Arthur V. Straube

The slow-scale linear noise approximation: an accurate, reduced stochastic description of biochemical networks under timescale separation conditions

BackgroundIt is well known that the deterministic dynamics of biochemical reaction networks can be more easily studied if timescale separation conditions are invoked (the quasi-steady-state assumption). In this case the deterministic dynamics of a large network of elementary reactions are well described by the dynamics of a smaller network of effective reactions. Each of the latter represents a group of elementary reactions in the large network and has associated with it an effective macroscopic rate law. A popular method to achieve model reduction in the presence of intrinsic noise consists of using the effective macroscopic rate laws to heuristically deduce effective probabilities for the effective reactions which then enables simulation via the stochastic simulation algorithm (SSA). The validity of this heuristic SSA method is a priori doubtful because the reaction probabilities for the SSA have only been rigorously derived from microscopic physics arguments for elementary reactions.ResultsWe here obtain, by rigorous means and in closed-form, a reduced linear Langevin equation description of the stochastic dynamics of monostable biochemical networks in conditions characterized by small intrinsic noise and timescale separation. The slow-scale linear noise approximation (ssLNA), as the new method is called, is used to calculate the intrinsic noise statistics of enzyme and gene networks. The results agree very well with SSA simulations of the non-reduced network of elementary reactions. In contrast the conventional heuristic SSA is shown to overestimate the size of noise for Michaelis-Menten kinetics, considerably under-estimate the size of noise for Hill-type kinetics and in some cases even miss the prediction of noise-induced oscillations.ConclusionsA new general method, the ssLNA, is derived and shown to correctly describe the statistics of intrinsic noise about the macroscopic concentrations under timescale separation conditions. The ssLNA provides a simple and accurate means of performing stochastic model reduction and hence it is expected to be of widespread utility in studying the dynamics of large noisy reaction networks, as is common in computational and systems biology.

How accurate are the nonlinear chemical Fokker-Planck and chemical Langevin equations?

The chemical Fokker-Planck equation and the corresponding chemical Langevin equation are commonly used approximations of the chemical master equation. These equations are derived from an uncontrolled, second-order truncation of the Kramers-Moyal expansion of the chemical master equation and hence their accuracy remains to be clarified. We use the system-size expansion to show that chemical Fokker-Planck estimates of the mean concentrations and of the variance of the concentration fluctuations about the mean are accurate to order Ω(-3∕2) for reaction systems which do not obey detailed balance and at least accurate to order Ω(-2) for systems obeying detailed balance, where Ω is the characteristic size of the system. Hence, the chemical Fokker-Planck equation turns out to be more accurate than the linear-noise approximation of the chemical master equation (the linear Fokker-Planck equation) which leads to mean concentration estimates accurate to order Ω(-1∕2) and variance estimates accurate to order Ω(-3∕2). This higher accuracy is particularly conspicuous for chemical systems realized in small volumes such as biochemical reactions inside cells. A formula is also obtained for the approximate size of the relative errors in the concentration and variance predictions of the chemical Fokker-Planck equation, where the relative error is defined as the difference between the predictions of the chemical Fokker-Planck equation and the master equation divided by the prediction of the master equation. For dimerization and enzyme-catalyzed reactions, the errors are typically less than few percent even when the steady-state is characterized by merely few tens of molecules.

Hydrodynamically Enforced Entropic Trapping of Brownian Particles

We study the transport of Brownian particles through a corrugated channel caused by a force field containing curl-free (scalar potential) and divergence-free (vector potential) parts. We develop a generalized Fick-Jacobs approach leading to an effective one-dimensional description involving the potential of mean force. As an application, the interplay of a pressure-driven flow and an oppositely oriented constant bias is considered. We show that for certain parameters, the particle diffusion is significantly suppressed via the property of hydrodynamically enforced entropic particle trapping.

Stochastic theory of large-scale enzyme-reaction networks: finite copy number corrections to rate equation models.

Chemical reactions inside cells occur in compartment volumes in the range of atto- to femtoliters. Physiological concentrations realized in such small volumes imply low copy numbers of interacting molecules with the consequence of considerable fluctuations in the concentrations. In contrast, rate equation models are based on the implicit assumption of infinitely large numbers of interacting molecules, or equivalently, that reactions occur in infinite volumes at constant macroscopic concentrations. In this article we compute the finite-volume corrections (or equivalently the finite copy number corrections) to the solutions of the rate equations for chemical reaction networks composed of arbitrarily large numbers of enzyme-catalyzed reactions which are confined inside a small subcellular compartment. This is achieved by applying a mesoscopic version of the quasisteady-state assumption to the exact Fokker-Planck equation associated with the Poisson representation of the chemical master equation. The procedure yields impressively simple and compact expressions for the finite-volume corrections. We prove that the predictions of the rate equations will always underestimate the actual steady-state substrate concentrations for an enzyme-reaction network confined in a small volume. In particular we show that the finite-volume corrections increase with decreasing subcellular volume, decreasing Michaelis-Menten constants, and increasing enzyme saturation. The magnitude of the corrections depends sensitively on the topology of the network. The predictions of the theory are shown to be in excellent agreement with stochastic simulations for two types of networks typically associated with protein methylation and metabolism.

Communication: Limitations of the stochastic quasi-steady-state approximation in open biochemical reaction networks

It is commonly believed that, whenever timescale separation holds, the predictions of reduced chemical master equations obtained using the stochastic quasi-steady-state approximation are in very good agreement with the predictions of the full master equations. We use the linear noise approximation to obtain a simple formula for the relative error between the predictions of the two master equations for the Michaelis-Menten reaction with substrate input. The reduced approach is predicted to overestimate the variance of the substrate concentration fluctuations by as much as 30%. The theoretical results are validated by stochastic simulations using experimental parameter values for enzymes involved in proteolysis, gluconeogenesis, and fermentation.

Stick-slip dynamics of an oscillated sessile drop

We consider theoretically the dynamics of an oscillated sessile drop of incompressible liquid and focus on the contact line hysteresis. We address the situation of the small-amplitude and high-frequency oscillations imposed normally to the substrate surface. We deal with the drop whose equilibrium surface is hemispherical and the equilibrium contact angle equals π/2. We apply the dynamic boundary condition that involves an ambiguous dependence of the contact angle on the contact line velocity: The contact line starts to slide only when the deviation of the contact angle exceeds a certain critical value. As a result, the stick-slip dynamics can be observed. The frequency response of surface oscillations on the substrate and at the pole of the drop are analyzed. It is shown that novel features such as the emergence of antiresonant frequency bands and nontrivial competition of different resonances are caused by contact line hysteresis.

Rigorous elimination of fast stochastic variables from the linear noise approximation using projection operators

The linear noise approximation (LNA) offers a simple means by which one can study intrinsic noise in monostable biochemical networks. Using simple physical arguments, we have recently introduced the slow-scale LNA (ssLNA), which is a reduced version of the LNA under conditions of timescale separation. In this paper we present the first rigorous derivation of the ssLNA using the projection operator technique and show that the ssLNA follows uniquely from the standard LNA under the same conditions of timescale separation as those required for the deterministic quasi-steady-state approximation. We also show that the large molecule number limit of several common stochastic model reduction techniques under timescale separation conditions constitutes a special case of the ssLNA.

Signatures of nonlinearity in single cell noise-induced oscillations

A class of theoretical models seeks to explain rhythmic single cell data by postulating that they are generated by intrinsic noise in biochemical systems whose deterministic models exhibit only damped oscillations. The main features of such noise-induced oscillations are quantified by the power spectrum which measures the dependence of the oscillatory signals power with frequency. In this paper we derive an approximate closed-form expression for the power spectrum of any monostable biochemical system close to a Hopf bifurcation, where noise-induced oscillations are most pronounced. Unlike the commonly used linear noise approximation which is valid in the macroscopic limit of large volumes, our theory is valid over a wide range of volumes and hence affords a more suitable description of single cell noise-induced oscillations. Our theory predicts that the spectra have three universal features: (i) a dominant peak at some frequency, (ii) a smaller peak at twice the frequency of the dominant peak and (iii) a peak at zero frequency. Of these, the linear noise approximation predicts only the first feature while the remaining two stem from the combination of intrinsic noise and nonlinearity in the law of mass action. The theoretical expressions are shown to accurately match the power spectra determined from stochastic simulations of mitotic and circadian oscillators. Furthermore it is shown how recently acquired single cell rhythmic fibroblast data displays all the features predicted by our theory and that the experimental spectrum is well described by our theory but not by the conventional linear noise approximation.

Synchronous vs. asynchronous transport of a paramagnetic particle in a modulated ratchet potential

We present a combined experimental and theoretical study describing the dynamical regimes displayed by a paramagnetic colloidal particle externally driven above a stripe-patterned magnetic garnet film. A circularly polarized rotating magnetic field modulates the stray field of the garnet film and generates a translating periodic potential which induces particle motion. Increasing the driving frequency, we observe a transition from a phase-locked motion with constant speed to a sliding dynamics characterized by a lower speed due to the loss of synchronization with the traveling potential. We explain the experimental findings with an analytically tractable theoretical model and interpret the particle dynamics in the presence of thermal noise. The model is in good quantitative agreement with the experiments.

Linear oscillations of a compressible hemispherical bubble on a solid substrate

The linear natural and forced oscillations of a compressible hemispherical bubble on a solid substrate are under theoretical consideration. The contact line dynamics is taken into account by application of the Hocking condition, which eventually leads to nontrivial interaction of the shape and volume oscillations. Resonant phenomena, mostly pronounced for the bubble with the fixed contact line or with the fixed contact angle, are found out. A double resonance, where independent of the Hocking parameter, an unbounded growth of the amplitude occurs, is detected. The limiting case of weakly compressible bubble is studied. The general criterion identifying whether the compressibility of a bubble can be neglected is obtained.