Structural Basis for p53 Binding-induced DNA Bending

Abstract

Specific p53 binding-induced DNA bending has important biological implications such as transcription activation. However, the detailed structures of the bent DNA and the p53-DNA complex are still unavailable, hampering our understanding of the mechanism for p53-induced DNA bending and its consequent biological significance. To gain insight into the p53 binding-induced DNA bending, we performed molecular dynamics simulations on DNA segments with the consensus sequence for p53-specific binding, half site DNA-p53 complexes, and full site DNA-p53 complexes. We show that each DNA-bound p53 core domain caused a local DNA conformational change within the quarter site; upon the binding of the p53 dimer, there was an apparent DNA bending at the center of the half site; when bound with two p53 dimers, the full site DNAs with two different sequences bent 20 and 35°, respectively. These results are in agreement with experimental observations. Our simulations demonstrate that the two p53 dimers favored a staggered conformation in which they make favorable interactions at the interface. This dimer-dimer interface organization necessitated conformational changes in the DNA, leading to the bending at the center of the full site, which in turn is dependent on the DNA sequence. Overall, our results provide the detailed atomic model for the DNA-p53 tetramer complex and delineate the roles of DNA-p53, p53 dimer-dimer interactions, and DNA sequence in specific p53 binding-induced DNA conformational changes.

p53-Induced DNA Bending: The Interplay between p53−DNA and p53−p53 Interactions

“…The most favorable interaction energy was from the 5 th position base pair, consistent with previous results 28 , while the interaction of the second most conserved base pair at the 2 nd position was much weaker. Therefore, 4 th and 5 th position base pairs dominate the DNA quarter site interactions with p53.…”

“…These data suggest that regardless of the DNA sequence differences, the p53 dimers tend to reach similar extent of favorable interactions. Such typical p53 dimer-dimer interface has been proposed previously 28 and the organizations of the complexes at the dimer-dimer interface were similar to each other as well (Figure 3). Comparison of the interfaces for the four complexes further shows that important interactions between the p53 monomers at the dimer-dimer interface and the residues involved were similar among the four complexes.…”

“…This result is expected since the initial specific interactions were optimized for the p53 core domain monomer-DNA contact; that is, it was not in the tetramer complex environment. The interactions for each p53 core domain-DNA relaxed to some extent in the p53 tetramer-DNA complex environment, as observed previously 28 . After 30 ns, each of the systems became equilibrated and the interaction energies were stabilized.…”

“…Nature seems to have used the variations of the DNA sequence to modulate the response to the environmental stress. This was illustrated by previous experimental and simulation results which showed that CATG and CAAG containing p53 response elements can bind p53 efficiently and bend significantly 45,19,28 . Many factors may contribute to the DNA bending; other parts of the protein or base pairs flanking the p53-response elements may also be involved in triggering additional conformational change and in stabilizing the bent DNA conformation.…”

“…In addition, biophysical studies show that the p53 core domain alone can bend the DNA by only 30-35 degrees while the full length p53 can induce bending of 50-70 degrees, depending on the techniques used in the estimation 14 . Molecular dynamics simulation also demonstrates a DNA bending of 35 degrees by p53 core domain alone 28 . This information provided the structural basis for computational investigation of the underlying forces that trigger the DNA bending.…”