Computer Simulations of the Dissociation Mechanism of Gleevec from Abl Kinase with Milestoning

Gleevec (a.k.a., imatinib) is an important anticancer (e.g., chronic myeloid leukemia) chemotherapeutic drug due to its inhibitory interaction with the Abl kinase. Here, we use atomically detailed simulations within the Milestoning framework to study the molecular dissociation mechanism of Gleevec from Abl kinase. We compute the dissociation free energy profile, the mean first passage time for unbinding, and explore the transition state ensemble of conformations. The milestones form a multidimensional network with average connectivity of about 2.93, which is significantly higher than the connectivity for a one-dimensional reaction coordinate. The free energy barrier for Gleevec dissociation is estimated to be similar to 10 kcal/mol, and the exit time is similar to 55 ms. We examined the transition state conformations using both, the committor and transition function. We show that near the transition state the highly conserved salt bridge K217 and E286 is transiently broken. Together with the calculated free energy profile, these calculations can advance the understanding of the molecular interaction mechanisms between Gleevec and Abl kinase and play a role in future drug design and optimization studies.

Automated summary

This study used atomically detailed simulations within the Milestoning framework to investigate the molecular dissociation mechanism of Gleevec from Abl kinase. The researchers calculated the dissociation free energy profile, mean first passage time for unbinding, and explored the transition state ensemble of conformations. The study revealed that near the transition state, the highly conserved salt bridge between K217 and E286 is transiently broken.