Disordered binding regions (DBRs), which are embedded within intrinsically disordered proteins or regions (IDPs or IDRs), enable IDPs or IDRs to mediate multiple protein-protein interactions. DBR-protein complexes were collected from the Protein Data Bank for which two or more DBRs having different amino acid sequences bind to the same (100% sequence identical) globular protein partner, a type of interaction herein called many-to-one binding. Two distinct binding profiles were identified: independent and overlapping. For the overlapping binding profiles, the distinct DBRs interact by means of almost identical binding sites (herein called “similar”), or the binding sites contain both common and divergent interaction residues (herein called “intersecting”). Further analysis of the sequence and structural differences among these three groups indicate how IDP flexibility allows different segments to adjust to similar, intersecting, and independent binding pockets.
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This content will become publicly available on August 14, 2025
Deciphering the Mystery in p300 Taz2–p53 TAD2 Recognition
Intrinsically disordered proteins (IDPs) engage in
various fundamental biological activities, and their behavior is of
particular importance for a better understanding of the verbose but
well-organized signal transduction in cells. IDPs exhibit uniquely
paradoxical features with low affinity but simultaneously high
specificity in recognizing their binding targets. The transcription
factor p53 plays a crucial role in cancer suppression, carrying out
some of its biological functions using its disordered regions, such as
N-terminal transactivation domain 2 (TAD2). Exploration of the
binding and unbinding processes between proteins is challenging, and
the inherently disordered properties of these regions further
complicate the issue. Computer simulations are a powerful tool to
complement the experiments to fill gaps to explore the binding/unbinding processes between proteins. Here, we investigated the binding mechanism between p300 Taz2 and p53 TAD2 through extensive molecular dynamics (MD) simulations using the physics- based UNited RESidue (UNRES) force field with additional Go̅-like potentials. Distance restraints extracted from the NMR- resolved structures were imposed on intermolecular residue pairs to accelerate binding simulations, in which Taz2 was immobilized in a native-like conformation and disordered TAD2 was fully free. Starting from six structures with TAD2 placed at different positions around Taz2, we observed a metastable intermediate state in which the middle helical segment of TAD2 is anchored in the binding pocket, highlighting the significance of the TAD2 helix in directing protein recognition. Physics-based binding simulations show that successful binding is achieved after a series of stages, including (1) protein collisions to initiate the formation of encounter complexes, (2) partial attachment of TAD2, and finally (3) full attachment of TAD2 to the correct binding pocket of Taz2. Furthermore, machine-learning-based PathDetect-SOM was used to identify two binding pathways, the encounter complexes, and the intermediate states.
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- Award ID(s):
- 2237369
- PAR ID:
- 10533476
- Publisher / Repository:
- ACS Publications
- Date Published:
- Journal Name:
- Journal of Chemical Theory and Computation
- ISSN:
- 1549-9618
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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