  BioNetFit is a software tool designed for solving parameter identification
problems that arise in the development of rule-based models. It solves these
problems through curve fitting (i.e., nonlinear regression). BioNetFit is
compatible with deterministic and stochastic simulators that accept BioNetGen
language (BNGL)-formatted files as inputs, such those available within the
BioNetGen framework. BioNetFit can be used on a laptop or standalone multicore
workstation as well as on many Linux clusters, such as those that use the Slurm
Workload Manager to schedule jobs. BioNetFit implements a metaheuristic
population-based global optimization procedure, an evolutionary algorithm (EA),
to minimize a user-defined objective function, such as a residual sum of
squares (RSS) function. BioNetFit also implements a bootstrapping procedure for
determining confidence intervals for parameter estimates. Here, we provide
step-by-step instructions for using BioNetFit to estimate the values of
parameters of a BNGL-encoded model and to define bootstrap confidence
intervals. The process entails the use of several plain-text files, which are
processed by BioNetFit and BioNetGen. In general, these files include 1) one or
more EXP files, which each contains (experimental) data to be used in parameter
identification/bootstrapping; 2) a BNGL file containing a model section, which
defines a (rule-based) model, and an actions section, which defines simulation
protocols that generate GDAT and/or SCAN files with model predictions
corresponding to the data in the EXP file(s); and 3) a CONF file that
configures the fitting/bootstrapping job and that defines algorithmic parameter
settings.
