Dynamic conformational states of apo and cabozantinib bound TAM kinases to differentiate active-inactive kinetic models

Abstract

AbstractTyro3, Axl, Mer (TAM) receptor tyrosine kinases (RTKs) are overexpressed in several human cancers. Cabozantinib, a small molecule inhibitor constrains the activity of TAM kinases at nanomolar concentrations. The dynamic active and inactive conformations of kinases play a crucial role in inhibitor binding and the activation of intracellular downstream signalling pathways. The all atom molecular dynamics (MD) simulations at microsecond timescale and longer provide robust insights into the structural details of conformational alterations of proteins due to their role cellular metabolic activities and signaling pathways. In this current study we report microsecond molecular dynamics (MD) simulations of apo, cabozantinib complexed active and inactive TAM RTKs and analysed the post-MD trajectories using the principal component analysis (PCA). Markov State Models (MSM) and transition pathways from Perron-cluster cluster analysis. For consensus, the 1µs atomistic simulations with enhanced computational algorithms indicated us to treat tyrosine kinase family by overwhelming dynamic states existence when bound to kinase inhibitors. The dynamic mechanistic pathways intrinsic to the kinase activity and protein conformational landscape in the TAM kinases are revealed due to the alterations in the P-loop, αC-helix, activation loop and αF-helix that result in breaking the regulatory and catalytic spines. We deciphered the long lived kinetic transition states of distinct active and inactive structural models from MD simulations trajectories of TAM RTKs bound inhibitor complex that have not been revealed so far.