Recognizing the Binding Pattern and Dissociation Pathways of the p300 Taz2-p53 TAD2 Complex.

Area of Science:

• Molecular Biology
• Biophysics
• Computational Biology

Background:

• Protein-protein interactions are fundamental to cellular signal transduction.
• Intrinsically disordered proteins (IDPs) add complexity due to disorder-to-order transitions upon binding.
• The p53 transcription factor, with disordered regions, is crucial in cellular signaling pathways.

Purpose of the Study:

• To elucidate the residue-level dissociation mechanisms of the intrinsically disordered N-terminal transactivation domain 2 (TAD2) of p53 and the transcriptional adaptor zinc-binding 2 (Taz2) domain of p300.
• To identify key residues and pathways governing the unbinding process.
• To explore general principles of binding/unbinding for Taz2-containing complexes.

Main Methods:

• Classical molecular dynamics (MD) simulations.
• Steered molecular dynamics (sMD).
• Self-organizing maps (SOMs).
• Time-resolved force distribution analysis (TRFDA).
• Statistical analysis of existing complex structures.

Main Results:

• Two distinct dissociation pathways were identified for the TAD2-Taz2 complex, differing in directionality (N-terminus to C-terminus and vice versa).
• TRFDA pinpointed critical residues in TAD2, including previously unrecognized ones, that influence dissociation.
• Non-native interactions were observed to transiently stabilize the complex during dissociation.
• Analysis suggests Taz2's binding site dictates the complex's behavior, with three primary binding regions.

Conclusions:

• The dissociation of the p53 TAD2-p300 Taz2 complex is complex, involving multiple pathways and critical residue interactions.
• Understanding these mechanisms provides insights into p53's biological functions and signaling roles.
• The findings suggest potential common binding/unbinding principles for complexes involving Taz2, enabling further comparative studies.