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1. Universal energy-accuracy tradeoffs in nonequilibrium cellular sensing

   https://doi.org/10.1103/PhysRevE.108.014403  

   Harvey, Sarah E; Lahiri, Subhaneil; Ganguli, Surya (July 2023, Physical Review E)

   We combine stochastic thermodynamics, large deviation theory, and information theory to derive fundamental limits on the accuracy with which single cell receptors can estimate external concentrations. As expected, if the estimation is performed by an ideal observer of the entire trajectory of receptor states, then no energy consuming nonequilibrium receptor that can be divided into bound and unbound states can outperform an equilibrium two- state receptor. However, when the estimation is performed by a simple observer that measures the fraction of time the receptor is bound, we derive a fundamental limit on the accuracy of general nonequilibrium receptors as a function of energy consumption. We further derive and exploit explicit formulas to numerically estimate a Pareto-optimal tradeoff between accuracy and energy. We find this tradeoff can be achieved by nonuniform ring receptors with a number of states that necessarily increases with energy. Our results yield a thermodynamic uncertainty relation for the time a physical system spends in a pool of states and generalize the classic Berg- Purcell limit [H. C. Berg and E. M. Purcell, Biophys. J. 20, 193 (1977)] on cellular sensing along multiple dimensions. 

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2. 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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3. A statistical mechanics framework for constructing nonequilibrium thermodynamic models

   https://doi.org/10.1093/pnasnexus/pgad417  

   Leadbetter, Travis; Purohit, Prashant K; Reina, Celia (December 2023, PNAS Nexus)

   Sharma, Pradeep (Ed.)

   Far-from-equilibrium phenomena are critical to all natural and engineered systems, and essential to biological processes responsible for life. For over a century and a half, since Carnot, Clausius, Maxwell, Boltzmann, and Gibbs, among many others, laid the foundation for our understanding of equilibrium processes, scientists and engineers have dreamed of an analogous treatment of nonequilibrium systems. But despite tremendous efforts, a universal theory of nonequilibrium behavior akin to equilibrium statistical mechanics and thermodynamics has evaded description. Several methodologies have proved their ability to accurately describe complex nonequilibrium systems at the macroscopic scale, but their accuracy and predictive capacity is predicated on either phenomenological kinetic equations fit to microscopic data or on running concurrent simulations at the particle level. Instead, we provide a novel framework for deriving stand-alone macroscopic thermodynamic models directly from microscopic physics without fitting in overdamped Langevin systems. The only necessary ingredient is a functional form for a parameterized, approximate density of states, in analogy to the assumption of a uniform density of states in the equilibrium microcanonical ensemble. We highlight this framework’s effectiveness by deriving analytical approximations for evolving mechanical and thermodynamic quantities in a model of coiled-coil proteins and double-stranded DNA, thus producing, to the authors’ knowledge, the first derivation of the governing equations for a phase propagating system under general loading conditions without appeal to phenomenology. The generality of our treatment allows for application to any system described by Langevin dynamics with arbitrary interaction energies and external driving, including colloidal macromolecules, hydrogels, and biopolymers. 

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4. Dynamic scaling of stochastic thermodynamic observables for chemical reactions at and away from equilibrium

   https://doi.org/10.1063/5.0106714  

   Mondal, Shrabani; Greenberg, Jonah S.; Green, Jason R. (November 2022, The Journal of Chemical Physics)

   Physical kinetic roughening processes are well-known to exhibit universal scaling of observables that fluctuate in space and time. Are there analogous dynamic scaling laws that are unique to the chemical reaction mechanisms available synthetically and occurring naturally? Here, we formulate an approach to the dynamic scaling of stochastic fluctuations in thermodynamic observables at and away from equilibrium. Both analytical expressions and numerical simulations confirm our dynamic scaling ansatz with associated scaling exponents, function, and law. A survey of common chemical mechanisms reveals classes that organize according to the molecularity of the reactions involved, the nature of the reaction vessel and external reservoirs, (non)equilibrium conditions, and the extent of autocatalysis in the reaction network. Varying experimental parameters, such as temperature, can cause coupled reactions capable of chemical feedback to transition between these classes. While path observables, such as the dynamical activity, have scaling exponents that are time-independent, the variance in the entropy production and flow can have time-dependent scaling exponents and self-averaging properties as a result of temporal correlations that emerge during thermodynamically irreversible processes. Altogether, these results establish dynamic universality classes in the nonequilibrium fluctuations of thermodynamic observables for well-mixed chemical reactions. 

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5. Thermodynamics of ion binding and occupancy in potassium channels

   https://doi.org/10.1039/D1SC01887F  

   Jing, Zhifeng; Rackers, Joshua A.; Pratt, Lawrence R.; Liu, Chengwen; Rempe, Susan B.; Ren, Pengyu (June 2021, Chemical Science)

   Potassium channels modulate various cellular functions through efficient and selective conduction of K + ions. The mechanism of ion conduction in potassium channels has recently emerged as a topic of debate. Crystal structures of potassium channels show four K + ions bound to adjacent binding sites in the selectivity filter, while chemical intuition and molecular modeling suggest that the direct ion contacts are unstable. Molecular dynamics (MD) simulations have been instrumental in the study of conduction and gating mechanisms of ion channels. Based on MD simulations, two hypotheses have been proposed, in which the four-ion configuration is an artifact due to either averaged structures or low temperature in crystallographic experiments. The two hypotheses have been supported or challenged by different experiments. Here, MD simulations with polarizable force fields validated by ab initio calculations were used to investigate the ion binding thermodynamics. Contrary to previous beliefs, the four-ion configuration was predicted to be thermodynamically stable after accounting for the complex electrostatic interactions and dielectric screening. Polarization plays a critical role in the thermodynamic stabilities. As a result, the ion conduction likely operates through a simple single-vacancy and water-free mechanism. The simulations explained crystal structures, ion binding experiments and recent controversial mutagenesis experiments. This work provides a clear view of the mechanism underlying the efficient ion conduction and demonstrates the importance of polarization in ion channel simulations. 

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