Cancer Cell: Linking Oncogenic Signaling to Molecular Structure.

A multiscale strategy is presented for constructing models of intracellular signaling networks in which the oncogenic behavior of the network is encoded through alternate parameterization of the kinetic and structural properties of mutant oncoproteins. The approach uses molecular dynamics and docking simulations to quantify altered topologies of interactions as well as to provide the missing parameters for network models of both wild-type and oncogenic signaling. Through simulation of the resulting signaling networks, the global behavior of these networks may then be compared and functional roles may be assigned to the mutant oncoproteins. An example of this approach is presented in which structural alterations found in a mutant form of the epidermal growth factor receptor are represented as kinetic perturbations in a model of growth factor signaling. Based on network parameters estimated from molecular-level simulations, simulations at the network level show that small perturbations in molecular structure can lead to profoundly altered cellular phenotype.