Approximating solutions of the Chemical Master equation using neural networks.

The Chemical Master Equation (CME) provides an accurate description of stochastic biochemical reaction networks in well-mixed conditions, but it cannot be solved analytically for most systems of practical interest. Although Monte Carlo methods provide a principled means to probe system dynamics, the large number of simulations typically required can render the estimation of molecule number distributions and other quantities infeasible. In this article, we aim to leverage the representational power of neural networks to approximate the solutions of the CME and propose a framework for the Neural Estimation of Stochastic Simulations for Inference and Exploration (Nessie). Our approach is based on training neural networks to learn the distributions predicted by the CME from relatively few stochastic simulations. We show on biologically relevant examples that simple neural networks with one hidden layer can capture highly complex distributions across parameter space, thereby accelerating computationally intensive tasks such as parameter exploration and inference.

MomentClosure.jl: automated moment closure approximations in Julia.

SUMMARY: MomentClosure.jl is a Julia package providing automated derivation of the time-evolution equations of the moments of molecule numbers for virtually any chemical reaction network using a wide range of moment closure approximations. It extends the capabilities of modelling stochastic biochemical systems in Julia and can be particularly useful when exact analytic solutions of the chemical master equation are unavailable and when Monte Carlo simulations are computationally expensive. AVAILABILITY AND IMPLEMENTATION: MomentClosure.jl is freely accessible under the MIT licence. Source code and documentation are available at https://github.com/augustinas1/MomentClosure.jl.

Stochastic time-dependent enzyme kinetics: Closed-form solution and transient bimodality.

We derive an approximate closed-form solution to the chemical master equation describing the Michaelis-Menten reaction mechanism of enzyme action. In particular, assuming that the probability of a complex dissociating into an enzyme and substrate is significantly larger than the probability of a product formation event, we obtain expressions for the time-dependent marginal probability distributions of the number of substrate and enzyme molecules. For delta function initial conditions, we show that the substrate distribution is either unimodal at all times or else becomes bimodal at intermediate times. This transient bimodality, which has no deterministic counterpart, manifests when the initial number of substrate molecules is much larger than the total number of enzyme molecules and if the frequency of enzyme-substrate binding events is large enough. Furthermore, we show that our closed-form solution is different from the solution of the chemical master equation reduced by means of the widely used discrete stochastic Michaelis-Menten approximation, where the propensity for substrate decay has a hyperbolic dependence on the number of substrate molecules. The differences arise because the latter does not take into account enzyme number fluctuations, while our approach includes them. We confirm by means of a stochastic simulation of all the elementary reaction steps in the Michaelis-Menten mechanism that our closed-form solution is accurate over a larger region of parameter space than that obtained using the discrete stochastic Michaelis-Menten approximation.