p53-Induced DNA bending: the interplay between p53-DNA and p53-p53 interactions.

Specific p53 binding-induced DNA bending and its underlying responsible forces are crucial for the understanding of selective transcription activation. Diverse p53-response elements exist in the genome; however, it is not known what determines the DNA bending and to what extent. In order to gain knowledge of the forces that govern the DNA bending, molecular dynamics simulations were performed on a series of p53 core domain tetramer-DNA complexes in which each p53 core domain was bound to a DNA quarter site specifically. By varying the sequence of the central 4-base pairs of each half-site, different DNA bending extents were observed. The analysis showed that the dimer-dimer interactions in p53 were similar for the complexes; on the other hand, the specific interactions between the p53 and DNA, including the interactions of Arg280, Lys120, and Arg248 with the DNA, varied more significantly. In particular, the Arg280 interactions were better maintained in the complex with the CATG-containing DNA sequence and were mostly lost in the complex with the CTAG-containing DNA sequence. Structural analysis shows that the base pairings for the CATG sequence were stable throughout the simulation trajectory, whereas those for the CTAG sequence were partially dissociated in part of the trajectory, which affected the stability of the nearby Arg280-Gua base interactions. Thus, DNA bending depends on the balance between the p53 dimer-dimer interactions and p53-DNA interactions, which is in turn related to the DNA sequence and DNA flexibility.