Activation Pathways of Kinases Reveal Intermediate States as Novel Targets for Drug Design

Abstract

Unregulated activation of kinases leads to aberrant signaling, uncontrolled growth, and differentiation of cancerous cells. Reaching a complete mechanistic understanding of the large scale conformational transformations underlying the activation of kinases could greatly help in the development of therapeutic drugs for the treatment of these pathologies. In princi- ple, the nature of conformational transition could be modeled by in silico via atomistic molecular dynamics simulations, although this is very challenging due to the long timescales (100s of μs) associated with activation. In this study, we employ a computational paradigm that couples transition pathway generation techniques and Markov State Model (MSM) based massively (total simulation time of ∼3 milliseconds) distributed simulations for mapping the conformational landscape of several key tyrosine kinases. The computations provide the thermodynamics and kinetics of kinase activation for the first time, and help identify key intermediates along the activation pathway. Furthermore, the presence of a novel allosteric sites in an intermediate states of kinases that could be potentially utilized for drug design is predicted.View Large Image | View Hi-Res Image | Download PowerPoint Slide