<p>We investigate
association and dissociation mechanisms of a typical intrinsically disordered
region (IDR), transcriptional activation subdomain of tumor repressor protein
p53 (TAD-p53) with murine double-minute clone 2 protein (MDM2). Using the
combination of cycles of association and dissociation parallel cascade
molecular dynamics, multiple standard MD, and Markov state model, we are
successful in obtaining the lowest free energy structure of MDM2/TAD-p53
complex as the structure very close to that in crystal without prior knowledge.
This method also reproduces the experimentally measured standard binding free
energy, and association and dissociation rate constants solely with the accumulated
MD simulation cost of 11.675 μs, in spite of the fact that actual dissociation
occurs in the order of a second. Although there exist a few complex
intermediates with similar free energies, TAD-p53 first binds MDM2 as the second
lowest free energy intermediate dominantly (> 90% in flux), taking a form
similar to one of the intermediate structures in its monomeric state. The
mechanism of this step has a feature of conformational selection. In the second
step, dehydration of the interface, formation of π-π stackings of the
side-chains, and main-chain relaxation/hydrogen bond formation to complete
α-helix take place, showing features of induced fit. In addition, dehydration (dewetting)
is a key process for the final relaxation around the complex interface. These
results demonstrate a more fine-grained view of the IDR association/dissociation
beyond classical views of protein conformational change upon binding.</p>
MloK1 Ligand Binding Simulations: Induced Fit Versus Conformational Selection
