Mohan R Pradhan, Jia Wei Siau, Srinivasaraghavan Kannan, Minh N Nguyen, Zohra Ouaray, Chee Keong Kwoh, David P Lane, Farid Ghadessy, Chandra S Verma, Simulations of mutant p53 DNA binding domains reveal a novel druggable pocket, Nucleic Acids Research, Volume 47, Issue 4, 28 February 2019, Pages 1637–1652, https://doi.org/10.1093/nar/gky1314
The DNA binding domain (DBD) of the tumor suppressor p53 is the site of several oncogenic mutations. A subset of these mutations lowers the unfolding temperature of the DBD. Unfolding leads to the exposure of a hydrophobic β-strand and nucleates aggregation which results in pathologies through loss of function and dominant negative/gain of function effects. Inspired by the hypothesis that structural changes that are associated with events initiating unfolding in DBD are likely to present opportunities for inhibition, we investigate the dynamics of the wild type (WT) and some aggregating mutants through extensive all atom explicit solvent MD simulations. Simulations reveal differential conformational sampling between the WT and the mutants of a turn region (S6–S7) that is contiguous to a known aggregation-prone region (APR). The conformational properties of the S6–S7 turn appear to be modulated by a network of interacting residues. We speculate that changes that take place in this network as a result of the mutational stress result in the events that destabilize the DBD and initiate unfolding. These perturbations also result in the emergence of a novel pocket that appears to have druggable characteristics. FDA approved drugs are computationally screened against this pocket.
Research Scholarship Award by Bioinformatics Institute-NTU/SCE Joint PhD Program (to M.R.P.); A*STAR’s Biomedical Sciences Institute (BMSI). Funding for open access charge: BII, A*STAR.