The interplay between discrete noise and nonlinear chemical kinetics in a signal amplification cascade

We used various analytical and numerical techniques to elucidate signal propagation in a small enzymatic cascade which is subjected to external and internal noise. The nonlinear character of catalytic reactions, which underlie protein signal transduction cascades, renders stochastic signaling dynamics in cytosol biochemical networks distinct from the usual description of stochastic dynamics in gene regulatory networks. For a simple 2-step enzymatic cascade which underlies many important protein signaling pathways, we demonstrated that the commonly used techniques such as the linear noise approximation and the Langevin equation become inadequate when the number of proteins becomes too low. Consequently, we developed a new analytical approximation, based on mixing the generating function and distribution function approaches, to the solution of the master equation that describes nonlinear chemical signaling kinetics for this important class of biochemical reactions. Our techniques work in a much wider range of protein number fluctuations than the methods used previously. We found that under certain conditions the burst-phase noise may be injected into the downstream signaling network dynamics, resulting possibly in unusually large macroscopic fluctuations. In addition to computing first and second moments, which is the goal of commonly used analytical techniques, our new approach provides the full time-dependent probability distributions of the colored non-Gaussian processes in a nonlinear signal transduction cascade.Comment: 16 pages, 9 figure

Stochastic Ratcheting on a Funneled Energy Landscape is Necessary for Highly Efficient Contractility of Actomyosin Force Dipoles

Current understanding of how contractility emerges in disordered actomyosin networks of non-muscle cells is still largely based on the intuition derived from earlier works on muscle contractility. This view, however, largely overlooks the free energy gain following passive cross-linker binding, which, even in the absence of active fluctuations, provides a thermodynamic drive towards highly overlapping filamentous states. In this work, we shed light on this phenomenon, showing that passive cross-linkers, when considered in the context of two anti-parallel filaments, generate noticeable contractile forces. However, as binding free energy of cross-linkers is increased, a sharp onset of kinetic arrest follows, greatly diminishing effectiveness of this contractility mechanism, allowing the network to contract only with weakly resisting tensions at its boundary. We have carried out stochastic simulations elucidating this mechanism, followed by a mean-field treatment that predicts how contractile forces asymptotically scale at small and large binding energies, respectively. Furthermore, when considering an active contractile filament pair, based on non-muscle myosin II, we found that the non-processive nature of these motors leads to highly inefficient force generation, due to recoil slippage of the overlap during periods when the motor is dissociated. However, we discovered that passive cross-linkers can serve as a structural ratchet during these unbound motor time spans, resulting in vast force amplification. Our results shed light on the non-equilibrium effects of transiently binding proteins in biological active matter, as observed in the non-muscle actin cytoskeleton, showing that highly efficient contractile force dipoles result from synergy of passive cross-linker and active motor dynamics, via a ratcheting mechanism on a funneled energy landscape.Comment: 13 pages, 6 figure

Multiscale stochastic reaction-diffusion modelling: application to actin dynamics in filopodia

Two multiscale (hybrid) stochastic reaction-diffusion models of actin dynamics in a filopodium are investigated. Both hybrid algorithms combine compartment-based and molecular-based stochastic reaction-diffusion models. The first hybrid model is based on the models previously\ud developed in the literature. The second hybrid model is based on the application of recently developed two-regime method (TRM) to a fully molecular-based model which is also developed in this paper. The results of hybrid models are compared with the results of the molecular-based model. It is shown that both approaches give comparable results, although the TRM model better agrees quantitatively with the molecular-based model

Noncommutativity Effects in FRW Scalar Field Cosmology

We study effects of noncommutativity on the phase space generated by a non-minimal scalar field which is conformally coupled to the background curvature in an isotropic and homogeneous FRW cosmology. These effects are considered in two cases, when the potential of scalar field has zero and nonzero constant values. The investigation is carried out by means of a comparative detailed analysis of mathematical features of the evolution of universe and the most probable universe wave functions in classically commutative and noncommutative frames and quantum counterparts. The influence of noncommutativity is explored by the two noncommutative parameters of space and momentum sectors with a relative focus on the role of the noncommutative parameter of momentum sector. The solutions are presented with some of their numerical diagrams, in the commutative and noncommutative scenarios, and their properties are compared. We find that impose of noncommutativity in the momentum sector causes more ability in tuning time solutions of variables in classical level, and has more probable states of universe in quantum level. We also demonstrate that special solutions in classical and allowed wave functions in quantum models impose bounds on the values of noncommutative parameters.Comment: 13 pages, 5 figure

The Stochastic Dynamics of Filopodial Growth

AbstractA filopodium is a cytoplasmic projection, exquisitely built and regulated, which extends from the leading edge of the migrating cell, exploring the cell's neighborhood. Commonly, filopodia grow and retract after their initiation, exhibiting rich dynamical behaviors. We model the growth of a filopodium based on a stochastic description which incorporates mechanical, physical, and biochemical components. Our model provides a full stochastic treatment of the actin monomer diffusion and polymerization of each individual actin filament under stress of the fluctuating membrane. We investigated the length distribution of individual filaments in a growing filopodium and studied how it depends on various physical parameters. The distribution of filament lengths turned out to be narrow, which we explained by the negative feedback created by the membrane load and monomeric G-actin gradient. We also discovered that filopodial growth is strongly diminished upon increasing retrograde flow, suggesting that regulating the retrograde flow rate would be a highly efficient way to control filopodial extension dynamics. The filopodial length increases as the membrane fluctuations decrease, which we attributed to the unequal loading of the membrane force among individual filaments, which, in turn, results in larger average polymerization rates. We also observed significant diffusional noise of G-actin monomers, which leads to smaller G-actin flux along the filopodial tube compared with the prediction using the diffusion equation. Overall, partial cancellation of these two fluctuation effects allows a simple mean field model to rationalize most of our simulation results. However, fast fluctuations significantly renormalize the mean field model parameters. The biological significance of our filopodial model and avenues for future development are also discussed

Steric Effects Induce Geometric Remodeling of Actin Bundles in Filopodia.

Filopodia are ubiquitous fingerlike protrusions, spawned by many eukaryotic cells, to probe and interact with their environments. Polymerization dynamics of actin filaments, comprising the structural core of filopodia, largely determine their instantaneous lengths and overall lifetimes. The polymerization reactions at the filopodial tip require transport of G-actin, which enter the filopodial tube from the filopodial base and diffuse toward the filament barbed ends near the tip. Actin filaments are mechanically coupled into a tight bundle by cross-linker proteins. Interestingly, many of these proteins are relatively short, restricting the free diffusion of cytosolic G-actin throughout the bundle and, in particular, its penetration into the bundle core. To investigate the effect of steric restrictions on G-actin diffusion by the porous structure of filopodial actin filament bundle, we used a particle-based stochastic simulation approach. We discovered that excluded volume interactions result in partial and then full collapse of central filaments in the bundle, leading to a hollowed-out structure. The latter may further collapse radially due to the activity of cross-linking proteins, hence producing conical-shaped filament bundles. Interestingly, electron microscopy experiments on mature filopodia indeed frequently reveal actin bundles that are narrow at the tip and wider at the base. Overall, our work demonstrates that excluded volume effects in the context of reaction-diffusion processes in porous networks may lead to unexpected geometric growth patterns and complicated, history-dependent dynamics of intermediate metastable configurations.he research leading to these results received funding from the European Research Council under the European Community’s Seventh Framework Programme (FP7/2007-2013) / ERC grant agreement No. 239870. R.E. thanks the Royal Society for a University Research Fellowship, and the Leverhulme Trust for a Philip Leverhulme Prize (this prize money was used to support research visits of G.A.P. in Oxford). G.A.P. was supported by National Science Foundation grant No. CHE-1363081. U.D. was supported by a Junior Interdisciplinary Fellowship via Wellcome Trust grant No. 105602/Z/14/Z. This work was partially carried out during a visit by R.E. and U.D. to the Isaac Newton Institute. This work was partially supported by a grant from the Simons Foundation