Robustness analysis identifies the plausible model of the Bcl-2 apoptotic switch

In this paper two competing models of the B-cell lymphoma 2 (Bcl-2) apoptotic switch were contrasted by mathematical modeling and robustness analysis. Since switch-like behaviors are required for models that attempt to explain the all-or-none decisions of apoptosis, ultrasensitivity was employed as a criterion for comparison. Our results successfully exhibit that the direct activation model operates more reliably to achieve a robust switch in cellular conditions. Moreover, by investigating the robustness of other important features of the Bcl-2 apoptotic switch (including low Bax basal activation, inhibitory role of anti-apoptotic proteins and insensitivity to small perturbations) the direct activation model was further supported. In all, we identified the direct activation model as a more plausible explanation for the Bcl-2 apoptotic switch.