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p53docking-v17AK47chemRxiv.pdf (3.77 MB)
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Association/dissociation Mechanisms of Intrinsically Disordered Region of Protein Beyond Conformational Selection and Induced Fit

preprint
submitted on 18.09.2019 and posted on 24.09.2019 by Duy Phuoc Tran, Akio Kitao

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.

Funding

JP19K23721

JP25104002

JP15H04357

JP17KT0026

JP19H03191

"Priority Issue on Post-K Computer” (Building Innovative Drug Discovery Infrastructure through Functional Control of Biomolecular Systems)

History

Email Address of Submitting Author

akitao@bio.titech.ac.jp

Institution

Tokyo Institute of Technology

Country

Japan

ORCID For Submitting Author

0000-0002-5221-0806

Declaration of Conflict of Interest

no conflict of interest

Version Notes

2ndversion

Exports