Constructing and Analyzing Computational Models of Cell Signaling with BioModelAnalyzer

Abstract

BioModelAnalyzer (BMA) is an open‐source graphical tool for the development of executable models of protein and gene networks within cells. Based upon the Qualitative Networks formalism, the user can rapidly construct large networks, either manually or by connecting motifs selected from a built‐in library. After the appropriate functions for each variable are defined, the user has access to three analysis engines to test the model. In addition to standard simulation tools, BMA includes an interface to the stability‐testing algorithm and to a graphical Linear Temporal Logic (LTL) editor and analysis tool. Alongside this, we have developed a novel ChatBot to aid users constructing LTL queries and to explain the interface and run through tutorials. Here we present worked examples of model construction and testing via the interface. As an initial example, we discuss fate decisions in Dictyostelium discoidum and cAMP signaling. We go on to describe the workflow leading to the construction of a published model of the germline of C. elegans. Finally, we demonstrate how to construct simple models from the built‐in network motif library. © 2020 by John Wiley & Sons, Inc. Basic Protocol 1: Modeling the signaling network of Dictyostelium discoidum Basic Protocol 2: Modeling the germline progression of Caenorhabditis elegans Basic Protocol 3: Constructing a model of the cell cycle using motifs

Large-scale computational modelling of the M1 and M2 synovial macrophages in Rheumatoid Arthritis

“…To investigate such complex mechanisms, we developed a framework to calibrate large-scale Boolean models that can be either automatically inferred from molecular interaction maps using the CaSQ tool 24 or manually built in the BMA JSON format. We analyse the models using a newly developed BMA tool 26 version that can be deployed on Linux-based high-performance computing clusters to identify all their steady states. Given the high number of inputs combinations in large-scale Boolean models, using HPC clusters enables high throughput model analysis.…”

“…BioModelAnalyzer (BMA) is a tool for constructing, analysing, and importing executable models of biological mechanisms 26 . The user is presented with a web-based interface, allowing for rapid and straightforward model construction and analysis.…”

“…The framework uses publicly available molecular interaction maps to automatically infer their corresponding executable Boolean models via the CaSQ tool 24 . Our approach enables the analysis of the generated models in a synchronous scheme using a new version of the BMA tool 26 deployed to a high-performance computing cluster set-up. The framework identifies all the existing attractors of the models using parallel computing and then tests their coherence against gene expression datasets and prior knowledge.…”

Data Integration in Logic-based Models of Biological Mechanisms

“…These heuristics focus on retrieving stable states in lieu of searching the whole state space and significantly reducing the calculation burden, though the results are limited to analysing stable states. BMA [41,42] focuses on analysing stable states and, more particularly, fixed points, offering several highly scalable algorithms for model analysis, including stability proof, cycle searching, and linear temporal logic [43][44][45]. The specialisation of tools emphasises the importance of commonly agreed standards for model storage.…”

Verifiable biology

“…Due to its novel features to infer information about system behaviour, there is growing interest in applying this technique in systems biology [38,39]. Model checking has been applied to the analysis of various biological systems such as ERK/MAPK or FGF signalling pathway [40][41][42], EGFR pathway [43,44], T-cell receptor signalling pathway [45][46][47][48], cell cycle in eukaryotes [49,50], cell cycle control [51][52][53][54][55], mammalian cell cycle regulation [56,57], apoptosis network [58,59], bladder tumorigenesis [60], quorum sensing [61][62][63], biological control mechanisms [64], DNA computing [65][66][67], genetic oscillator [68,69], genetic Boolean gates [61,[70][71][72][73] and switches [73][74][75].…”