Stem-loop formation drives RNA folding in mechanical unzipping experiments.

Accurate knowledge of RNA hybridization is essential for understanding RNA structure and function. Here we mechanically unzip and rezip a 2-kbp RNA hairpin and derive the 10 nearest-neighbor base pair (NNBP) RNA free energies in sodium and magnesium with 0.1 kcal/mol precision using optical tweezers. Notably, force-distance curves (FDCs) exhibit strong irreversible effects with hysteresis and several intermediates, precluding the extraction of the NNBP energies with currently available methods. The combination of a suitable RNA synthesis with a tailored pulling protocol allowed us to obtain the fully reversible FDCs necessary to derive the NNBP energies. We demonstrate the equivalence of sodium and magnesium free-energy salt corrections at the level of individual NNBP. To characterize the irreversibility of the unzipping-rezipping process, we introduce a barrier energy landscape of the stem-loop structures forming along the complementary strands, which compete against the formation of the native hairpin. This landscape correlates with the hysteresis observed along the FDCs. RNA sequence analysis shows that base stacking and base pairing stabilize the stem-loops that kinetically trap the long-lived intermediates observed in the FDC. Stem-loops formation appears as a general mechanism to explain a wide range of behaviors observed in RNA folding.

Stochastic Thermodynamics of a Finite Quantum System Coupled to Two Heat Baths.

We consider a situation where an N-level system (NLS) is coupled successively to two heat baths with different temperatures without being necessarily thermalized and approaches a steady state. For this situation we apply a general Jarzynski-type equation and conclude that heat and entropy is flowing from the hot bath to the cold one. The Clausius relation between increase of entropy and transfer of heat divided by a suitable temperature assumes the form of two inequalities. Our approach is illustrated by an analytical example. For the linear regime, i.e., for small temperature differences between the two heat baths, we derive an expression for the heat conduction coefficient.

Jarzyski's Equality and Crooks' Fluctuation Theorem for General Markov Chains with Application to Decision-Making Systems.

We define common thermodynamic concepts purely within the framework of general Markov chains and derive Jarzynski's equality and Crooks' fluctuation theorem in this setup. In particular, we regard the discrete-time case, which leads to an asymmetry in the definition of work that appears in the usual formulation of Crooks' fluctuation theorem. We show how this asymmetry can be avoided with an additional condition regarding the energy protocol. The general formulation in terms of Markov chains allows transferring the results to other application areas outside of physics. Here, we discuss how this framework can be applied in the context of decision-making. This involves the definition of the relevant quantities, the assumptions that need to be made for the different fluctuation theorems to hold, as well as the consideration of discrete trajectories instead of the continuous trajectories, which are relevant in physics.

Crooks Fluctuation Theorem for Single Polymer Dynamics in Time-Dependent Flows: Understanding Viscoelastic Hysteresis.

Nonequilibrium work relations have fundamentally advanced our understanding of molecular processes. In recent years, fluctuation theorems have been extensively applied to understand transitions between equilibrium steady-states, commonly described by simple control parameters such as molecular extension of a protein or polymer chain stretched by an external force in a quiescent fluid. Despite recent progress, far less is understood regarding the application of fluctuation theorems to processes involving nonequilibrium steady-states such as those described by polymer stretching dynamics in nonequilibrium fluid flows. In this work, we apply the Crooks fluctuation theorem to understand the nonequilibrium thermodynamics of dilute polymer solutions in flow. We directly determine the nonequilibrium free energy for single polymer molecules in flow using a combination of single molecule experiments and Brownian dynamics simulations. We further develop a time-dependent extensional flow protocol that allows for probing viscoelastic hysteresis over a wide range of flow strengths. Using this framework, we define quantities that uniquely characterize the coil-stretch transition for polymer chains in flow. Overall, generalized fluctuation theorems provide a powerful framework to understand polymer dynamics under far-from-equilibrium conditions.

Joint Fluctuation Theorems for Sequential Heat Exchange.

We study the statistics of heat exchange of a quantum system that collides sequentially with an arbitrary number of ancillas. This can describe, for instance, an accelerated particle going through a bubble chamber. Unlike other approaches in the literature, our focus is on the joint probability distribution that heat Q 1 is exchanged with ancilla 1, heat Q 2 is exchanged with ancilla 2, and so on. This allows us to address questions concerning the correlations between the collisional events. For instance, if in a given realization a large amount of heat is exchanged with the first ancilla, then there is a natural tendency for the second exchange to be smaller. The joint distribution is found to satisfy a Fluctuation theorem of the Jarzynski-Wójcik type. Rather surprisingly, this fluctuation theorem links the statistics of multiple collisions with that of independent single collisions, even though the heat exchanges are statistically correlated.

Testing the Steady-State Fluctuation Relation in the Solar Photospheric Convection.

The turbulent thermal convection on the Sun is an example of an irreversible non-equilibrium phenomenon in a quasi-steady state characterized by a continuous entropy production rate. Here, the statistical features of a proxy of the local entropy production rate, in solar quiet regions at different timescales, are investigated and compared with the symmetry conjecture of the steady-state fluctuation theorem by Gallavotti and Cohen. Our results show that solar turbulent convection satisfies the symmetries predicted by the fluctuation relation of the Gallavotti and Cohen theorem at a local level.

Information Thermodynamics for Time Series of Signal-Response Models.

The entropy production in stochastic dynamical systems is linked to the structure of their causal representation in terms of Bayesian networks. Such a connection was formalized for bipartite (or multipartite) systems with an integral fluctuation theorem in [Phys. Rev. Lett. 111, 180603 (2013)]. Here we introduce the information thermodynamics for time series, that are non-bipartite in general, and we show that the link between irreversibility and information can only result from an incomplete causal representation. In particular, we consider a backward transfer entropy lower bound to the conditional time series irreversibility that is induced by the absence of feedback in signal-response models. We study such a relation in a linear signal-response model providing analytical solutions, and in a nonlinear biological model of receptor-ligand systems where the time series irreversibility measures the signaling efficiency.

Free-energy inference from partial work measurements in small systems.

Fluctuation relations (FRs) are among the few existing general results in nonequilibrium systems. Their verification requires the measurement of the total work performed on a system. Nevertheless in many cases only a partial measurement of the work is possible. Here we consider FRs in dual-trap optical tweezers where two different forces (one per trap) are measured. With this setup we perform pulling experiments on single molecules by moving one trap relative to the other. We demonstrate that work should be measured using the force exerted by the trap that is moved. The force that is measured in the trap at rest fails to provide the full dissipation in the system, leading to a (incorrect) work definition that does not satisfy the FR. The implications to single-molecule experiments and free-energy measurements are discussed. In the case of symmetric setups a second work definition, based on differential force measurements, is introduced. This definition is best suited to measure free energies as it shows faster convergence of estimators. We discuss measurements using the (incorrect) work definition as an example of partial work measurement. We show how to infer the full work distribution from the partial one via the FR. The inference process does also yield quantitative information, e.g., the hydrodynamic drag on the dumbbell. Results are also obtained for asymmetric dual-trap setups. We suggest that this kind of inference could represent a previously unidentified and general application of FRs to extract information about irreversible processes in small systems.

Free energy calculations, enhanced by a Gaussian ansatz, for the "chemical work" distribution.

The evaluation of the free energy is essential in molecular simulation because it is intimately related with the existence of multiphase equilibrium. Recently, it was demonstrated that it is possible to evaluate the Helmholtz free energy using a single statistical ensemble along an entire isotherm by accounting for the "chemical work" of transforming each molecule, from an interacting one, to an ideal gas. In this work, we show that it is possible to perform such a free energy perturbation over a liquid vapor phase transition. Furthermore, we investigate the link between a general free energy perturbation scheme and the novel nonequilibrium theories of Crook's and Jarzinsky. We find that for finite systems away from the thermodynamic limit the second law of thermodynamics will always be an inequality for isothermal free energy perturbations, resulting always to a dissipated work that may tend to zero only in the thermodynamic limit. The work, the heat, and the entropy produced during a thermodynamic free energy perturbation can be viewed in the context of the Crooks and Jarzinsky formalism, revealing that for a given value of the ensemble average of the "irreversible" work, the minimum entropy production corresponded to a Gaussian distribution for the histogram of the work. We propose the evaluation of the free energy difference in any free energy perturbation based scheme on the average irreversible "chemical work" minus the dissipated work that can be calculated from the variance of the distribution of the logarithm of the work histogram, within the Gaussian approximation. As a consequence, using the Gaussian ansatz for the distribution of the "chemical work," accurate estimates for the chemical potential and the free energy of the system can be performed using much shorter simulations and avoiding the necessity of sampling the computational costly tails of the "chemical work." For a more general free energy perturbation scheme that the Gaussian ansatz may not be valid, the free energy calculation can be expressed in terms of the moment generating function of the "chemical work" distribution.

Nonequilibrium thermodynamics in cavity optomechanics.

Classical thermodynamics has been a great achievement in dealing with systems that are in equilibrium or near equilibrium. As an emerging field, nonequilibrium thermodynamics provides a general framework for understanding the nonequilibrium processes, particularly in small systems that are typically far-from-equilibrium and are dominated by thermal or quantum fluctuations. Cavity optomechanical systems hold great promise among the various experimental platforms for studying nonequilibrium thermodynamics owing to their high controllability, excellent mechanical performance, and ability to operate deep in the quantum regime. Here, we present an overview of the recent advances in nonequilibrium thermodynamics with cavity optomechanical systems. The experimental results in entropy production assessment, fluctuation theorems, heat transfer, and heat engines are highlighted.

Nucleic Acid Thermodynamics Derived from Mechanical Unzipping Experiments.

Force-spectroscopy techniques have led to significant progress in studying the physicochemical properties of biomolecules that are not accessible in bulk assays. The application of piconewton forces with laser optical tweezers to single nucleic acids has permitted the characterization of molecular thermodynamics and kinetics with unprecedented accuracy. Some examples are the hybridization reaction between complementary strands in DNA and the folding of secondary, tertiary, and other heterogeneous structures, such as intermediate and misfolded states in RNA. Here we review the results obtained in our lab on deriving the nearest-neighbor free energy parameters in DNA and RNA duplexes from mechanical unzipping experiments. Remarkable nonequilibrium effects are also observed, such as the large irreversibility of RNA unzipping and the formation of non-specific secondary structures in single-stranded DNA. These features originate from forming stem-loop structures along the single strands of the nucleic acid. The recently introduced barrier energy landscape model quantifies kinetic trapping effects due to stem-loops being applicable to both RNA and DNA. The barrier energy landscape model contains the essential features to explain the many behaviors observed in heterogeneous nucleic-acid folding.