Kinases are cellular signaling proteins involved in various physiological functions. Small molecules and other allosteric enhancers bind to these proteins and modulate their function. The drug binding sites of kinases share a high degree of similarity but differ significantly in their selectivity towards the same binding partner. Designing selective molecules and elucidating functional mechanisms is a key challenge in the drug discovery pipeline. Since the conformational changes of these proteins occur at long time scales, powerful computational resources are required to study these complex systems. Using Blue Waters Supercomputer, we have been able to study these rare biological events at multi-microsecond time scales. In particular, we employed computational ancestral gene resurrection methodology to investigate ancestral proteins along the evolutionary tree connecting the modern proteins to shed light on the molecular origin of the differences in selectivity of the modern proteins. Our results reveal the molecular mechanisms of ligand selectivity in kinases along with the atomic level details of conformational changes associated with these binding events. We have also investigated Kinases associated with plant growth to elucidate molecular mechanisms responsible for plant growth under adverse environmental conditions. These simulations have revealed new mechanisms for conformational control of kinase activity in plants.
