The Secrets in Their Landscapes: Elucidating Activation Mechanism of Key Signaling Proteins for Selective Drug Design

Mechanistic understanding of the large scale conformational transformations coupled with activation of key signaling proteins such as G-Protein Coupled Receptors (GPCRs) and Kinases are of enormous importance for the development of therapeutic drugs for the treatment of diseases such as cancer, asthma, cardiovascular disorders etc. In principle, the nature of conformational transition could be modeled in silico via atomistic molecular dynamics simulations, although this is very challenging due to the long activation timescales (in milliseconds). We employ a computational paradigm that couples cloud computing, transition pathway techniques and Markov State Model (MSM) based novel sampling algorithms for mapping the conformational landscape of β₂ adrenergic receptor (β₂AR) - a major drug target G protein-coupled receptor (GPCR) and c-Src kinase - a key enzyme involved in uncontrolled cell growth and differentiation in cancerous cells. These computations provide the thermodynamics and kinetics of their activation for the first time, and help identify key structural intermediates and novel allosteric sites for targeted drug design.