Multiscale Modeling of Macromolecular-Assembly Networks

Jose Vilar

Computational Biology Center, Memorial Sloan-Kettering Cancer Center

The formation and regulation of macromolecular complexes provides the backbone of most cellular processes, including gene regulation and signal transduction. The inherent complexity of assembling macromolecular structures makes current theoretical and computational methods strongly limited for understanding how the physical interactions between cellular components give rise to systemic properties of cells. I will present a stochastic approach to study the collective dynamics of macromolecular complexes in terms of the molecular interactions of their components. Exploiting key thermodynamic concepts, this approach makes it possible to both estimate reaction rates and incorporate the resulting assembly dynamics into the stochastic kinetics of cellular networks. As prototype systems, I will discuss the lac operon and phage lambda genetic switches, which rely on the formation of DNA loops by proteins and on the integration of these protein-DNA complexes into intracellular networks. In the case of phage lambda, we consider 1458 different macromolecular species that are connected to each other through 18,954 reactions. With this methodology we can study simultaneously scales that range from milliseconds, including molecular binding events, to days and hours, including cell physiology and cell-population behavior.