(63b) Activation Mechanism of c-Src Tyrosine Kinase

Mechanistic understanding of the large scale conformational transformations coupled with activation of kinases is of enormous importance for treating aberrant kinase signaling, which leads to uncontrolled growth and differentiation of cancerous cells. Atomistic molecular dynamics simulations of kinases could capture these conformational transitions. However, due to the long timescales (100’s of μs) associated with activation, such simulations are not feasible except on dedicated hardware. In this study, we employ an alternative computational paradigm that couples transition pathway generation techniques and Markov State Model (MSM) based massively distributed simulations for mapping the conformational landscape of c-src tyrosine kinase. MSMs of c-src tyrosine kinase capture the thermodynamics and kinetics of kinase activation for the first time, and help identify key intermediates along the activation pathway. We also predict the existence of a novel allosteric site in c-src intermediate state, which could be potentially utilized for drug design. Furthermore, kinetic model of kinase autophosphorylation built using the data obtained from atomistic simulations predict the experimentally observed induction time in the time evolution of active kinase population.