Research Article

Systems and Synthetic Biology

, Volume 2, Issue 1, pp 49-66

First online:

Open Access This content is freely available online to anyone, anywhere at any time.

Mathematical modeling of the formation of apoptosome in intrinsic pathway of apoptosis

  • Seongho RyuAffiliated withDepartment of Biology, New York UniversityNYU/Courant Bioinformatics Group, Courant Institute, New York University
  • , Shih-chieh LinAffiliated withCold Spring Harbor Laboratory
  • , Nadia UgelAffiliated withNYU/Courant Bioinformatics Group, Courant Institute, New York University
  • , Marco AntoniottiAffiliated withNYU/Courant Bioinformatics Group, Courant Institute, New York UniversityDISCo Università Milano Bicocca
  • , Bud MishraAffiliated withNYU/Courant Bioinformatics Group, Courant Institute, New York UniversityNYU School of Medicine, New York University Email author 

Abstract

Caspase-9 is the protease that mediates the intrinsic pathway of apoptosis, a type of cell death. Activation of caspase-9 is a multi-step process that requires dATP or ATP and involves at least two proteins, cytochrome c and Apaf-1. In this study, we mathematically model caspase-9 activation by using a system of ordinary differential equations (an ODE model) generated by a systems biology tool Simpathica—a simulation and reasoning system, developed to study biological pathways. A rudimentary version of “model checking” based on comparing simulation data with that obtained from a recombinant system of caspase-9 activation, provided several new insights into regulation of this protease. The model predicts that the activation begins with binding of dATP to Apaf-1, which initiates the interaction between Apaf-1 and cytochrome c, thus forming a complex that oligomerizes into an active caspase-9 holoenzyme via a linear binding model with cooperative interaction rather than through network formation.

Keywords

Model checking Model comparison and selection Apoptosis Apoptosome Caspase-9 ODE model Computational systems biology