Modeling possible scenarios of single and double synthetic lethal mutations (continued).

<p>Pathway steady states depicted as <b>Normal states</b> (<b>N</b>) as Normal Robust (<b>NR</b>) and Normal Fragile (<b>NF</b>); <b>Mutant states</b> (<b>M</b>) as compensated state dependent on compensatory pathway EC(<b>C</b>); death from DNA damage (<b>DD</b>) and death from toxicity (<b>DT</b>). <b>Dynamic plots</b> show prediction of model for evolution of substrate (<b>S</b>), intermediate (<b>I</b>) and product (<b>P</b>) amounts over time corresponding to the choice of kinetic parameters shown on the <b>Model diagram</b>. (<b>X-axis</b>)-time, (<b>Y-axis</b>)-substances level. <b>F1</b>, <b>F2</b>, <b>R1</b>, <b>R2</b>, and <b>EC</b> refer to the enzymes catalyzing the two forward and two backward reactions as well as the compensatory pathway, respectively (see <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003016#pcbi-1003016-g003" target="_blank">Figure 3</a>). (↓)-complete knock-down or mutational loss of function; (↑)-over-expression. A deletion mutant was simulated by setting the corresponding kinetic rate constant to zero. An overexpression mutant was simulated by setting the corresponding kinetic rate constant sufficiently high to have a qualitative effect onto the steady state or the dynamics in the simulations. Some double mutants are not shown due to their triviality (such as F1↓F2↓) or difficulties with interpretation (such as F1↓R1↓). For more modeling scenarios see Figure S5 in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003016#pcbi.1003016.s001" target="_blank">Text S1</a>.