Considering how the tetramerization domain modulates protein-protein interactions, it is no surprise that this domain is targeted by HIV-Tat protein. Of course, the full biological function of p53-Tat interaction is not fully understood yet; however, it is implied that this may enhance Tat potency in transcribing its target viral genes. This notion is bolstered by the observation that both p53 and Tat proteins are, in fact, nuclear proteins acting as transcription factors . Considering the importance of Tat for the pathogenesis, investigating the interaction between Tat and p53 will certainly contribute to better understanding of the biochemistry of Tat and the deleterious effects of HIV disease within cells. Driven by this motivation, we investigated the complexation of p53 and Tat proteins, using molecular docking and MD simulations. In the MD simulations of Tat-p53 complexes, we observed that our most favorable model aligns with the experimental findings previously reported by Gabizon et al., highlighting the significance of non-ionic interactions observed during the complexation of these two proteins. Of greater significance, it appears that the interactions primarily occur via Tat the basic patch and N-terminal domains. Overall, these finding reported herein may lead to the discovery of anti-HIV agents with previously unprecedented activity.