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1. Proceedings of the 29th International Conference on DNA Computing and Molecular Programming (DNA 29)

   https://doi.org/10.4230/LIPIcs.DNA.29.8  

   Petrack, Joshua; Soloveichik, David; Doty, David (January 2023, Schloss Dagstuhl – Leibniz-Zentrum für Informatik)

   Chen, Ho-Lin; Evans, Constantine G. (Ed.)

   The field of chemical computation attempts to model computational behavior that arises when molecules, typically nucleic acids, are mixed together. By modeling this physical phenomenon at different levels of specificity, different operative computational behavior is observed. Thermodynamic binding networks (TBNs) is a highly abstracted model that focuses on which molecules are bound to each other in a "thermodynamically stable" sense. Stability is measured based only on how many bonds are formed and how many total complexes are in a configuration, without focusing on how molecules are binding or how they became bound. By defocusing on kinetic processes, TBNs attempt to naturally model the long-term behavior of a mixture (i.e., its thermodynamic equilibrium). We study the problem of signal amplification: detecting a small quantity of some molecule and amplifying its signal to something more easily detectable. This problem has natural applications such as disease diagnosis. By focusing on thermodynamically favored outcomes, we seek to design chemical systems that perform the task of signal amplification robustly without relying on kinetic pathways that can be error prone and require highly controlled conditions (e.g., PCR amplification). It might appear that a small change in concentrations can result in only small changes to the thermodynamic equilibrium of a molecular system. However, we show that it is possible to design a TBN that can "exponentially amplify" a signal represented by a single copy of a monomer called the analyte: this TBN has exactly one stable state before adding the analyte and exactly one stable state afterward, and those two states "look very different" from each other. In particular, their difference is exponential in the number of types of molecules and their sizes. The system can be programmed to any desired level of resilience to false positives and false negatives. To prove these results, we introduce new concepts to the TBN model, particularly the notions of a TBN’s entropy gap to describe how unlikely it is to be observed in an undesirable state, and feed-forward TBNs that have a strong upper bound on the number of polymers in a stable configuration. We also show a corresponding negative result: a doubly exponential upper bound, meaning that there is no TBN that can amplify a signal by an amount more than doubly exponential in the number and sizes of different molecules that comprise it. We leave as an open question to close this gap by either proving an exponential upper bound, or giving a construction with a doubly-exponential difference between the stable configurations before and after the analyte is added. Our work informs the fundamental question of how a thermodynamic equilibrium can change as a result of a small change to the system (adding a single molecule copy). While exponential amplification is traditionally viewed as inherently a non-equilibrium phenomenon, we find that in a strong sense exponential amplification can occur at thermodynamic equilibrium as well - where the "effect" (e.g., fluorescence) is exponential in types and complexity of the chemical components. 

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2. Is stochastic thermodynamics the key to understanding the energy costs of computation?

   https://doi.org/10.1073/pnas.2321112121  

   Wolpert, David H; Korbel, Jan; Lynn, Christopher W; Tasnim, Farita; Grochow, Joshua A; Kardeş, Gülce; Aimone, James B; Balasubramanian, Vijay; De_Giuli, Eric; Doty, David; et al (November 2024, Proceedings of the National Academy of Sciences)

   The relationship between the thermodynamic and computational properties of physical systems has been a major theoretical interest since at least the 19th century. It has also become of increasing practical importance over the last half-century as the energetic cost of digital devices has exploded. Importantly, real-world computers obey multiple physical constraints on how they work, which affects their thermodynamic properties. Moreover, many of these constraints apply to both naturally occurring computers, like brains or Eukaryotic cells, and digital systems. Most obviously, all such systems must finish their computation quickly, using as few degrees of freedom as possible. This means that they operate far from thermal equilibrium. Furthermore, many computers, both digital and biological, are modular, hierarchical systems with strong constraints on the connectivity among their subsystems. Yet another example is that to simplify their design, digital computers are required to be periodic processes governed by a global clock. None of these constraints were considered in 20th-century analyses of the thermodynamics of computation. The new field of stochastic thermodynamics provides formal tools for analyzing systems subject to all of these constraints. We argue here that these tools may help us understand at a far deeper level just how the fundamental thermodynamic properties of physical systems are related to the computation they perform. 

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3. Thermodynamic consistency and fluctuations in mesoscopic stochastic simulations of reactive gas mixtures

   https://doi.org/10.1063/5.0251770  

   Polimeno, Matteo; Kim, Changho; Blanchette, François; Srivastava, Ishan; Garcia, Alejandro_L; Nonaka, Andy_J; Bell, John_B (April 2025, The Journal of Chemical Physics)

   It is essential that mesoscopic simulations of reactive systems reproduce the correct statistical distributions at thermodynamic equilibrium. By considering a compressible fluctuating hydrodynamics (FHD) simulation method of ideal gas mixtures undergoing reversible reactions described by the chemical Langevin equations, we show that thermodynamic consistency in reaction rates and the use of instantaneous temperatures for the evaluation of reaction rates is required for fluctuations for the overall system to be correct. We then formulate the required properties of a thermodynamically consistent reaction (TCR) model. As noted in the literature, while reactions are often discussed in terms of forward and reverse rates, these rates should not be modeled independently because they must be compatible with thermodynamic equilibrium for the system. Using a simple TCR model where each chemical species has constant heat capacity, we derive the explicit condition that the forward and reverse reaction rate constants must satisfy in order for the system to be thermodynamically consistent. We perform equilibrium and non-equilibrium simulations of ideal gas mixtures undergoing a reversible dimerization reaction to measure the fluctuational behavior of the system numerically. We confirm that FHD simulations with the TCR model give the correct static structure factor of equilibrium fluctuations. For the statistically steady simulation of a gas mixture between two isothermal walls with different temperatures, we show using the TCR model that the temperature variance agrees with the corresponding thermodynamic-equilibrium temperature variance in the interior of the system, whereas noticeable deviations are present in regions near walls, where chemistry is far from equilibrium. 

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4. Foundations of a finite non-equilibrium statistical thermodynamics: extrinsic quantities

   https://doi.org/10.1088/1751-8121/ac798a  

   Ericok, O B; Mason, J K (July 2022, Journal of Physics A: Mathematical and Theoretical)

   Abstract Statistical thermodynamics is valuable as a conceptual structure that shapes our thinking about equilibrium thermodynamic states. A cloud of unresolved questions surrounding the foundations of the theory could lead an impartial observer to conclude that statistical thermodynamics is in a state of crisis though. Indeed, the discussion about the microscopic origins of irreversibility has continued in the scientific community for more than a hundred years. This paper considers these questions while beginning to develop a statistical thermodynamics for finite non-equilibrium systems. Definitions are proposed for all of the extrinsic variables of the fundamental thermodynamic relation that are consistent with existing results in the equilibrium thermodynamic limit. The probability density function on the phase space is interpreted as a subjective uncertainty about the microstate, and the Gibbs entropy formula is modified to allow for entropy creation without introducing additional physics or modifying the phase space dynamics. Resolutions are proposed to the mixing paradox, Gibbs’ paradox, Loschmidt’s paradox, and Maxwell’s demon thought experiment. Finally, the extrinsic variables of the fundamental thermodynamic relation are evaluated as functions of time and space for a diffusing ideal gas, and the initial and final values are shown to coincide with the expected equilibrium values. 

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5. Lower Bounds on Implementing Mediators in Asynchronous Systems with Rational and Malicious Agents

   https://doi.org/10.1145/3578579  

   Geffner, Ivan; Halpern, Joseph Y. (April 2023, Journal of the ACM)

   Abraham, Dolev, Geffner, and Halpern [ 1 ] proved that, in asynchronous systems, a (k, t)-robust equilibrium for n players and a trusted mediator can be implemented without the mediator as long as n > 4( k+t ), where an equilibrium is ( k, t )-robust if, roughly speaking, no coalition of t players can decrease the payoff of any of the other players, and no coalition of k players can increase their payoff by deviating. We prove that this bound is tight, in the sense that if n ≤ 4( k+t ) there exist ( k, t )-robust equilibria with a mediator that cannot be implemented by the players alone. Even though implementing ( k, t )-robust mediators seems closely related to implementing asynchronous multiparty ( k+t )-secure computation [ 6 ], to the best of our knowledge there is no known straightforward reduction from one problem to another. Nevertheless, we show that there is a non-trivial reduction from a slightly weaker notion of ( k+t )-secure computation, which we call ( k+t )-strict secure computation , to implementing ( k, t )-robust mediators. We prove the desired lower bound by showing that there are functions on n variables that cannot be ( k+t )-strictly securely computed if n ≤ 4( k+t ). This also provides a simple alternative proof for the well-known lower bound of 4 t +1 on asynchronous secure computation in the presence of up to t malicious agents [ 4 , 8 , 10 ]. 

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