Both the strategies of using a negative binding free-energy difference to drive the catalyst-bound reaction forward and of using a positive binding free-energy difference to enhance detachment of the product are limited in their efficacy.
Lankinen A, Ruiz IM, Ouldridge TE, 2020, Implementing non-equilibrium networks with active circuits of duplex catalysts, 26th International Conference on DNA Computing and Molecular Programming (DNA 26), Publisher: Schloss Dagstuhl--Leibniz-Zentrum, Pages: 1-25
DNA strand displacement (DSD) reactions have been used to construct chemicalreaction networks in which species act catalytically at the level of theoverall stoichiometry of reactions. These effective catalytic reactions aretypically realised through one or more of the following: many-stranded gatecomplexes to coordinate the catalysis, indirect interaction between thecatalyst and its substrate, and the recovery of a distinct ``catalyst'' strandfrom the one that triggered the reaction. These facts make emulation of theout-of-equilibrium catalytic circuitry of living cells more difficult. Here, wepropose a new framework for constructing catalytic DSD networks: ActiveCircuits of Duplex Catalysts (ACDC). ACDC components are all double-strandedcomplexes, with reactions occurring through 4-way strand exchange. Catalystsdirectly bind to their substrates, and and the ``identity'' strand of thecatalyst recovered at the end of a reaction is the same molecule as the onethat initiated it. We analyse the capability of the framework to implementcatalytic circuits analogous to phosphorylation networks in living cells. Wealso propose two methods of systematically introducing mismatches within DNAstrands to avoid leak reactions and introduce driving through net base pairformation. We then combine these results into a compiler to automate theprocess of designing DNA strands that realise any catalytic network allowed byour framework.
Irmisch P, Ouldridge TE, Seidel R, 2020, Modelling DNA-strand displacement reactions in the presence of base-pair mismatches, Journal of the American Chemical Society, Vol: 142, Pages: 11451-11463, ISSN: 0002-7863
Toehold-mediated strand displacement is the most abundantly used method to achieve dynamic switching in DNA-based nanotechnology. An ‘invader’ strand binds to the ‘toehold’ overhang of a target strand and replaces a target-bound ’incumbent’ strand. Hereby, complementarity of the invader to the single-stranded toehold provides the energetic bias of the reaction. Despite the widespread use of strand displacement reactions for realizing dynamic DNA nanostructures, variants on the basic motif have not been completely characterized. Here we introduce a simple thermodynamic model, which is capable of quantitatively describing the kinetics of strand displacement reactions in the presence of mismatches, using a minimal set of parameters. Furthermore, our model highlights that base pair fraying and internal loop formation are important mechanisms when involving mismatches in the displacement process. Our model should provide a helpful tool for the rational design of strand-displacement reaction networks.
Ouldridge T, Turberfield A, Mullor Ruiz I, et al., 2020, Design of hidden thermodynamic driving for non-equilibrium systems via mismatch elimination during DNA strand displacement, Nature Communications, Vol: 11, ISSN: 2041-1723
Recent years have seen great advances in the development of synthetic self-assembling molecular systems. Designing out-of-equilibrium architectures, however, requires a more subtle control over the thermodynamics and kinetics of reactions. We propose a mechanism for enhancing the thermodynamic drive of DNA strand-displacement reactions whilst barely perturbing forward reaction rates: the introduction of mismatches within the initial duplex. Through a combination of experiment and simulation, we demonstrate that displacement rates are strongly sensitive to mismatch location and can be tuned by rational design. By placing mismatches away from duplex ends, the thermodynamic drive for a strand-displacement reaction can be varied without significantly affecting the forward reaction rate. This hidden thermodynamic driving motif is ideal for the engineering of non-equilibrium systems that rely on catalytic control and must be robust to leak reactions.
Harrison RM, Romano F, Ouldridge TE, et al., 2019, Identifying physical causes of apparent enhanced cyclization of short DNA molecules with a coarse-grained model, Journal of Chemical Theory and Computation, Vol: 15, Pages: 4660-4672, ISSN: 1549-9618
DNA cyclization is a powerful technique to gain insight into the nature of DNA bending. While the worm-like chain model provides a good description of small to moderate bending fluctuations, it is expected to break down for large bending. Recent cyclization experiments on strongly-bent shorter molecules indeed suggest enhanced flexibility over and above that expected from the worm-like chain. Here, we use a coarse-grained model of DNA to investigate the subtle thermodynamics of DNA cyclization for molecules ranging from 30 to 210 base pairs. As the molecules get shorter we find increasing deviations between our computed equilibrium j-factor and the classic worm-like chain predictions of Shimada and Yamakawa for a torsionally aligned looped molecule. These deviations are due to sharp kinking, first at nicks, and only subsequently in the body of the duplex. At the shortest lengths, substantial fraying at the ends of duplex domains is the dominant method of relaxation. We also estimate the dynamic j-factor measured in recent FRET experiments. We find that the dynamic j-factor is systematically larger than its equilibrium counterpart - with the deviation larger for shorter molecules - because not all the stress present in the fully cyclized state is present in the transition state. These observations are important for the interpretation of recent cyclization experiments, suggesting that measured anomalously high j-factors may not necessarily indicate non-WLC behavior in the body of duplexes.
Brittain R, Jones N, Ouldridge T, 2019, Biochemical Szilard engines for memory-limited inference, New Journal of Physics, Vol: 21, ISSN: 1367-2630
By designing and leveraging an explicit molecular realisation of a measurement-and-feedback-powered Szilard engine, we investigate the extraction of work from complex environments by minimal machines with finite capacity for memory and decision-making. Living systems perform inference to exploit complex structure, or correlations, in their environment, but the physical limits and underlying cost/benefit trade-offs involved in doing so remain unclear. To probe these questions, we consider a minimal model for a structured environment—a correlated sequence of molecules—and explore mechanisms based on extended Szilard engines for extracting the work stored in these non-equilibrium correlations. We consider systems limited to a single bit of memory making binary 'choices' at each step. We demonstrate that increasingly complex environments allow increasingly sophisticated inference strategies to extract more free energy than simpler alternatives, and argue that optimal design of such machines should also consider the free energy reserves required to ensure robustness against fluctuations due to mistakes.
Quast N, Ouldridge T, 2019, Simulation of DNA tile self-assembly
Submitted in accompaniment with final year report of MEng Project. DNA tile self-assembly is the spontaneous assembly of nano-structures made from short single-stranded DNA sequences. Successful assembly occurs within a narrow parameter window. Thisproject presents a model with which DNA self-assembly is simulated. Simulations for different tem-perature, sequence binding specificity and DNA tile concentrations indicate that: the growth rateof assemblies from uniform strand solutions is linear and highly temperature dependent; the aver-age nucleation times of assembly increase exponentially with temperature; high binding strengthsof boundary strands improve the stability of the complete assembly; locally high concentrations ofstrands seed the growth of the assembly; and locally low strand concentrations spatially direct thegrowth of the assembly. The source code is written in C.
Stopnitzky E, Still S, Ouldridge TE, et al., 2019, Physical limitations of work extraction from temporal correlations., Physical Review E, Vol: 99, ISSN: 1539-3755
Recently proposed information-exploiting systems extract work from a single heat bath by using temporal correlations on an input tape. We study how enforcing time-continuous dynamics, which is necessary to ensure that the device is physically realizable, constrains possible designs and drastically diminishes efficiency. We show that these problems can be circumvented by means of applying an external, time-varying protocol, which turns the device from a "passive," free-running machine into an "actively" driven one.
Poulton J, Wolde PRT, Ouldridge TE, 2019, Non-equilibrium correlations in minimal dynamical models of polymer copying, Proceedings of the National Academy of Sciences, Vol: 116, Pages: 1946-1951, ISSN: 0027-8424
Living systems produce "persistent" copies of information-carrying polymers, in which template and copy sequences remain correlated after physically decoupling. We identify a general measure of the thermodynamic efficiency with which these non-equilibrium states are created, and analyze the accuracy and efficiency of a family of dynamical models that produce persistent copies. For the weakest chemical driving, when polymer growth occurs in equilibrium, both the copy accuracy and, more surprisingly, the efficiency vanish. At higher driving strengths, accuracy and efficiency both increase, with efficiency showing one or more peaks at moderate driving. Correlations generated within the copy sequence, as well as between template and copy, store additional free energy in the copied polymer and limit the single-site accuracy for a given chemical work input. Our results provide insight in the design of natural self-replicating systems and can aid the design of synthetic replicators.
Lawrence J, Chang S, Rodriguez LC, et al., 2019, Students go through the gears at the iGEM competition for engineering biology, Biochemist, Vol: 41, Pages: 58-61, ISSN: 0954-982X
The annual International Genetically Engineered Machine (iGEM) competition, represents an exciting opportunity for students to experience first-hand the potential of synthetic biology approaches to solve real-world problems. In this article, an iGEM team based at Imperial College London share some of the highlights from their participation in the 2018 iGEM event, including sharing their work at the annual Jamboree in Boston, Massachusetts.
Stopnitzky E, Still S, Ouldridge TE, et al., 2018, Physical Limitations of Work Extraction from Temporal Correlations, The Interplay of Thermodynamics and Computation in Both Natural and Artificial Systems, Publisher: SFI Press
Ouldridge TE, Brittain R, ten Wolde PR, 2018, The power of being explicit: demystifying work, heat, and free energy in the physics of computation, The Interplay of Thermodynamics and Computation in Both Natural and Artificial Systems
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.
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