  The bistable gene regulatory switch controlling the transition from lysogeny
to lysis in bacteriophage lambda presents a unique challenge to quantitative
modeling. Despite extensive characterization of this regulatory network, the
origin of the extreme stability of the lysogenic state remains unclear. We have
constructed a stochastic model for this switch. Using Forward Flux Sampling
simulations, we show that this model predicts an extremely low rate of
spontaneous prophage induction in a recA mutant, in agreement with experimental
observations. In our model, the DNA loop formed by octamerization of CI bound
to the O_L and O_R operator regions is crucial for stability, allowing the
lysogenic state to remain stable even when a large fraction of the total CI is
depleted by nonspecific binding to genomic DNA. DNA looping also ensures that
the switch is robust to mutations in the order of the O_R binding sites. Our
results suggest that DNA looping can provide a mechanism to maintain a stable
lysogenic state in the face of a range of challenges including noisy gene
expression, nonspecific DNA binding and operator site mutations.
