P53 Induced Dna Bending

Abstract

Specific p53 binding-induced DNA bending and its underlying driving forces are crucial for the understanding of selective transcription activation. Diverse p53-response elements exist in the genome; however, it is not known how p53 specific binding induced DNA bending and DNA sequence influences the bending extent. Molecular dynamics simulations were performed on a series of p53 core domain tetramer-DNA complexes with various DNA sequences with difference in the central 4-base pairs of each half site to compare the DNA bending extent and pinpoint the underlying driving forces. The results show that the specific interactions between p53 dimer and DNA and between p53 dimers triggered intra- and inter-half sites DNA bending . The central 4 base pairs were important to the bending extent due to its variant flexibility. Specifically, the more flexible CATG containing DNA was able to maintain the specific interactions with the p53 including those from residues Arg280, Lys120 and Arg248 while those with CTAG that had low flexibility were less capable of maintaining the specific interactions . As a result, base pairings for the CATG sequence were stable throughout the simulation trajectory while those for the CTAG sequence was partially dissociated for part of the trajectory, which affected the stability of nearby Arg280-Gua base interactions. Thus, DNA bending was induced by the specific p53-DNA and p53 dimer-dimer interactions and the bending extent was dependent on DNA sequence that was correlated with its flexibility and ability to maintain specific interactions in bent conformations.This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number NO1-CO-12400.1. Pan, Y. & Nussinov, R. (2007) J Biol Chem 282, 691-699.2. Pan, Y. & Nussinov, R. (2008) The journal of physical chemistry 112, 6716-6724.