Updated project metadata. Structural biology studies indicate that proteins often undergo large conformational changes when binding small molecules, but atomic-level descriptions of binding events involving such changes have been elusive. A prominent example of binding accompanied by a large conformational change is the binding of Abl kinase to the cancer drug imatinib, a detailed understanding of which could potentially inform future drug-discovery efforts targeting kinases. Here, we report unguided molecular dynamics simulations of Abl-imatinib binding that start from an unbound state and ultimately reach a bound state that is highly consistent with known crystal structures of the Abl- imatinib complex. In the course of this process, we observed that imatinib first selectively engages Abl kinase in its autoinhibitory conformation. Consistent with inferences drawn from previous experimental studies, imatinib then induces a large conformational change of the protein, and this motion is captured in atomic detail by the simulations. Moreover, the simulations reveal a surprising local structural instability in the C-terminal lobe of Abl kinase during binding and, to a lesser degree, in the bound state. The unstable region, which is distal to the imatinib-binding site, includes a number of residues that, when mutated, confer resistance to imatinib therapy by an unknown mechanism. Using NMR, thermostability, and hydrogen-deuterium exchange (HDX) measurements, along with energetic estimates, we determined that these mutations likely destabilize the Abl kinase structure. These findings, along with the simulations, suggest that these mutations confer imatinib resistance by a previously undescribed mechanism in which they exacerbate structural instability in the C-terminal lobe to the degree that the imatinib-bound state is energetically unfavorable.