As a simple but illustrative example of the model construction process,
we present a small biochemical model of the first few steps of ICL
detection and repair by the FA/BRCA pathway (58, 59). During DNA
replication, the presence of an ICL causes the replication fork to
stall. This stressed fork is detected by the protein FANCM, which binds
to the branched DNA structure caused by replication fork arrest and
recruits the FA “core complex” to the damage site (Fig. 5A).
The FA core complex is composed of three protein subcomplexes, each of
which is composed of three proteins (Fig. 5B): AG20 is a
complex of the proteins FANCA, FANCG, and FAAP20 (FA core complex
associated protein 20); BL100 is a complex of FANCB, FANCL, and FAAP100;
and CEF is a complex of FANCC, FANCE, and FANCF. For simplicity, we have
chosen to represent in the model each of these subcomplexes as distinct
molecular species that reversibly bind to each other to form the FA core
complex. The complete computational model includes these subcomplex
binding reactions, the binding of FANCM to the ICL, and binding of the
FA core complex to ICL-bound FANCM (Fig. 5C). By defining
parameter values for the rates of each of these individual reactions,
the model becomes executable, i.e., the populations (or
concentrations) of the constituent species can be simulated over time
(Fig. 5D). In this way, hypotheses regarding the effects of
mutations (changing parameter values) and/or adding external
perturbagens (e.g., drugs) can be explored in silico.