Debashis Barik

A model of yeast cell-cycle regulation based on multisite phosphorylation

In order for the cells genome to be passed intact from one generation to the next, the events of the cell cycle (DNA replication, mitosis, cell division) must be executed in the correct order, despite the considerable molecular noise inherent in any protein‐based regulatory system residing in the small confines of a eukaryotic cell. To assess the effects of molecular fluctuations on cell‐cycle progression in budding yeast cells, we have constructed a new model of the regulation of Cln‐ and Clb‐dependent kinases, based on multisite phosphorylation of their target proteins and on positive and negative feedback loops involving the kinases themselves. To account for the significant role of noise in the transcription and translation steps of gene expression, the model includes mRNAs as well as proteins. The model equations are simulated deterministically and stochastically to reveal the bistable switching behavior on which proper cell‐cycle progression depends and to show that this behavior is robust to the level of molecular noise expected in yeast‐sized cells (∼50 fL volume). The model gives a quantitatively accurate account of the variability observed in the G1‐S transition in budding yeast, which is governed by an underlying sizer+timer control system.

Bistability by multiple phosphorylation of regulatory proteins

The activity of a protein can be reversibly modulated by post-translational, covalent modifications, such as phosphorylation and dephosphorylation. In many cases, the modulated protein may be phosphorylated by the same kinase on many different amino acid residues. Such multisite phosphorylations may occur progressively (during a single binding event of kinase to substrate) or distributively (the kinase dissociates from its substrate after each phosphorylation reaction). If a protein is phosphorylated by a distributive multisite mechanism, then the net activity of a population of these protein molecules can be a highly nonlinear function of the ratio of activities of the kinase and phosphatase enzymes. If the multiply phosphorylated protein is embedded in a positive feedback loop with its kinase and/or phosphatase, then the network may exhibit robust bistable behavior. Using numerical simulations and bifurcation theory, we study the properties of a particular bistable reaction network motivated by the antagonistic relationship between cyclin-dependent kinase and its multiply phosphorylated target, Cdh1, which is involved in the degradation of cyclin molecules. We characterize the bistable switch in terms of (i) the mechanism of distributive phosphorylation (ordered or disordered), (ii) the number of phosphorylation sites on the target protein, (iii) the effect of phosphorylation on the target protein (abrupt or progressive inactivation), and (iv) the effects of stochastic fluctuations in small cells with limited numbers of kinase, phosphatase and target proteins.

T cells translate individual, quantal activation into collective, analog cytokine responses via time-integrated feedbacks

Variability within isogenic T cell populations yields heterogeneous ‘local’ signaling responses to shared antigenic stimuli, but responding clones may communicate ‘global’ antigen load through paracrine messengers, such as cytokines. Such coordination of individual cell responses within multicellular populations is critical for accurate collective reactions to shared environmental cues. However, cytokine production may saturate as a function of antigen input, or be dominated by the precursor frequency of antigen-specific T cells. Surprisingly, we found that T cells scale their collective output of IL-2 to total antigen input over a large dynamic range, independently of population size. Through experimental quantitation and computational modeling, we demonstrate that this scaling is enforced by an inhibitory cross-talk between antigen and IL-2 signaling, and a nonlinear acceleration of IL-2 secretion per cell. Our study reveals how time-integration of these regulatory loops within individual cell signaling generates scaled collective responses and can be leveraged for immune monitoring. DOI: http://dx.doi.org/10.7554/eLife.01944.001

Langevin dynamics with dichotomous noise; direct simulation and applications

We consider the motion of a Brownian particle moving in a potential field and driven by dichotomous noise with exponential correlation. Traditionally, the analytic as well as the numerical treatments of the problem, in general, rely on a Fokker–Planck description. We present a method for direct numerical simulation of dichotomous noise to solve the Langevin equation. The method is applied to calculate the nonequilibrium fluctuation induced current in a symmetric periodic potential using asymmetric dichotomous noise and compared to a Fokker–Planck–master equation based algorithm for a range of parameter values. Our second application concerns the study of resonant activation over a fluctuating barrier.

Escape rate from a metastable state weakly interacting with a heat bath driven by external noise

Based on a system-reservoir model, where the reservoir is driven by an external stationary, Gaussian noise with arbitrary decaying correlation function, we study the escape rate from a metastable state in the energy diffusion regime. For the open system we derive the Fokker-Planck equation in the energy space and subsequently calculate the generalized non-Markovian escape rate from a metastable well in the energy diffusion domain. By considering the dynamics in a model cubic potential we show that the results obtained from numerical simulation are in good agreement with the theoretical prediction. It has been also shown numerically that the well-known turnover feature can be restored from our model.

Quantum State-Dependent Diffusion and Multiplicative Noise: A Microscopic Approach

The state-dependent diffusion, which concerns the Brownian motion of a particle in inhomogeneous media has been described phenomenologically in a number of ways. Based on a system-reservoir nonlinear coupling model we present a microscopic approach to quantum state-dependent diffusion and multiplicative noise in terms of a quantum Markovian Langevin description and an associated Fokker–Planck equation in position space in the overdamped limit. We examine the thermodynamic consistency and explore the possibility of observing a quantum current, a generic quantum effect, as a consequence of this state-dependent diffusion similar to one proposed by Büttiker [Z. Phys. B 68:161 (1987)] in a classical context several years ago.

Noise-induced transition in a quantum system

We examine the noise-induced transition in a fluctuating bistable potential of a driven quantum system in thermal equilibrium. Making use of a Wigner canonical thermal distribution for description of the statistical properties of the thermal bath, we explore the generic effects of quantization like vacuum field fluctuation and tunneling in the characteristic stationary probability distribution functions undergoing transition from unimodal to bimodal nature and in signal-to-noise ratio characterizing the cooperative effect among the noise processes and the weak periodic signal.

Quantum escape kinetics over a fluctuating barrier

The escape rate of a particle over a fluctuating barrier in a double-well potential exhibits resonance at an optimum value of correlation time of fluctuation. This has been shown to be important in several variants of kinetic model of chemical reactions. We extend the analysis of this phenomenon of resonant activation to quantum domain to show how quantization significantly enhances resonant activation at low temperature due to tunneling.

Quantum phase-space function formulation of reactive flux theory

On the basis of a coherent-state representation of the quantum noise operator and an ensemble averaging procedure a scheme for quantum Brownian motion has been proposed recently [Banerjee et al., Phys. Rev. E 65, 021109 (2002); 66, 051105 (2002)]. We extend this approach to formulate reactive flux theory in terms of quantum phase space distribution functions and to derive a time-dependent quantum transmission coefficient—a quantum analog of the classical Kramers–Grote–Hynes coefficient in the spirit of Kohen and Tannor’s classical formulation. The theory is valid for arbitrary noise correlation and temperature. The specific forms of this coefficient in the Markovian as well as in the non-Markovian limits have been worked out in detail for the intermediate to strong damping regimes with an analysis of quantum effects. While the classical transmission coefficient is independent of temperature, its quantum counterpart has significant temperature dependence particularly in the low-temperature regime.

Dynamics of a metastable state nonlinearly coupled to a heat bath driven by external noise.

Based on a system-reservoir model, where the system is nonlinearly coupled to a heat bath and the heat bath is modulated by an external stationary Gaussian noise, we derive the generalized Langevin equation with space-dependent friction and multiplicative noise and construct the corresponding Fokker-Planck equation, valid for short correlation time, with space-dependent diffusion coefficient to study the escape rate from a metastable state in the moderate- to large-damping regime. By considering the dynamics in a model cubic potential we analyze the results numerically which are in good agreement with theoretical predictions. It has been shown numerically that enhancement of the rate is possible by properly tuning the correlation time of the external noise.