SUMMARY: Bayesian inference in biological modeling commonly relies on Markov chain Monte Carlo (MCMC) sampling of a multidimensional and non-Gaussian posterior distribution that is not analytically tractable. Here, we present the implementation of a practical MCMC method in the open-source software package PyBioNetFit (PyBNF), which is designed to support parameterization of mathematical models for biological systems. The new MCMC method, am, incorporates an adaptive move proposal distribution. For warm starts, sampling can be initiated at a specified location in parameter space and with a multivariate Gaussian proposal distribution defined initially by a specified covariance matrix. Multiple chains can be generated in parallel using a computer cluster. We demonstrate that am can be used to successfully solve real-world Bayesian inference problems, including forecasting of new Coronavirus Disease 2019 case detection with Bayesian quantification of forecast uncertainty. AVAILABILITY AND IMPLEMENTATION: PyBNF version 1.1.9, the first stable release with am, is available at PyPI and can be installed using the pip package-management system on platforms that have a working installation of Python 3. PyBNF relies on libRoadRunner and BioNetGen for simulations (e.g. numerical integration of ordinary differential equations defined in SBML or BNGL files) and Dask.Distributed for task scheduling on Linux computer clusters. The Python source code can be freely downloaded/cloned from GitHub and used and modified under terms of the BSD-3 license (https://github.com/lanl/pybnf). Online documentation covering installation/usage is available (https://pybnf.readthedocs.io/en/latest/). A tutorial video is available on YouTube (https://www.youtube.com/watch?v=2aRqpqFOiS4&t=63s). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Receptor tyrosine kinases (RTKs) typically contain multiple autophosphorylation sites in their cytoplasmic domains. Once activated, these autophosphorylation sites can recruit downstream signaling proteins containing Src homology 2 (SH2) and phosphotyrosine-binding (PTB) domains, which recognize phosphotyrosine-containing short linear motifs (SLiMs). These domains and SLiMs have polyspecific or promiscuous binding activities. Thus, multiple signaling proteins may compete for binding to a common SLiM and vice versa. To investigate the effects of competition on RTK signaling, we used a rule-based modeling approach to develop and analyze models for ligand-induced recruitment of SH2/PTB domain-containing proteins to autophosphorylation sites in the insulin-like growth factor 1 (IGF1) receptor (IGF1R). Models were parameterized using published datasets reporting protein copy numbers and site-specific binding affinities. Simulations were facilitated by a novel application of model restructuration, to reduce redundancy in rule-derived equations. We compare predictions obtained via numerical simulation of the model to those obtained through simple prediction methods, such as through an analytical approximation, or ranking by copy number and/or KD value, and find that the simple methods are unable to recapitulate the predictions of numerical simulations. We created 45 cell line-specific models that demonstrate how early events in IGF1R signaling depend on the protein abundance profile of a cell. Simulations, facilitated by model restructuration, identified pairs of IGF1R binding partners that are recruited in anti-correlated and correlated fashions, despite no inclusion of cooperativity in our models. This work shows that the outcome of competition depends on the physicochemical parameters that characterize pairwise interactions, as well as network properties, including network connectivity and the relative abundances of competitors.

UNLABELLED: Rule-based models are analyzed with specialized simulators, such as those provided by the BioNetGen and NFsim open-source software packages. Here, we present BioNetFit, a general-purpose fitting tool that is compatible with BioNetGen and NFsim. BioNetFit is designed to take advantage of distributed computing resources. This feature facilitates fitting (i.e. optimization of parameter values for consistency with data) when simulations are computationally expensive. AVAILABILITY AND IMPLEMENTATION: BioNetFit can be used on stand-alone Mac, Windows/Cygwin, and Linux platforms and on Linux-based clusters running SLURM, Torque/PBS, or SGE. The BioNetFit source code (Perl) is freely available (http://bionetfit.nau.edu). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. CONTACT: [email protected].

BACKGROUND: The system-level dynamics of many molecular interactions, particularly protein-protein interactions, can be conveniently represented using reaction rules, which can be specified using model-specification languages, such as the BioNetGen language (BNGL). A set of rules implicitly defines a (bio)chemical reaction network. The reaction network implied by a set of rules is often very large, and as a result, generation of the network implied by rules tends to be computationally expensive. Moreover, the cost of many commonly used methods for simulating network dynamics is a function of network size. Together these factors have limited application of the rule-based modeling approach. Recently, several methods for simulating rule-based models have been developed that avoid the expensive step of network generation. The cost of these "network-free" simulation methods is independent of the number of reactions implied by rules. Software implementing such methods is now needed for the simulation and analysis of rule-based models of biochemical systems. RESULTS: Here, we present a software tool called RuleMonkey, which implements a network-free method for simulation of rule-based models that is similar to Gillespie's method. The method is suitable for rule-based models that can be encoded in BNGL, including models with rules that have global application conditions, such as rules for intramolecular association reactions. In addition, the method is rejection free, unlike other network-free methods that introduce null events, i.e., steps in the simulation procedure that do not change the state of the reaction system being simulated. We verify that RuleMonkey produces correct simulation results, and we compare its performance against DYNSTOC, another BNGL-compliant tool for network-free simulation of rule-based models. We also compare RuleMonkey against problem-specific codes implementing network-free simulation methods. CONCLUSIONS: RuleMonkey enables the simulation of rule-based models for which the underlying reaction networks are large. It is typically faster than DYNSTOC for benchmark problems that we have examined. RuleMonkey is freely available as a stand-alone application http://public.tgen.org/rulemonkey. It is also available as a simulation engine within GetBonNie, a web-based environment for building, analyzing and sharing rule-based models.

MOTIVATION: Interactions of molecules, such as signaling proteins, with multiple binding sites and/or multiple sites of post-translational covalent modification can be modeled using reaction rules. Rules comprehensively, but implicitly, define the individual chemical species and reactions that molecular interactions can potentially generate. Although rules can be automatically processed to define a biochemical reaction network, the network implied by a set of rules is often too large to generate completely or to simulate using conventional procedures. To address this problem, we present DYNSTOC, a general-purpose tool for simulating rule-based models. RESULTS: DYNSTOC implements a null-event algorithm for simulating chemical reactions in a homogenous reaction compartment. The simulation method does not require that a reaction network be specified explicitly in advance, but rather takes advantage of the availability of the reaction rules in a rule-based specification of a network to determine if a randomly selected set of molecular components participates in a reaction during a time step. DYNSTOC reads reaction rules written in the BioNetGen language which is useful for modeling protein-protein interactions involved in signal transduction. The method of DYNSTOC is closely related to that of StochSim. DYNSTOC differs from StochSim by allowing for model specification in terms of BNGL, which extends the range of protein complexes that can be considered in a model. DYNSTOC enables the simulation of rule-based models that cannot be simulated by conventional methods. We demonstrate the ability of DYNSTOC to simulate models accounting for multisite phosphorylation and multivalent binding processes that are characterized by large numbers of reactions. AVAILABILITY: DYNSTOC is free for non-commercial use. The C source code, supporting documentation and example input files are available at http://public.tgen.org/dynstoc/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

SUMMARY: GetBonNie is a web-based application for building, analyzing and sharing rule-based models encoded in the BioNetGen language (BNGL). Tools accessible within the GetBonNie environment include (i) an applet for drawing graphs that correspond to BNGL code; (ii) a network-generation engine for translating a set of rules into a chemical reaction network; (iii) simulation engines that implement generate-first, on-the-fly and network-free methods for simulating rule-based models; and (iv) a database for sharing models, parameter values, annotations, simulation tasks and results. AVAILABILITY: GetBonNie is free at (http://getbonnie.org).