p53 is a transcription factor with intrinsically disordered regions that plays an essential role in many cellular processes. As a tumor suppressor, the dysfunction of p53 causes various cancers. p53 can be activated by binding with cofactors in the cell due to stresses or DNA damages. The N-terminal transactivation domain (TAD) of p53 can regulate cell apoptosis by interacting with its binding partners, such as the transcriptional adaptor zinc-binding 2 (Taz2) domain of p300, and cofactors, i.e. cyclic-AMP response element-binding protein (CREB)-binding protein (CBP). The experimentally solved structure of p300 Taz2 and p53 TAD2 has provided insights into the interactions that potentially lead to the structural changes of p53 TAD2 and stabilize the complex. To explore the structural changes as well as the residues that lead to such changes from an isolated state to a bound state in p53 TAD2, we used all-atom molecular dynamics (MD) to simulate two different systems: (1) the p300 Taz2–p53 TAD2 complex and (2) isolated p53 TAD2 (residues 35–59). Although still largely unstructured, residues across the p53 TAD2 contribute significantly to stabilizing the binding between p300 Taz2 and p53 TAD2. Our results suggest that the binding affinity of the p300 Taz2–p53 TAD2 complex originates from hydrophobic and electrostatic interactions. The results are in agreement with previous reports and experimental data. By comparing the two simulated systems, our results not only demonstrate the structural changes of p53 TAD2 after binding with Taz2 but also identify the key residues leading to such changes. We also identify the critical residues that can provide insight into the interaction network between p300 Taz2 and p53 TAD2.