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.