Our paper “Activation pathway of Src kinase reveals intermediate states as targets for drug design” in Nature Communications has just come out. As with Nature journals, it’s unfortunately behind a pay wall, but per NIH rules, it will become open access in a year. The key results in this paper is the use of FAH simulations to understand a key protein target in cancer (src kinase), especially to find new ways to target it for novel drug design.
A more technical summary is given in our abstract:
Unregulated activation of Src kinases leads to aberrant signaling, uncontrolled growth and differentiation of cancerous cells. Reaching a complete mechanistic understanding of 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 principle, the nature of conformational transition could be modeled in silico via atomistic molecular dynamics simulations, although this is very challenging because of the long activation timescales. Here we employ a computational paradigm that couples transition pathway techniques and Markov state model-based massively distributed simulations for mapping the conformational landscape of c-src tyrosine kinase. The computations provide the thermodynamics and kinetics of kinase activation for the first time, and help identify key structural intermediates. Furthermore, the presence of a novel allosteric site in an intermediate state of c-src that could be potentially used for drug design is predicted.