Conformational plasticity presents a challenge and opportunity in kinase drug discovery. The ability to predictively model various conformational states could accelerate selective inhibitor design. In this talk, I will present our recent study utilizing the continous constant pH molecular dynamics simulations to understand the factors modulating the conformational free energy landscape of a c-Src kinase. Our study addresses the controversy regarding the protonation dependence of the DFG flip, and reveals how populations of the various inactive states and the active state are modulated by protonation state changes of  titratable residues playing key roles in kinase activation and catalysis. Our work suggests that accouting for proton coupling may significantly improve our ability to predictively model kinase conformational landscapes.

Proton coupling modulates the free energy landscape of c-Src kinase

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.