P53 is a major tumor suppressor that is mutated and inactivated in ˜ 50% of all human cancers. Thus, reactivation of mutant p53 using small molecules has been a long sought-after anticancer therapeutic strategy. Full structural characterization of the full-length oligomeric p53 is challenging because of its complex architecture and multiple highly flexible regions. To explore p53 structural dynamics, here we developed a series of atomistic integrative models with available crystal structures of the full-length p53 (fl-p53) tetramer bound to three different DNA sequences: a p21 response element, a puma response element and a nonspecific DNA sequence. Explicitly solvated, all-atom molecular dynamics simulations of the three complexes (totaling nearly 1 μs of aggregate simulation time) yield final structures consistent with electron microscopy maps and, for the first time, show the direct interactions of the p53 C-terminal with DNA. Through a collective principal component analysis, we identify sequence-dependent differential quaternary binding modes of the p53 tetramer interfacing with DNA. Additionally, L1 loop dynamics of fl-p53 in the presence of DNA is revealed, and druggable pockets of p53 are identified via solvent mapping to aid future drug discovery studies.