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Targeted cancer therapies use drugs to block.specific molecules, including many protein kinases, involved in cancer growth.A successful targeted drug exploits the unique structural and dynamic properties of its target.Large-timescale molecular-dynamics simulation, in conjunction with to X-ray crystallography and other experimental techniques, is a powerful tool for studies of structural dynamics of such target proteins.Some examples of our studies on protein kinases will be presented here, with a particular focus on our study of a conserved conformational change called the "DFG flip." The "DFG flip" connects catalytically active and inactive conformations.Many kinase inhibitors "including the cancer drug imatinib" selectively target a specific DFG conformation, but the function and mechanism of the flip remain unclear.Using long molecular dynamics simulations of the Abl kinase, we simulated the DFG flip in atomic-level detail and formulated an energetic model predicting that protonation of the DFG aspartate controls the flip.Consistent with our models predictions, we demonstrated experimentally that the kinetics of imatinib binding to Abl kinase have a pH dependence that disappears when the DFG aspartate is mutated.Our model suggests a possible explanation for the high degree of conservation of the DFG motif: that the flip, modulated by electrostatic changes inherent to the catalytic cycle, allows the kinase to access flexible conformations facilitating nucleotide binding and release.