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1. Geometric Enumeration of Localized DNA Strand Displacement Reaction Networks

   https://doi.org/10.4230/LIPIcs.DNA.30.1  

   Lakin, Matthew R; Kumar, Sarika (January 2024, Schloss Dagstuhl – Leibniz-Zentrum für Informatik)

   Seki, Shinnosuke; Stewart, Jaimie Marie (Ed.)

   Localized molecular devices are a powerful tool for engineering complex information-processing circuits and molecular robots. Their practical advantages include speed and scalability of interactions between components tethered near to each other on an underlying nanostructure, and the ability to restrict interactions between more distant components. The latter is a critical feature that must be factored into computational tools for the design and simulation of localized molecular devices: unlike in solution-phase systems, the geometries of molecular interactions must be accounted for when attempting to determine the network of possible reactions in a tethered molecular system. This work aims to address that challenge by integrating, for the first time, automated approaches to analysis of molecular geometry with reaction enumeration algorithms for DNA strand displacement reaction networks that can be applied to tethered molecular systems. By adapting a simple approach to solving the biophysical constraints inherent in molecular interactions to be applicable to tethered systems, we produce a localized reaction enumeration system that enhances previous approaches to reaction enumeration in tethered system by not requiring users to explicitly specify the subsets of components that are capable of interacting. This greatly simplifies the user’s task and could also be used as the basis of future systems for automated placement or routing of signal-transmission and logical processing in molecular devices. We apply this system to several published example systems from the literature, including both tethered molecular logic systems and molecular robots. 

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2. A geometric framework for reaction enumeration in computational nucleic acid devices

   https://doi.org/10.1098/rsif.2023.0259  

   Kumar, Sarika; Lakin, Matthew R (November 2023, Journal of The Royal Society Interface)

   Cascades of DNA strand displacement reactions enable the design of potentially large circuits with complex behaviour. Computational modelling of such systems is desirable to enable rapid design and analysis. In previous work, the expressive power of graph theory was used to enumerate reactions implementing strand displacement across a wide range of complex structures. However, coping with the rich variety of possible graph-based structures required enumeration rules with complicated side-conditions. This paper presents an alternative approach to tackle the problem of enumerating reactions at domain level involving complex structures by integrating with a geometric constraint solving algorithm. The rule sets from previous work are simplified by replacing side-conditions with a general check on the geometric plausibility of structures generated by the enumeration algorithm. This produces a highly general geometric framework for reaction enumeration. Here, we instantiate this framework to solve geometric constraints by a structure sampling approach in which we randomly generate sets of coordinates and check whether they satisfy all the constraints. We demonstrate this system by applying it to examples from the literature where molecular geometry plays an important role, including DNA hairpin and remote toehold reactions. This work therefore enables integration of reaction enumeration and structural modelling. 

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3. Renewable Time‐Responsive DNA Circuits

   https://doi.org/10.1002/smll.201801470  

   Garg, Sudhanshu; Shah, Shalin; Bui, Hieu; Song, Tianqi; Mokhtar, Reem; Reif, John (July 2018, Small)

   Abstract DNA devices have been shown to be capable of evaluating Boolean logic. Several robust designs for DNA circuits have been demonstrated. Some prior DNA‐based circuits are use‐once circuits since the gate motifs of the DNA circuits get permanently destroyed as a side effect of the computation, and hence cannot respond correctly to subsequent changes in inputs. Other DNA‐based circuits use a large reservoir of buffered gates to replace the working gates of the circuit and can be used to drive a finite number of computation cycles. In many applications of DNA circuits, the inputs are inherently asynchronous, and this necessitates that the DNA circuits be asynchronous: the output must always be correct regardless of differences in the arrival time of inputs. This paper demonstrates: 1) renewable DNA circuits, which can be manually reverted to their original state by addition of DNA strands, and 2) time‐responsive DNA circuits, where if the inputs change over time, the DNA circuit can recompute the output correctly based on the new inputs, that are manually added after the system has been reset. The properties of renewable, asynchronous, and time‐responsiveness appear to be central to molecular‐scale systems; for example, self‐regulation in cellular organisms. 

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4. Visualization of Tethered Particle Motion with a Multidimensional Simulation

   https://doi.org/10.35459/tbp.2022.000238  

   Ramdin, Khovesh; Hackl, Markus; Chundawat, Shishir PS (January 2024, The Biophysicist)

   ABSTRACT The analysis of particles bound to surfaces by tethers can facilitate understanding of biophysical phenomena (e.g., DNA–protein or protein–ligand interactions and DNA extensibility). Modeling such systems theoretically aids in understanding experimentally observed motions, and the limitations of such models can provide insight into modeling complex systems. The simulation of tethered particle motion (TPM) allows for analysis of complex behaviors exhibited by such systems; however, this type of experiment is rarely taught in undergraduate science classes. We have developed a MATLAB simulation package intended to be used in academic contexts to concisely model and graphically represent the behavior of different tether–particle systems. We show how analysis of the simulation results can be used in biophysical research using single-molecule force spectroscopy (SMFS). Students in physics, engineering, and chemistry will be able to make connections with principles embedded in the field of study and understand how those principles can be used to create meaningful conclusions in a multidisciplinary context. The simulation package can model any given tether–particle system and allows the user to generate a parameter space with static and dynamic model components. Our simulation was successfully able to recreate generally observed experimental trends by using acoustic force spectroscopy (AFS). Further, the simulation was validated through consideration of the conservation of energy of the tether–bead system, trend analyses, and comparison of particle positional data from actual TPM in silico experiments conducted to simulate data with a parameter space similar to the AFS experimental setup. Overall, our TPM simulator and graphical user interface is primarily for demonstrating behaviors characteristic to TPM in a classroom setting but can serve as a template for researchers to set up TPM simulations to mimic a specific SMFS experimental setup. 

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5. DEVELOPING INTEGRATED DNA MOLECULAR CIRCUITS

   Bardales, Andrea C (December 2024, University of Central Florida)

   Due to nucleic acid’s programmability, it is possible to realize DNA structures with computing functions, and thus a new generation of molecular computers is evolving to solve biological and medical problems. There is evidence that genetic heredity diseases and cancer can be the result of genetic heterogeneity, thus there is a need for diagnostics and therapeutic tools with multiplex and smart components to compute all the molecular drivers. DNA molecular computers mimics electronic computers by programming synthetic nucleic acids to perform similarly to central processing units. Considering how the evolution of integrated circuits made possible the revolution of silicon-based computers, integrated DNA molecular circuits can be developed to allow modular designing and scale to complex DNA nano-processors. This dissertation covers the development of four-way junction (4J) DNA logic gates that can be wired to result in functionally complete gates, and their immobilization on a modular DNA board that serves as a scaffold for logic gate integration, fast signal processing, and cascading. Connecting 4J DNA logic gates YES and NOT resulted in OR, NAND, and IMPLY logic circuits; the three circuits can operate under the input of miRNAs, either oncogenic or/and tumor-suppressors, and give two possible diagnoses: healthy or cancerous. The DNA board can expand as the DNA circuit grows in the number of integrated 4J units. Signal propagation across a wired of 4J YES logic gates showed signal completion in < 3 min, accounting for a signal propagation rate of 4.5 nm/min and that up to 6 units can be cascaded before the signal dissipates. Lastly, an approach to chemically ligate all oligonucleotide components of the DNA molecular device is presented, in which we also found a route for the bioconjugation of 5’ to 5’ and 3’ to 3’ oligonucleotides. 

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