COVRECON: Combining Genome-scale Metabolic Network Reconstruction and Data-driven Inverse Modeling to Reveal Changes in Metabolic Interaction Networks

One central goal of systems biology is to infer biochemical regulations from large-scale OMICS data. Many aspects of cellular physiology and organism phenotypes could be understood as a result of the metabolic interaction network dynamics. Previously, we have derived a mathematical method addressing this problem using metabolomics data for the inverse calculation of a biochemical Jacobian network. However, these algorithms for this inference are limited by two issues: they rely on structural network information that needs to be assembled manually, and they are numerically unstable due to ill-conditioned regression problems, which makes them inadequate for dealing with large-scale metabolic networks. In this work, we present a novel regression-loss based inverse Jacobian algorithm and related workflow COVRECON. It consists of two parts: a, Sim-Network and b, Inverse differential Jacobian evaluation. Sim-Network automatically generates an organism-specific enzyme and reaction dataset from Bigg and KEGG databases, which is then used to reconstruct the Jacobian's structure for a specific metabolomics dataset. Instead of directly solving a regression problem, the new inverse differential Jacobian part is based on a more robust approach and rates the biochemical interactions according to their relevance from large-scale metabolomics data. This approach is illustrated by in silico stochastic analysis with different-sized metabolic networks from the BioModels database. The advantages of COVRECON are that 1) it automatically reconstructs a data-driven superpathway metabolic interaction model; 2) more general network structures can be considered; 3) the new inverse algorithms improve stability, decrease computation time, and extend to large-scale modelsComment: non

Simulation and inference algorithms for stochastic biochemical reaction networks: from basic concepts to state-of-the-art

Stochasticity is a key characteristic of intracellular processes such as gene regulation and chemical signalling. Therefore, characterising stochastic effects in biochemical systems is essential to understand the complex dynamics of living things. Mathematical idealisations of biochemically reacting systems must be able to capture stochastic phenomena. While robust theory exists to describe such stochastic models, the computational challenges in exploring these models can be a significant burden in practice since realistic models are analytically intractable. Determining the expected behaviour and variability of a stochastic biochemical reaction network requires many probabilistic simulations of its evolution. Using a biochemical reaction network model to assist in the interpretation of time course data from a biological experiment is an even greater challenge due to the intractability of the likelihood function for determining observation probabilities. These computational challenges have been subjects of active research for over four decades. In this review, we present an accessible discussion of the major historical developments and state-of-the-art computational techniques relevant to simulation and inference problems for stochastic biochemical reaction network models. Detailed algorithms for particularly important methods are described and complemented with MATLAB implementations. As a result, this review provides a practical and accessible introduction to computational methods for stochastic models within the life sciences community

Kinetic Intersections as a Source of Information on Rate Coefficients

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Revealing networks from dynamics: an introduction

What can we learn from the collective dynamics of a complex network about its interaction topology? Taking the perspective from nonlinear dynamics, we briefly review recent progress on how to infer structural connectivity (direct interactions) from accessing the dynamics of the units. Potential applications range from interaction networks in physics, to chemical and metabolic reactions, protein and gene regulatory networks as well as neural circuits in biology and electric power grids or wireless sensor networks in engineering. Moreover, we briefly mention some standard ways of inferring effective or functional connectivity.Comment: Topical review, 48 pages, 7 figure

Analysis of Brownian dynamics simulations of reversible biomolecular reactions

A class of Brownian dynamics algorithms for stochastic reaction-diffusion models which include reversible bimolecular reactions is presented and analyzed. The method is a generalization of the λ-rho model for irreversible bimolecular reactions which was introduced in [11]. The formulae relating the experimentally measurable quantities (reaction rate constants and diffusion constants) with the algorithm parameters are derived. The probability of geminate recombination is also investigated