Glycolytic Wave Patterns in a Simple Reaction-diffusion System with Inhomogeneous Influx: Dynamic Transitions.

An inhomogeneous profile of chemostatted species generates a rich variety of patterns in glycolytic waves depicted in a Selkov reaction-diffusion framework here. A key role played by diffusion amplitude and symmetry in the chemostatted species profile in dictating the fate of local spatial dynamics involving periodic, quasiperiodic, and chaotic patterns and transitions among them are investigated systematically. More importantly, various dynamic transitions, including wave propagation direction changes, are illustrated in interesting situations. Besides numerical results, our analytical formulation of the amplitude equation connecting complex Ginzburg-Landau and Lambda-omega representation shed light on the phase dynamics of the system. This systematic study of the glycolytic reaction-diffusion wave is in line with previous experimental results in open spatial reactor and will provide a knowledge about the dynamics that shape and control biological information processing and related phenomena.

A minimal kinetic model for the interpretation of complex catalysis in single enzyme molecules.

Multi-exponential waiting-time distribution and randomness parameter greater than unity ascribe dynamic disorder in single-enzyme catalysis corroborated to the interplay of transforming conformers [English et al., Nat. Chem. Biol., 2006, 2, 87]. The associated multi-state model of enzymatic turnovers with statically heterogeneous catalytic rates misdescribes the non-linear uprising of the randomness parameter from unity in relation to the attributes of the fall-offs of the waiting-time distribution at different substrate concentrations. To resolve this crucial issue, we first employ a comprehensive stochastic reaction scenario and further rationalize and work out the minimal indispensable dynamic-disorder model that ensures the foregoing relationship upon comparison with the data. We elucidate that specific disregard for the transition rate coefficients in the multi-state model on account of the especially slow conformational transitions is the underlying reason for not achieving interrelation between the observables.

Electron-Vibration Entanglement of Resonating Dimers in Quantum Transport.

Electron transport in a single molecule resulting from the superposition of its vibronic states depends on the coupling strength with the metallic leads. However, dynamical coherence and Fermionic correlation in molecule-molecule and molecule-lead coupling necessitates a critical approach to treat the current and its noise level, especially in the presence of a variable external bias for temperature-dependent conduction. Primarily, this work is a generalization of the theoretical approach of the atomic dimers to incorporate the effect of vibrational modes in current and conductance characteristics. The variation of current and differential conductance due to the external bias reveals a vibrational Coulomb blockade structure corresponding to the functioning vibrational mode in the system. The numerical demonstration for a diverse class of molecules generically shows that electron-vibration interaction can quantitatively predict the nature of coherent electron transport and current noise. Secondly, an attempt has been made to illustrate the effect of magnitude of coherence-induced noise suppression of current as a signature of electron-vibration entanglement. Finally, temperature-dependent conductance of the molecular junction in dimer structure has been estimated along with the peak shifts due to the applied gate voltage.

The guiding role of dissipation in kinetic proofreading networks: Implications for protein synthesis.

Major biological polymerization processes achieve remarkable accuracy while operating out of thermodynamic equilibrium by utilizing the mechanism known as kinetic proofreading. Here, we study the interplay of the thermodynamic and kinetic aspects of proofreading by exploring the dissipation and catalytic rate, respectively, under the realistic constraint of fixed chemical potential difference. Theoretical analyses reveal no-monotonic variations of the catalytic rate and total entropy production rate (EPR), the latter quantifying the dissipation, at steady state. Applying this finding to a tRNA selection network in protein synthesis, we observe that the network tends to maximize both the EPR and catalytic rate, but not the accuracy. Simultaneously, the system tries to minimize the ratio of the EPRs due to the proofreading steps and the catalytic steps. Therefore, dissipation plays a guiding role in the optimization of the catalytic rate in the tRNA selection network of protein synthesis.

Large deviation theory for the kinetics and energetics of turnover of enzyme catalysis in a chemiostatic flow.

In the framework of large deviation theory, we have characterized nonequilibrium turnover statistics of enzyme catalysis in a chemiostatic flow with externally controllable parameters, like substrate injection rate and mechanical force. In the kinetics of the process, we have shown the fluctuation theorems in terms of the symmetry of the scaled cumulant generating function (SCGF) in the transient and steady state regime and a similar symmetry rule is reflected in a large deviation rate function (LDRF) as a property of the dissipation rate through boundaries. Large deviation theory also gives the thermodynamic force of a nonequilibrium steady state, as is usually recorded experimentally by a single molecule technique, which plays a key role responsible for the dynamical symmetry of the SCGF and LDRF. Using some special properties of the Legendre transformation, here, we have provided a relation between the fluctuations of fluxes and dissipation rates, and among them, the fluctuation of the turnover rate is routinely estimated but the fluctuation in the dissipation rate is yet to be characterized for small systems. Such an enzymatic reaction flow system can be a very good testing ground to systematically understand the rare events from the large deviation theory which is beyond fluctuation theorem and central limit theorem.

Nonequilibrium response of a voltage gated sodium ion channel and biophysical characterization of dynamic hysteresis.

Here we have studied the dynamic as well as the non-equilibrium thermodynamic response properties of voltage-gated Na-ion channel. Using sinusoidally oscillating external voltage protocol we have both kinetically and energetically studied the non-equilibrium steady state properties of dynamic hysteresis in details. We have introduced a method of estimating the work done associated with the dynamic memory due to a cycle of oscillating voltage. We have quantitatively characterised the loop area of ionic current which gives information about the work done to sustain the dynamic memory only for ion conduction, while the loop area of total entropy production rate gives the estimate of work done for overall gating dynamics. The maximum dynamic memory of Na-channel not only depends on the frequency and amplitude but it also depends sensitively on the mean of the oscillating voltage and here we have shown how the system optimize the dynamic memory itself in the biophysical range of field parameters. The relation between the average ionic current with increasing frequency corresponds to the nature of the average dissipative work done at steady state. It is also important to understand that the utilization of the energy from the external field can not be directly obtained only from the measurement of ionic current but also requires nonequilibrium thermodynamic study.

Emission rate, vibronic entanglement, and coherence in aggregates of conjugated polymers.

Here we have studied a dimer model of conjugated polymer aggregates based on the traditional J and H structures, with the extension in treating the electronic and vibrational degrees of freedom at par. We have considered various exchange symmetries corresponding to the parameters of the excited state Hamiltonian in assigning the symmetry of the vibronic states of the aggregate, going beyond the homodimer case. The emission rates are determined as a function of system parameters at low temperature for both types of aggregates. We have also determined the vibronic entanglement as a measure of the coupled electronic and vibrational motion as well as the exciton coherence number in the emitting state. As a function of interchain interaction strength, emission rate and entanglement grossly follow similar trends for the J-aggregate and opposite trends for the H-aggregate in totally symmetric as well as asymmetric cases. Variation of other system parameters, like electronic excitation energy and electron-vibration coupling parameter are also thoroughly investigated in governing these quantities. The role of symmetry of the wave function in governing the spectra and the exciton coherence are also analyzed thoroughly, which offers a way to realize the connection between such macroscopic and microscopic quantum features.

Propensity approach to nonequilibrium thermodynamics of a chemical reaction network: controlling single E-coli ß-galactosidase enzyme catalysis through the elementary reaction steps.

In this work, we develop an approach to nonequilibrium thermodynamics of an open chemical reaction network in terms of the elementary reaction propensities. The method is akin to the microscopic formulation of the dissipation function in terms of the Kullback-Leibler distance of phase space trajectories in Hamiltonian system. The formalism is applied to a single oligomeric enzyme kinetics at chemiostatic condition that leads the reaction system to a nonequilibrium steady state, characterized by a positive total entropy production rate. Analytical expressions are derived, relating the individual reaction contributions towards the total entropy production rate with experimentally measurable reaction velocity. Taking a real case of Escherichia coli ß-galactosidase enzyme obeying Michaelis-Menten kinetics, we thoroughly analyze the temporal as well as the steady state behavior of various thermodynamic quantities for each elementary reaction. This gives a useful insight in the relative magnitudes of various energy terms and the dissipated heat to sustain a steady state of the reaction system operating far-from-equilibrium. It is also observed that, the reaction is entropy-driven at low substrate concentration and becomes energy-driven as the substrate concentration rises.

On the estimation of cooperativity in ion channel kinetics: activation free energy and kinetic mechanism of Shaker K+ channel.

In this paper, we have explored generic criteria of cooperative behavior in ion channel kinetics treating it on the same footing with multistate receptor-ligand binding in a compact theoretical framework. We have shown that the characterization of cooperativity of ion channels in terms of the Hill coefficient violates the standard Hill criteria defined for allosteric cooperativity of ligand binding. To resolve the issue, an alternative measure of cooperativity is proposed here in terms of the cooperativity index that sets a unified criteria for both the systems. More importantly, for ion channel this index can be very useful to describe the cooperative kinetics as it can be readily determined from the experimentally measured ionic current combined with theoretical modelling. We have analyzed the correlation between the voltage value and slope of the voltage-activation curve at the half-activation point and consequently determined the standard free energy of activation of the ion channel using two well-established mechanisms of cooperativity, namely, Koshland-Nemethy-Filmer (KNF) and Monod-Wyman-Changeux (MWC) models. Comparison of the theoretical results for both the models with appropriate experimental data of mutational perturbation of Shaker K(+) channel supports the experimental fact that the KNF model is more suitable to describe the cooperative behavior of this class of ion channels, whereas the performance of the MWC model is unsatisfactory. We have also estimated the mechanistic performance through standard free energy of channel activation for both the models and proposed a possible functional disadvantage in the MWC scheme.

Nonequilibrium thermodynamic signatures of collective dynamical states around chimera in a chemical reaction network.

Different dynamical states ranging from coherent, incoherent to chimera, multichimera, and related transitions are addressed in a globally coupled nonlinear continuum chemical oscillator system by implementing a modified complex Ginzburg-Landau equation. Besides dynamical identifications of observed states using standard qualitative metrics, we systematically acquire nonequilibrium thermodynamic characterizations of these states obtained via coupling parameters. The nonconservative work profiles in collective dynamics qualitatively reflect the time-integrated concentration of the activator, and the majority of the nonconservative work contributes to the entropy production over the spatial dimension. It is illustrated that the evolution of spatial entropy production and semigrand Gibbs free-energy profiles associated with each state are connected yet completely out of phase, and these thermodynamic signatures are extensively elaborated to shed light on the exclusiveness and similarities of these states. Moreover, a relationship between the proper nonequilibrium thermodynamic potential and the variance of activator concentration is established by exhibiting both quantitative and qualitative similarities between a Fano factor like entity, derived from the activator concentration, and the Kullback-Leibler divergence associated with the transition from a nonequilibrium homogeneous state to an inhomogeneous state. Quantifying the thermodynamic costs for collective dynamical states would aid in efficiently controlling, manipulating, and sustaining such states to explore the real-world relevance and applications of these states.

Entropic estimate of cooperative binding of substrate on a single oligomeric enzyme: an index of cooperativity.

Here we have systematically studied the cooperative binding of substrate molecules on the active sites of a single oligomeric enzyme in a chemiostatic condition. The average number of bound substrate and the net velocity of the enzyme catalyzed reaction are studied by the formulation of stochastic master equation for the cooperative binding classified here as spatial and temporal. We have estimated the entropy production for the cooperative binding schemes based on single trajectory analysis using a kinetic Monte Carlo technique. It is found that the total as well as the medium entropy production shows the same generic diagnostic signature for detecting the cooperativity, usually characterized in terms of the net velocity of the reaction. This feature is also found to be valid for the total entropy production rate at the non-equilibrium steady state. We have introduced an index of cooperativity, C, defined in terms of the ratio of the surprisals or equivalently, the stochastic system entropy associated with the fully bound state of the cooperative and non-cooperative cases. The criteria of cooperativity in terms of C is compared with that of the Hill coefficient of some relevant experimental result and gives a microscopic insight on the mechanism of cooperative binding of substrate on a single oligomeric enzyme which is usually estimated from the macroscopic reaction rate.

Nonequilibrium thermodynamic characterization of chimeras in a continuum chemical oscillator system.

The emergence of the chimera state as the counterintuitive spatial coexistence of synchronous and asynchronous regimes is addressed here in a continuum chemical oscillator system by implementing a relevant complex Ginzburg-Landau equation with global coupling. This study systematically acquires and characterizes the evolution of nonequilibrium thermodynamic entities corresponding to the chimera state. The temporal evolution of the entropy production rate exhibits a beat pattern with a series of equidistant spectral lines in the frequency domain. Symmetric profiles associated with the incoherent regime appear in descriptions of the dynamics and thermodynamics of the chimera. It is shown that identifying the semigrand Gibbs free energy of the state as the Gabor elementary function can reveal the guiding role of the information uncertainty principle in shaping the chimera energetics.

Universality in bio-rhythms: A perspective from nonlinear dynamics.

Bio-rhythms are ubiquitous in all living organisms. A prototypical bio-rhythm originates from the chemical oscillation of intermediates or metabolites around the steady state of a thermodynamically open bio-chemical reaction network with autocatalysis and feedback and is often described by minimal kinetics with two state variables. It has been shown that notwithstanding the diverse nature of the underlying bio-chemical and biophysical processes, the associated kinetic equations can be mapped into the universal form of the Lie´nard equation which admits of mono-rhythmic and bi-rhythmic solutions. Several examples of bio-kinetic schemes are examined to illustrate this universality.

Nonequilibrium thermodynamics of glycolytic traveling wave: Benjamin-Feir instability.

Evolution of the nonequilibrium thermodynamic entities corresponding to dynamics of the Hopf instabilities and traveling waves at a nonequilibrium steady state of a spatially extended glycolysis model is assessed here by implementing an analytically tractable scheme incorporating a complex Ginzburg-Landau equation (CGLE). In the presence of self and cross diffusion, a more general amplitude equation exploiting the multiscale Krylov-Bogoliubov averaging method serves as an essential tool to reveal the various dynamical instability criteria, especially Benjamin-Feir (BF) instability, to estimate the corresponding nonlinear dispersion relation of the traveling wave pattern. The critical control parameter, wave-number selection criteria, and magnitude of the complex amplitude for traveling waves are modified by self- and cross-diffusion coefficients within the oscillatory regime, and their variabilities are exhibited against the amplitude equation. Unlike the traveling waves, a low-amplitude broad region appears for the Hopf instability in the concentration dynamics as the system phase passes through minima during its variation with the control parameter. The total entropy production rate of the uniform Hopf oscillation and glycolysis wave not only qualitatively reflects the global dynamics of concentrations of intermediate species but almost quantitatively. Despite the crucial role of diffusion in generating and shaping the traveling waves, the diffusive part of the entropy production rate has a negligible contribution to the system's total entropy production rate. The Hopf instability shows a more complex and colossal change in the energy profile of the open nonlinear system than in the traveling waves. A detailed analysis of BF instability shows a contrary nature of the semigrand Gibbs free energy with discrete and continuous wave numbers for the traveling wave. We hope the Hopf and traveling wave pattern around the BF instability in terms of energetics and dissipation will open up new applications of such dynamical phenomena.

On the Role of Magnesium Ions in the DNA-Scissoring Activity of the Restriction Endonuclease ApaI: Stochastic Kinetics from a Single Molecule to Mesoscopic Paradigm.

Biochemical reactions occurring inside cells have significant stochastic signatures due to the low copy number of reacting species. Kinetics of DNA cleavage by restriction endonucleases are no exception as established by single-molecule experiments. Here, we propose a simple reaction scheme to understand the role of the cofactor magnesium ion in the action of the endonuclease ApaI. The methodology is based on the waiting time distribution of cleavage product formation that enables us to determine the corresponding rate both analytically and numerically. The theory is developed at the single-molecule level and then generalized to the biologically relevant case of a population of DNA-endonuclease complexes present inside a cell. The theoretical rate versus cofactor concentration curve is matched with relevant single-molecule experimental data that reveals positive cooperativity of cofactor binding and provides a reliable estimate of model parameters. Furthermore, a parameter range is identified where the dispersion of the waiting time, measured using the coefficient of variation, is significantly lower than the Poisson limit and becomes minimum at the in vivo magnesium ion concentration level. Such low dispersion can play a role in the robust DNA-scissoring activity of ApaI under in vivo conditions.

A Revisit to Turnover Kinetics of Individual Escherichia coli ß-Galactosidase Molecules.

Single-molecule experiments on ß-galactosidase from Escherichia coli that catalyzes the hydrolysis of resorufin-ß-d-galactopyranoside revealed important observations like fluctuating catalytic rate, memory effects arising from temporal correlations between the enzymatic turnovers and nonexponential waiting time distributions. The root cause of the observed results is intrinsic fluctuations among the different conformers of the active species, during the course of the reaction, thereby imparting dynamic disorder in the system under investigation. Originally, a multistate stochastic kinetic theory was employed that, despite satisfying the measured waiting time distributions and the mean waiting times at different substrate concentrations, yields a constant estimate of the randomness parameter. Inevitably, this manifests a strong disagreement with the substrate-concentration-dependent time variations of the said distribution, which at the same time misinterprets the measured magnitudes of the randomness parameter at lower concentrations. Here, we suggest a dual approach to the single-enzyme reaction, independently, making important improvements over the parent study and the recently suggested two-state stochastic analyses followed by quantitative rationalization of the experimental data. In the first case, an off-pathway mechanism satisfied the Michaelis-Menten equation under the circumstance of prevailing disorder while tested against the single-molecule data. However, recovery of randomness data in the lower-concentration regime, albeit primarily marks a significant refinement, a qualitative agreement at the growing concentrations seems to be reasoned by an account of switching among the limited numbers of discrete conformers. Consequently, in the second case, we circumvented the conventional way of approaching the enzyme catalysis and mapped the dynamics of structural transitions of the biocatalyst with the temporal fluctuations of the spatial distance between the different locations along a coarse-grained polymer chain. Exploiting a general mechanism for dynamic disorder, a reaction-diffusion formalism yielded an analytical expression for the waiting time distribution of the enzymatic turnovers, from which the mean waiting time and the randomness parameter were readily determined. Application of our results to the findings of the experiment on single ß-galactosidase shows a quantitative agreement in each case. This soundly validates the usefulness of accounting for a more rigorous microscopic description pertinent to the conformational multiplicity in rationalizing the real-time data over the routine state-based sketch of the reaction system.

ApoE ε4 and IL-6-174G/C Polymorphism may Lead to Early Onset of Alzheimer's Disease with Atypical Presentation.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia. Although genetic mutations are known in rare familial form, exact cause of neurodegeneration in sporadic AD is still unknown. While ApoE ε4 and IL-6 C-174G/C patterns have been found to increase the risk of AD in Caucasians, the results are inconsistent in other ethnic groups. OBJECTIVE: The aim of this study was to evaluate the effect of ApoE and IL-6-174G/C polymorphisms among patients of AD in the Eastern part of India. MATERIALS AND METHODS: Consecutive patients of probable AD diagnosed as per National Institute on Aging-Alzheimer's Association (NIA-AA) criteria with age, gender, and education-matched healthy controls were recruited between December 2015 and September 2018. Patients were clinically evaluated and along with controls were genotyped for ApoE and IL-6-174G/C polymorphisms by the polymerase chain reaction method. RESULTS: A total 115 patients and 162 controls showed a similar pattern of ApoE and IL-6-174G/C polymorphism pattern. While ε3ε3 and GG patterns were the commonest, followed by ε3ε4 and GC pattern in ApoE and IL-6 respectively, the effect of ApoE ε4 and IL-6-174 C allele on AD symptoms could not be established. However, patients with onset before 50 years were found to have significantly higher proportion of ApoE ε4 and C allele of IL-6-174 in comparison to patients with onset above 50. These young patients were also having more atypical presentation than their older counterpart. CONCLUSION: Our study revealed a novel role of both ApoE ε4 and C allele of IL-6-174 together in developing early onset AD with more atypical clinical features.

Master equation approach to single oligomeric enzyme catalysis: mechanically controlled further catalysis.

Motivated by the single molecule enzymatic experiments, we have provided a master equation description of enzyme catalysis in a chemiostatic condition for an immobilized oligomeric molecule with many equivalent active sites. The random attachment and detachment of substrate molecules on the various active sites of the oligomeric enzyme is studied in terms of the classical parameters of the Michaelis-Menten type process. In the limit of single molecule process, the master equation approach gives the result of waiting time distribution. On the other hand, for a large number of equivalent active sites or a few numbers of active sites with large Michaelis constant, the master equation gives a Poisson distribution in the nonequilibrium steady state. For the oligomeric enzyme, the net rate of the reaction in the nonequilibrium steady state is multiplied by the number of active sites which is further enhanced by more than two orders of magnitude with the application of external force of 10-100 pN through the techniques of atomic force microscopy. Substrate flux and reaction rate constants have interesting consequences on the dynamics and at nonequilibrium steady state which can be the controlling factors for macroscopic biochemical processes.

Energetic and entropic cost due to overlapping of Turing-Hopf instabilities in the presence of cross diffusion.

A systematic introduction to nonequilibrium thermodynamics of dynamical instabilities are considered for an open nonlinear system beyond conventional Turing pattern in presence of cross diffusion. An altered condition of Turing instability in presence of cross diffusion is best reflected through a critical control parameter and wave number containing both the self- and cross-diffusion coefficients. Our main focus is on entropic and energetic cost of Turing-Hopf interplay in stationary pattern formation. Depending on the relative dispositions of Turing-Hopf codimensional instabilities from the reaction-diffusion equation it clarifies two aspects: energy cost of pattern formation, especially how Hopf instability can be utilized to dictate a stationary concentration profile, and the possibility of revealing nonequilibrium phase transition. In the Brusselator model, to understand these phenomena, we have analyzed through the relevant complex Ginzberg-Landau equation using multiscale Krylov-Bogolyubov averaging method. Due to Hopf instability it is observed that the cross-diffusion parameters can be a source of huge change in free-energy and concentration profiles.

Mechanical Unfolding of Single Polyubiquitin Molecules Reveals Evidence of Dynamic Disorder.

Mechanical unfolding of single polyubiquitin molecules subjected to a constant stretching force showed nonexponentiality in the measured probability density of unfolding (waiting time distribution) and the survival probability of the folded state during the course of the measurements. These observations explored the relevance of disorder present in the system under study with implications for a static disorder approach to rationalize the experimental results. Here, an approach for dynamic disorder is presented based on Zwanzig's fluctuating bottleneck (FB) model, in which the rate of the reaction is controlled by the passage through the cross-sectional area of the bottleneck. The radius of the latter undergoes stochastic fluctuations that in turn is described in terms of the end-to-end distance fluctuations of the Rouse-like dynamics using a non-Markovian generalized Langevin equation with a memory kernel and Gaussian colored noise. Our results are comprised of analytical expressions for the survival probability and waiting time distribution, which show excellent agreement with the experimental data throughout the range of the applied forces. In addition, by fitting the survival probabilities at different stretching forces, we quantify two system parameters, namely, the average free energy ΔG av and the average distance to the transition state Δx av, both perfectly recovered the experimental estimates. These agreements validate the present model of polymer dynamics, which captures the very essence of dynamic disorder in single-molecule pulling experiments.