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Title: Recognizing the Binding Pattern and Dissociation Pathways of the p300 Taz2-p53 TAD2 Complex
Authors: Li, T
Motta, S
Stevens, AO
Song, S
Hendrix, E
Pandini, A
He, Y
Keywords: dissociation pathway;p53 TAD2;p300 Taz2;steered molecular dynamics (SMD);self-organizing maps (SOMs);time-resolved force distribution analysis (TRFDA);machine learning
Issue Date: 1-Aug-2022
Publisher: American Chemical Society (ACS)
Citation: Li, T., Motta, S., Stevens, A.O., Song, S., Hendrix, E., Pandini, A. and He, Y. (2022) 'Recognizing the Binding Pattern and Dissociation Pathways of the p300 Taz2-p53 TAD2 Complex', JACS Au, 0 (in press), pp. 1-11. doi: 10.1021/jacsau.2c00358.
Abstract: Copyright © 2022 The Authors. The dynamic association and dissociation between proteins are the basis of cellular signal transduction. This process becomes much more complicated if one or both interaction partners are intrinsically disordered because intrinsically disordered proteins can undergo disorder-to-order transitions upon binding to their partners. p53, a transcription factor with disordered regions, plays significant roles in many cellular signaling pathways. It is critical to understand the binding/unbinding mechanism involving these disordered regions of p53 at the residue level to reveal how p53 performs its biological functions. Here, we studied the dissociation process of the intrinsically disordered N-terminal transactivation domain 2 (TAD2) of p53 and the transcriptional adaptor zinc-binding 2 (Taz2) domain of transcriptional coactivator p300 using a combination of classical molecular dynamics, steered molecular dynamics, self-organizing maps, and time-resolved force distribution analysis (TRFDA). We observed two different dissociation pathways with different probabilities. One dissociation pathway starts from the TAD2 N-terminus and propagates to the α-helix and finally the C-terminus. The other dissociation pathway is in the opposite order. Subsequent TRFDA results reveal that key residues in TAD2 play critical roles. Besides the residues in agreement with previous experimental results, we also highlighted some other residues that play important roles in the disassociation process. In the dissociation process, non-native interactions were formed to partially compensate for the energy loss due to the breaking of surrounding native interactions. Moreover, our statistical analysis results of other experimentally determined complex structures involving either Taz2 or TAD2 suggest that the binding of the Taz2-TAD2 complex is mainly governed by the binding site of Taz2, which includes three main binding regions. Therefore, the complexes involving Taz2 may follow similar binding/unbinding behaviors, which could be studied together to generate common principles.
Description: Supporting Information: The Supporting Information is available free of charge at MD and SMD simulation parameters, data analysis details of all 50 replicas of SMD simulations, all pre-processed simulation trajectories, and data analysis scripts available at (PDF).
ISSN: 2691-3704
Other Identifiers: ORCID iDs: Stefano Motta -; Yi He -; Alessandro Pandini -
Appears in Collections:Dept of Computer Science Research Papers

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