Activation of Abl1 Kinase Explored Using Well-Tempered Metadynamics Simulations on an Essential Dynamics Sampled Path

Well-tempered metadynamics
(wT-metaD) simulations using path collective
variables (CVs) have been successfully applied in recent years to
explore conformational transitions in protein kinases and other biomolecular
systems. While this methodology has the advantage of describing the
transitions with a limited number of predefined path CVs, it requires
as an input a reference path connecting the initial and target states
of the system. It is desirable to automate the path generation using
approaches that do not rely on the choice of geometric CVs to describe
the transition of interest. To this end, we developed an approach
that couples essential dynamics sampling with wT-metaD simulations.
We used this newly developed procedure to explore the activation mechanism
of Abl1 kinase and compute the associated free energy barriers. Through
these simulations, we identified a three-step mechanism for the activation
that involved two metastable intermediates that possessed a partially
open activation loop and differed primarily in the “in”
or “out” conformation of the aspartate residue of the
DFG motif. One of these states is similar to a conformation that was
detected in previous spectroscopic studies of Abl1 kinase, albeit
its mechanistic role in the activation was hitherto not well understood.
The present study establishes its intermediary role in the activation
and predicts a rate-determining free energy barrier of 13.8 kcal/mol
that is in good agreement with previous experimental and computational
estimates. Overall, our study demonstrates the usability of essential
dynamics sampling as a path CV in wT-metaD to conveniently study conformational
transitions and accurately calculate the associated barriers.