Here, we investigate the association and dissociation mechanisms of a typical intrinsically disordered region (IDR), transcriptional activation subdomain of tumor suppressor protein p53 (TAD-p53), with murine double-minute clone 2 protein (MDM2). Using a combination of cycles of association and dissociation parallel cascade molecular dynamics, multiple standard molecular dynamics (MD), and the Markov state model, we were successful in obtaining the lowest free energy structure of the MDM2/TAD-p53 complex as the structure closest to the crystal structure without prior knowledge of the crystal structure. This method also reproduced the experimentally measured standard binding free energy, and the association and dissociation rate constants, requiring only an accumulated MD simulation cost of 11.675 μs even though that actual dissociation occurs on the order of seconds. We identified few complex intermediates with similar free energies; yet TAD-p53 first binds MDM2 as the second lowest free energy intermediate kinetically with >90% of the flux, adopting a conformation similar to that of one of these few intermediates in its monomeric state. Even though the mechanism of the first step has a conformational-selection-type aspect, the second step shows induced-fit-like features and occurs as concomitant dehydration of the interface, side-chain π-π stacking, and main-chain hydrogen-bond formation to complete binding as an α-helix. In addition, dehydration is a key process for the final relaxation process around the complex interface. These results demonstrate that TAD-p53 kinetically selects its initial binding form and then relaxes to complete the binding.