Exploring the Conformational Space of MPS1 Kinase Using Metadynamics

ABSTRACT MPS1 kinase is a dual specificity kinase that plays an important role in the spindle assembly checkpoint mechanism during cell division. Overexpression of MPS1 kinase is reported in several cancers. However, drug discovery and development efforts targeting MPS1 kinase did not result in any clinically successful candidates. All the reported crystal structures of MPS1 kinase adopt the DFG “ in ” conformation. Knowledge of the other conformations of the kinase would be beneficial in the structure‐based drug design of novel inhibitors. This work employs well‐tempered metadynamics simulations to explore the conformational space of MPS1 kinase by using its experimentally determined DFG “ in ” conformation as the starting structure. The simulation could successfully predict the DFG “ out ” conformation and identify the possible transition states. The key interactions that stabilize the kinase in various conformations were identified, and the effect of phosphorylation of the key residues on the conformation of the kinase was determined.